Multidisciplinary Management

of Rectal Cancer
Vincenzo Valentini
Hans-Joachim Schmoll
Cornelis J.H. van de Velde
Editors

Multidisciplinary
Management of Rectal
Cancer
Questions and Answers
Editors
Vincenzo Valentini Cornelis J.H. van de Velde
Department of Radiation Therapy Leiden University
Università Cattolica S.Cuore Medical Center
Rome Leiden
Italy Netherlands

Hans-Joachim Schmoll
Klinik und Poliklinik Innere Medizin IV
Abt. Hämatologie und Onkologie
Universitätsklinikum Halle-Wittenberg
Halle, Sachsen-Anhalt
Germany

ISBN 978-3-642-25004-0 ISBN 978-3-642-25005-7 (eBook)

DOI 10.1007/978-3-642-25005-7
Springer Heidelberg New York Dordrecht London

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Foreword

During the past few decades there have been many advances in the
management of rectal cancer. Building on a more comprehensive
understanding of anatomy and patterns of local recurrence, new surgical
techniques such as total mesorectal resection and sphincter sparing coloanal
anastomosis have become standards. The move toward preoperative adjuvant
therapy has been facilitated by more effective chemoradiation programs.
Advances in radiation planning, delivery, and fractionation techniques
coupled with new cytotoxic and targeted chemotherapeutic agents hold the
promise of reduced toxicity and increased tumor response and control rates.
New diagnostic modalities such as high resolution MRI have helped identify
which therapeutic approaches and modalities are best suited to an individual
tumor, allowing a more selective approach. Lastly, a renewed focus on expert
pathologic analysis coupled with the evolving field of prognostic and
predictive molecular markers has facilitated the development of surrogate
endpoints of response.
Although each discipline has made their individual diagnostic and
therapeutic contributions, the cornerstone of success has been the unified
movement toward multidisciplinary management. It is the collaborative
efforts of surgeons, radiation oncologists, medical oncologists, radiologists,
and pathologists which have truly had the most significant impact on
outcome.
This exciting new book is a unique contribution to the field of rectal cancer.
In contrast to the traditional didactic approach, each chapter directly engages
the reader with timely questions and answers. Building on the value of
multidisciplinary management, Professors Valentini, Schmoll, and Van de
Velde have assembled an internationally known group of contributors from a
number of European centers of excellence. Broad areas of expertise include
risk factors, imaging, radiotherapy, chemotherapy, surgery, and pathology.
The advances of the past three decades as well as new emerging controversies
are discussed.
The editors have succeeded in providing us with the foundation, relevant
data, and guidance to multidisciplinary management of rectal cancer. This
team approach sets the standard for modern cancer management.

Chicago, IL, USA Bruce D. Minsky, M.D.

v
Preface

In an era where all patients are entitled to access healthcare systems that
enable the highest quality of treatment delivered within a safe healthcare
environment, and access to appropriate advice, support and long term follow-
up, the multidisciplinary team is of central importance and a critical require-
ment in the development of modern oncology.
Joint efforts of different specialists involved in the diagnosis, staging,
treatment and evaluation of outcomes in rectal cancer throughout Europe to
promote mutual understanding and collaboration by managing multidisci-
plinary consensus conferences (EURECA-CC1-2) and the publication of
their recommendation were undertaken.
This was extended to a multidisciplinary teaching course (5 editions across
Europe and 1 in China) and culminated to the endorsement of these activities
by European cancer societies like ESTRO, ESSO and ESMO and hence cre-
ating the background to the holistic approach in promoting the multidiscipli-
narity of this book.
The aim of this book is to report the most common questions that arose in
the practice of a multidisciplinary team, devoted to address the health request
of patients with rectal cancer. A recognised group of clinicians, mostly
involved in the management of the more significant trials published in Europe
in the last decade, were requested to provide simple and focused answers to
support the best choices in a multidisciplinary setting. We are very grateful to
their enthusiastic and fully supportive participation to this project.
With this book we hope to contribute to improve the overall care of the
patient, supporting the multidisciplinary teams in their unique responsibility
for patient’s on-going care and wellbeing.

Vincenzo Valentini
Hans-Joachim Schmoll
Cornelius J.H. van de Velde

vii
Contents

Part I Introduction

1 What Do We Consider Cancer of the Rectum?. . . . . . . . . . . . . 3

Marilyne M. Lange and Cornelis J.H. van de Velde
2 What Is the Ongoing Recommendation in the
Management of Rectal Cancer? . . . . . . . . . . . . . . . . . . . . . . . . . 9
Vincenzo Valentini, Hans-Joachim Schmoll,
and Cornelis J.H. van de Velde

Part II Q&As on Risk Factor Identification

3 What Prognostic Clinical Factors Must Be Considered

Before Treatment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Claus Rödel
4 What Are the Relevant Imaging Factors to Optimize
Treatment Decisions?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Manish Chand and Gina Brown
5 What Biochemical and Molecular Biological Factors
Have Greater Relevance to Treatment Decisions? . . . . . . . . . . 41
Guido Lammering and Jeroen Buijsen
6 Do Different Populations of Rectal Cancer Exist? . . . . . . . . . . 49
Vincenzo Valentini, Francesco Cellini, Maria Cristina Barba,
and Ruud van Stiphout

Part III Q&As on Imaging

7 How Can We Identify Tumour Penetration?. . . . . . . . . . . . . . . 59

Manish Chand and Gina Brown
8 How Can We Identify Mesorectal Fascia Involvement?. . . . . . 67
Regina G.H. Beets-Tan
9 How Can We Identify Nodal Involvement? . . . . . . . . . . . . . . . . 73
Regina G.H. Beets-Tan
10 How Can We Identify Pathologic Complete Responders
After Radiochemotherapy?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Brunella Barbaro and Lucia Leccisotti

ix
x Contents

11 How Can We Identify Local Relapse? . . . . . . . . . . . . . . . . . . . . 95

Doenja M.J. Lambregts and Regina G.H. Beets-Tan

Part IV Q&As on Radiotherapy

12 When Should Preoperative Short-Course Radiotherapy

or Long-Course Chemoradiotherapy Be Performed? . . . . . . . 105
David Sebag-Montefiore and Robert Glynne-Jones
13 Should We Tailor the Delineation of Pelvic Structures
According to Tumor Presentation? . . . . . . . . . . . . . . . . . . . . . . 117
Maria Antonietta Gambacorta and Vincenzo Valentini
14 What Is the Role of IMRT and IGRT in Rectal Cancer?. . . . . 129
Jasper Nijkamp, Karin Haustermans, and Corrie A.M. Marijnen
15 What Are the Dose-Volume Constraints to Reduce
Late Toxicity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Krzysztof Bujko
16 What Is the Contribution of Intraoperative Radiotherapy
(IORT) in Tailoring Local Therapy in Primary or Recurrent
Rectal Cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Felipe A. Calvo
17 What Is the Contribution of Brachytherapy in Tailoring
Local Therapy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Jean-Pierre Gérard, Te Vuong, Jean-Michel Hannoun-Lévi,
and Arthur Sun Myint

Part V Q&As on Chemotherapy

18 Should Oxaliplatin Be Added to Preoperative

Chemoradiation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Carlo Aschele
19 Should Biologic Targeted Agents Be Combined
with Preoperative Chemoradiation in Rectal Cancer? . . . . . . 181
Pieter-Jan Cuyle and Eric Van Cutsem
20 Should Upfront Chemotherapy Precede Preoperative
Chemoradiation and Surgery? . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Carlos Fernandez-Martos and Xabier Garcia de Albeniz
21 How to Achieve Long-Term Survival in Patients
with Metastatic Rectal Cancer? . . . . . . . . . . . . . . . . . . . . . . . . . 205
Alexander Stein and Hans-Joachim Schmoll
22 Will Adjuvant Chemotherapy Improve Outcome
After Preoperative Chemoradiation?. . . . . . . . . . . . . . . . . . . . . 217
Bengt Glimelius and Peter Nygren
Contents xi

Part VI Q&As on Surgery

23 How to Evaluate the Quality of Surgery? Suggestions

for Critical Reading of Surgical and Pathological Reports . . . 229
Lars Påhlman
24 How Is Nerve-Sparing Surgery Well Performed?. . . . . . . . . . . 233
Zoran Krivokapic and Ivan Dimitrijevic
25 Is Laparoscopic Rectal Surgery the Gold Standard? . . . . . . . . 249
David Jayne and Laeeq Khan
26 Is a Diverting Stoma Always Necessary for a Low
Anterior Resection of a Rectal Cancer?. . . . . . . . . . . . . . . . . . . 257
Geerard L. Beets
27 Will Extralevator Abdominoperineal Excision Become
the New Gold Standard? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Ingrid Martijnse, Nicholas West, Phil Quirke, Richard Heald,
Cornelius J.H. van de Velde, and Harm Rutten
28 Which Patients Do Benefit from Extended Resections
in Case of Locally Advanced Rectal Cancer? . . . . . . . . . . . . . . 275
Ralph L. Dudink, Miranda Kusters, and Harm Rutten
29 Can Standard Surgical Procedure Reliably Be Avoided
in Major Responders After Radio(chemo)therapy?. . . . . . . . . 291
Claudio Coco and Gianluca Rizzo

Part VII Q&As on Pathology

30 What Is the Correct Procedure for Handling

the Surgical Specimen? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Nigel Scott
31 What Is the Prognostic Value of (y)pT and (y)pN?. . . . . . . . . . 319
Nadine Ectors
32 What Is the Prognostic Value of CRM Involvement?. . . . . . . . 327
Iris D. Nagtegaal
33 What Is the Prognostic Value of TRG? . . . . . . . . . . . . . . . . . . . 333
Fabio M. Vecchio

Part VIII Q&As on Multidisciplinary Team Management

34 What Are the Recommendations to Ensure a Successful

Multidisciplinary Team in Rectal Cancer? . . . . . . . . . . . . . . . . 341
Sujay Shah, Pawan Mathur, and Robert Glynne-Jones
xii Contents

35 What Is the Appropriate Timetable for Tailored

Follow-up? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Lars Påhlman
36 How Should Data Be Shared and Rapid
Learning Health Care Promoted? . . . . . . . . . . . . . . . . . . . . . . . 355
Ruud van Stiphout, Erik Roelofs, Andre Dekker,
and Philippe Lambin
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
 Part I
Introduction
 What Do We Consider Cancer
of the Rectum? 1
Marilyne M. Lange and Cornelis J.H. van de Velde

Contents 1.1 Epidemiology

1.1 Epidemiology .............................................. 3
Rectal cancer constitutes one third of all col-
1.2 The Rectum ................................................ 4
orectal cancers, representing the cancer with the
1.2.1 Anatomy....................................................... 4
1.2.2 Function ....................................................... 5 second highest incidence and the second cause
of cancer death in the western society [1, 2]. An
1.3 Pathophysiology ......................................... 6
estimated 100,000 new cases of rectal cancer
1.4 Presentation ................................................ 7 are diagnosed each year in Europe. The inci-
1.5 Diagnosis ..................................................... 7 dence is increasing, mainly due to earlier detec-
References ................................................................. 7 tion and increasing age of the population, as the
highest incidence of rectal cancer is found in the
sixth and seventh decades. High incidence rates
are found especially in western world popula-
tions, i.e., Western Europe, North America and
Australia. This can probably be explained by a
combination of factors, including dietary pat-
terns with high amounts of red meat, obesity
and smoking [3]. The United States is the only
country with significantly decreasing incidence
rates in both males and females in the most
recent time period, which largely reflects detec-
tion and removal of precancerous lesions
through colorectal cancer screening [4]. Next to
M.M. Lange
Department of Surgery,
dietary and lifestyle factors, risk factors for rec-
Zaans Medical Center, tal cancer include inflammatory bowel disease
Koningin Julianaplein 58, and primary sclerosing cholangitis. Also, genetic
1500EE Zaandam, The Netherlands predisposition plays a role; however, rectal can-
e-mail: lange_marilyne@hotmail.com
cer most commonly occurs sporadically and is
C.J.H. van de Velde (*) inherited in only 5% of the cases. Five-year sur-
Leiden University Medical Center,
Albinusdreef 2,2300RC Leiden,
vival rate of rectal cancer is about 60% and
The Netherlands depends to a large extent on disease stage at
e-mail: c.j.h.van_de_velde@lumc.nl diagnosis [5].

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 3

DOI 10.1007/978-3-642-25005-7_1, © Springer-Verlag Berlin Heidelberg 2012
4 M.M. Lange and C.J.H. van de Velde
Fig. 1.1 Sagittal and transversal illustration of the male
pelvis. Sympathetic and parasympathetic nerves (green),
mesorectum (yellow), mesorectal fascia (blue), middle
1.2 The Rectum
The anatomic relations and physiology of the rec-
tum makes rectal cancer treatment a potential cause
of severe, long-term morbidity [6, 7]. In order to
comprehend rectal cancer, the principles of treat-
ment and its implications, it is necessary to under-
stand the anatomy and the function of the rectum.
1.2.1 Anatomy
Anatomically, the rectum extends from the anal
verge for about 12–15 cm, where it curves anteri-
orly and merges into the sigmoid. As a rule, one
third of the rectum is located intraperitoneally and
two thirds extraperitoneally. The definitions of
rectum and low rectal cancer are highly variable.
Some publications define the rectum as 15 cm
from the anal verge as measured by rigid endos-
copy, defining low rectal cancer within 5 cm from
the anus [8, 9]. Other definitions are related to
anatomy rather than endoscopic measurement.
These define the rectum as located below the bor-
der of the second sacral vertebra and low rectal
rectal artery (red), seminal vesicles (purple) (Illustrated
by J.F.M. Lange)
cancer as a tumour of which the major part is
located at or below the peritoneal reflection [10].
In women, the peritoneal reflection (4–7 cm from
the anal verge) can descend to 4 cm from the anal
verge. The rectum forms an acute 90–115° ano-
rectal angle with the dorsally directed anal canal.
This angle, widening during defaecation (more
than 130°), is caused by the puborectal sling of
the levator ani muscles, inserting just cranially to
the level of the mucocutaneous line, halfway the
anal canal [11]. Circumferentially, the rectum is
surrounded by fatty and connective tissue, which
is known as the mesorectum (Fig. 1.1). Starting at
the sacral promontory, the mesorectum being most
pronounced at the dorsal site of the rectum dimin-
ishes below the rectosacral fascia around the leva-
tor ani muscles at the end of the distal third of the
rectum. The mesorectum is enveloped by the vis-
ceral rectal (pelvic, proper rectal) fascia, separat-
ing it from the parietal endopelvic fascia. In
between is a dorsal layer of thin fat, containing
autonomic nerves to the pelvic organs, and the
more ventral retrorectal space, filled with loose
areolar tissue (‘holy plane of Heald’). The midline
hindgut (rectum) and the mesorectum, containing
1 What Do We Consider Cancer of the Rectum?
Fig. 1.2 Three-dimensional reconstruction of the male pelvis. The levator ani nerve, running just cranially to the pelvic
floor (green), is closely related to the mesorectum (light blue)
its vessels, fat and most of its lymph glands, are
embryologically derived together as a single unit.
The anatomy and embryological origin is respected
by the current golden standard for rectal cancer
resection (total mesorectal excision, TME) as it
involves en bloc resection of the rectum and the
mesorectal tissue to the level of the levator muscles
within the embryologically determined, avascular
plane outside the mesorectum between the parietal
and visceral rectal fascia [12]. This allows for radi-
cal resection of the tumour and preservation of the
pelvic autonomic nerves which are essential for
urogenital and anorectal functions [6, 7].
The mesorectum is suspended to the pelvic
wall by: (1) the ‘lateral ligaments’ which are
strands of condensed tissue, located ventrolater-
ally to the rectum, at the level of the seminal ves-
icles in men, containing the middle rectal blood
vessels and lymphatics [13]—these adhere close
to the sympathetic and parasympathetic inferior
hypogastric plexuses—(2) the rectosacral fascia,
just cranially to the pelvic floor, at the anorectal
junction at level S4; (3) levator ani complex, cov-
ered by fat and the parietal rectal fascia.
The arterial supply of the rectum is supported
by the superior rectal (haemorrhoidal) artery, rep-
resenting the inferior mesenteric artery after
spring-off of the left colic and sigmoid arteries.
The inferior haemorrhoidal arteries from the
internal iliac and the middle rectal artery also
contribute blood to the rectum. Venous return fol-
lows the arteries. The lymphatic drainage mirrors
its vasculature. The first nodal level is located in
the mesorectum, draining mostly to the inferior
5
mesenteric nodes and then the para-aortic nodes.
The lower lymph drainage is variable both proxi-
mally and laterally along the middle rectal ves-
sels towards nodes at the internal iliac vessels.
The nerve supply to the pelvic organs, i.e., the
rectum, vagina, uterus, vestibular bulbs, clitoris,
bladder, urethra, penis, prostate and pelvic floor,
are closely related to the rectum. From the supe-
rior hypogastric plexus (at level L4-S1, at the level
of the promontory) within the aorta bifurcation,
the two sympathetic hypogastric nerves descend
dorsally to the mesorectum, parallel to the ureters
towards the inferior hypogastric plexuses (plexi
pelvini), where they join the parasympathetic pel-
vic splanchnic nerves (nervi erigentes) coming
from S2–4 (Fig. 1.1). The levator ani nerve, which
is responsible for the innervation of the levator ani
muscle, also arises from S3–4 and runs over the
surface of the pelvic floor muscles, only covered
by the parietal fascia [14] (Fig. 1.2).
1.2.2 Function
The anorectum is responsible for maintaining
faecal continence and, when socially appropriate,
defaecation. This is possible as the rectum has a
capacity to store an amount of faeces, acting as a
reservoir [15]. Furthermore, the anal canal con-
tains a rich network of nerve endings sensitive to
pain, temperature and touch, which is used to dif-
ferentiate solid or liquid stool from flatus, and
allows for selective passage of flatus. The anal
sphincters keep the anal canal closed in a resting
6 M.M. Lange and C.J.H. van de Velde
state. In addition to the resting anal pressures, the
mesenteric plexus of the internal anal sphincter
enables the recto-inhibitory reflex, which implies
relaxation of the internal anal sphincter in
response to increased pressure in the rectum. And
finally, the pelvic floor (levator ani muscles) is
responsible for the anorectal angle, flattening
during defaecation [16].
1.3 Pathophysiology
The majority of rectal cancers develop from
benign preneoplastic lesions: the adenomatous
polyps or adenomas. Polyps are histologically
classified as tubular (5% malignant), villous
(40% malignant) or mixed (20% malignant),
depending on glandular structure. Degree of
dysplasia (atypical cells) is graded: chance of
malignancy varies from about 5% (low grade) to
about 35% (high grade). Risk of malignancy is
also collated with size: 90% of adenomas are less
than 1 cm (1% risk of malignancy), 10% are big-
ger than 1 cm (about 10% malignant). Progression
from a benign adenoma to a malignant carcinoma
passes through a series of well-defined histologi-
cal stages, which is referred to as the adenoma-
carcinoma sequence. Two major mechanisms of
genomic instability lead to colorectal carcinoma
development and progression: chromosomal
instability (CIN) and microsatellite instability
(MSI). The former mechanism is associated with
a series of genetic changes that involve the acti-
vation of oncogenes (uncontrolled cell growth;
k-ras gene) and inactivation of tumour suppres-
sor genes (uninhibited growth; APC gene, p53
gene, DCC/SMAD4 gene) and contributes pre-
dominantly to carcinogenesis in the rectum [17,
18]. Familial adenomatous polyposis (FAP) and
its attenuated variant (AFAP) represents the
(hereditary) syndrome dealing with APC muta-
tion. The MSI-pathway, in which mutations in
DNA mismatch repair (MMR) genes result in a
failure to repair errors that occur during DNA
replications in repetitive sequences (microsatel-
lites), results in an accumulation of frameshift
mutations. This failure leads to an MSI type of
tumour, which is more frequently poorly differ-
entiated and with an unusual histologic type
(mucinous and marked intra- and peritumoural
lymphocytic infiltration). It is also the hallmark
of hereditary nonpolyposis colorectal cancer,
HNPCC (Lynch syndrome). It has been observed
that MSI is most common in (right-sided) colon
cancer and rare in rectal carcinoma [19].
Nevertheless, compared with colon cancer, the
number of mutations detected is significantly
higher in rectal cancer [20]. Furthermore,
cyclooxygenase-2 (COX2) is overexpressed in
90% of rectal tumours but in only 20% of colonic
tumours [21]. These genetic characteristics
confirm that rectal cancer is a different entity in
colorectal cancer.
In the progression of rectal cancer microenvi-
ronmental interactions are important. Loss of
cell adhesion leads to reorganisation of epithe-
lial cells to make invasion and metastasis possi-
ble [22]. Angiogenesis is vital for tumour growth
and is mediated by multiple molecules, such as
vascular endothelial growth factor (VEGF),
which are released by tumour cells [23]. For a
full understanding of the process of normal cells
becoming malignant tumours, all the genetic
pathways and mechanisms need to be
identified.
Direct spread of rectal cancer occurs intramu-
rally and radially, resulting in invasion of adjacent
tissues or organs. Indirect spread through lymph
and blood vessels was first described by Harrison
Cripps in 1890 [24]. Consequently, his pupil,
William Ernest Miles stretched the importance of
resecting the rectal tumour en bloc with its
mesorectum, lymph nodes and blood supply,
introducing the first curative resection for rectal
cancer [25]. Lymphatic spread occurs in stepwise
progression. Skip metastases appear in less than
5%. Haematogenous spread is the most important
pattern of spread, most commonly involving the
liver. However, rectal cancer may also metastasise
initially to the lungs because the inferior rectal
vein drains into the inferior vena cava rather than
into the portal venous system. Other infrequent
sites are the adrenal glands, kidneys, bones and
brain. In addition, spread within the peritoneal
cavity happens, initially close to the tumour with
small nodules arising from cells shed from the pri-
1 What Do We Consider Cancer of the Rectum?
Fig. 1.3 Ulcerative rectal carcinoma. Resection specimen
after abdominoperineal resection for ulcerative rectal car-
cinoma located at the anal verge
mary tumour. Later, plaques become more wide-
spread, omentum is involved and ascites is
produced. Peritoneal involvement is a poor prog-
nostic factor (median survival less than 6 months)
[26, 27].
1.4 Presentation
Next to polypoidal disease, a rectal carcinoma
can appear as an atypical ulcer, with rolled edges
and a necrotic base (Fig. 1.3). This tends to
infiltrate more deeply and is more likely to perfo-
rate. Also stenosing or annular lesions have been
described. Lastly, rectal cancer can be a diffuse
infiltrative disease, appearing as an extensive
lesion infiltrating the bowel wall over many cen-
timetres. The macroscopic appearance influences
the symptomatology of rectal cancer. Patients
present either electively or as an emergency with
obstruction or perforation. Obstruction leads to
abdominal distension, pain, nausea and vomit-
ing. Elective symptoms include altered bowel
habit, rectal bleeding, mucus discharge, abdomi-
nal pain, fatigue, weight loss and palpable
abdominal mass. Less common symptoms
include tenesmus, in case of pelvic floor involve-
ment, and neuropathic pain syndrome due to sci-
atic or obturator nerve involvement in locally
advanced disease. Approximately 20% of patients
have distant metastatic disease at the time of pre-
sentation [27].
7
1.5 Diagnosis
Rectal cancer can be suspected from the symp-
toms and signs described above or may be asymp-
tomatic and discovered by routine screening
(faecal occult blood testing, colonoscopy).
Histological confirmation is sought through
colonoscopy and biopsy. In patients in whom
colonoscopy is impossible, computed tomogra-
phy (CT) colonoscopy can provide radiographic
diagnosis. The entire large bowel should be
examined for the presence of synchronous
lesions. Magnetic resonance imaging (MRI) and
endorectal ultrasound (EUS; differentiate T1
from T2) is used for staging and evaluating
locoregional disease and predicting if negative
surgical margins can be achieved, which is the
case in approximately 75% [28]. Colonic tomog-
raphy and/or abdominal ultrasound are used to
identify extrapelvic metastases. Furthermore, a
thorax x-ray is performed to identify lung metas-
tasis. Once the diagnosis is established and the
local and distant extent of disease spread is deter-
mined, therapy and prognosis are discussed in a
multidisciplinary setting. Modern multimodal
treatment of rectal cancer attempts to integrate
surgery, radiotherapy and chemotherapy and uses
the expertise and knowledge of pathology and
radiology to optimise oncologic and functional
results.
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 What Is the Ongoing
Recommendation in the 2
Management of Rectal Cancer?
Vincenzo Valentini, Hans-Joachim Schmoll,
and Cornelis J.H. van de Velde

Contents During the past 20 years, we have seen major

References ................................................................. 17 changes in the way patients with rectal cancer are
investigated and treated. The key components are
the improvements in preoperative staging, in sur-
gical technique and histopathological assessment
of the resected specimen, and in combining mul-
timodality treatments to ameliorate the long-term
outcome.
The concept of “mesorectal excision,” where
meticulous dissection of the anatomical plane
surrounding the mesorectal fat, is of crucial
importance and has been reported to result in
significantly lower rates of local recurrence in
specialist centers, population-based audit, and
within the framework of randomized controlled
trials. By far, surgery remains the most important
treatment of rectal cancer; nevertheless, the man-
agement of this disease has evolved to become
multidisciplinary.
Conclusive studies established the ability of
MRI to demonstrate the relationship of the mac-
roscopic tumor to the surrounding well-defined
V. Valentini (*)
anatomical plane of surgical excision. This
Department of Radiotherapy,
Università Cattolica Sacro Cuore, Rome, Italy development is closely linked with the ability of
e-mail: vvalentini@rm.unicatt.it relatively simple histopathological techniques
H.J. Schmoll to assess and measure the distance of micro-
Department for Internal Medicine, scopic tumor to the circumferential resection
Oncology and Hematology, margin (CRM) of the resected rectal cancer
University Clinic Halle (Saale),
specimen, providing the choice of optimal sur-
Halle, Germany
gical planes. MRI showed a great reliability in
C.J.H. van de Velde
predicting mesorectal fascia (MRF) involvement,
Department of Surgery,
Leiden University Medical Center, and more properly it was recently proposed to
Leiden, The Netherlands report it as MRF +/−.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 9

DOI 10.1007/978-3-642-25005-7_2, © Springer-Verlag Berlin Heidelberg 2012
10 V. Valentini et al.

In the last decade, several European phase III
trials evaluating the role of radiotherapy and che-
motherapy in rectal cancer have been published.
From these trials, the efficacy of both short-course
preoperative radiotherapy and preoperative con-
current chemoradiotherapy was determined [1–7].
Anyway, although the findings of large random-
ized trials have addressed important questions,
there remain patient care issues that cannot be
addressed by subgroup analyses of existing trials
and large areas of controversies are still in place.
To support physicians to deliver more tailored
choices—as the oncology profession moves into
the era of individualized medicine—some
European Consensus guidelines were proposed
under the collaboration of the major Oncology
Society ESTRO (European SocieTy of Radio-
therapy and Oncology), ESSO (European Society
of Surgical Oncology), and ESMO (European
Society of Medical Oncology) [8, 9].
Two papers summarized these efforts: The
EURECA project elaborated the Consensus
document using the Delphi method [8]. A group
of experts delegated by the three Oncology
Societies voted sentence by sentence for three
times a web-based document customized for the
consensus process. A meeting was openly held to
debate by attendees the more controversial sen-
tences. The total number of voted sentences was
207. Of the 207, 86% achieved large consensus,
13% achieved moderate consensus, and only 3 (1%)
resulted in minimum consensus. The document
addresses a wide range of topics relating to the man-
agement of rectal cancer and, of equal importance,
identifies areas where future research is a priority.
A second document was addressed by ESMO
inside their program of organ oriented guide-
lines. A group of experts invited by ESMO
debated in a 2-day meeting the key issues about
the management of rectal and colon cancer and a
document circulated between them till a final
approval [9].
To get more information about the different
strategies regarding staging and treatment of rec-
tal cancer, we recommend the reading of these
two documents as well as the different answers to
the main questions, which arose in a multidisci-
plinary group in the daily management of rectal
cancer patients, reported in this book (Figs. 2.1–2.10
and Tables 2.1–2.3). In this chapter, we tried to

Clinical Rectal Cancer

presentation

T stage
MRF Sphincter
Aim Location N stage Metastases
involvement involvement

T1 T2–3 T4

1° Abdomen MDCT
Choice ERUS MRI MRI MRI MRI MRI +
MRI
Exam chest –X ray or
CT (to be preferred)

MDCT
IF 1° Rigid ERUS MDCT MDCT high
choice ERUS slow ERUS mid ERUS
proctocopy high
exam is rectum mid rectum rectum
not
available

Flexible
2°
endoscopy MDCT Multidetector CT ERUS Endorectal US MRF Mesorectal Fascia
choice

Fig. 2.1 Imaging work-up

2 What Is the Ongoing Recommendation in the Management of Rectal Cancer? 11

Clinical cT1 N0 M0
stage

Local
TME
Primary excision
treatment

pT1NX
Pathological pT1NX high risk > pT2 or pN + pT1–2 N0
report Margin - features
or > pT1N0

Adjuvant Chemotherapy
Observation Observation
treatment + radiochemotherapy
(see table 20.1)

Fig. 2.2 Treatment strategy: cT1 N0 M0

Clinical cT2 N0 M0
stage

TME
Primary
treatment

pT3, CRM−, pN0

Pathological pT1−2 N0 pT2−3 and (CRM+ or pN+)
High Middle rectum
report

Adjuvant Observation Observation Chemotherapy

treatment + radiochemotherapy
(see Table 2.1)

Fig. 2.3 Treatment strategy: cT2 N0 M0

12 V. Valentini et al.

Clinical cT3 (MRF-) N0 -2 M0

stage

Preoperative
RT chemotherapy
Preoperative long course
Primary RT short course (see Table 2.1)
treatment

2−3 days 6−8 weeks

TME TME

Pathological
report CRM− CRM+ CRM− CRM+

Adjuvant Chemo+ Adjuvant

Adjuvant
treatment Observation RT chemo Observation chemo
chemo
A according to
(see Table 2.2)
(see Table 2.1) nomogram*
(see Table 2.2)

*V. Valentini JCO 2011 MRF Mesorectal Fascia

Fig. 2.4 Treatment modalities: cT3 (MRF−) N0–2 M0

Clinical
cT3 (MRF+) N0−2−M0 or cT4 any N M0
stage

Preoperative
RT chemotherapy
long course
Primary (see Table 2.1)
treatment

6–8 weeks

TME

Adjuvant
Adjuvant chemotherapy
treatment (see Table 2.2)

MRF Mesorectal Fascia

Fig. 2.5 Treatment modalities: cT3 (MRF+) N0–2–M0 or cT4 any N M0

2 What Is the Ongoing Recommendation in the Management of Rectal Cancer? 13

Clinical cT3 ab N0 M0 cT3 MRF+ M0

stage middle-upper cT3 (MRF–) N0–1 M0
cT4 any N M0
rectum

6−8 weeks
Preoperative
Preoperative
RT chemotherapy
RT short course
long course
TME
Primary
treatment 6−8 weeks

Preoperative
Restaging
CRM + chemotherapy
CRM− > clinical response?
or PN +
Pathological
report
Local excision TME

pT0 Nx pT1–2–3
CHEMO+
RT Chemo Adjuvant chemotherapy
Adjuvant Observation Observation TME (see Table 2.2)
(see Table 2.1)
treatment
pT0–2 N0 pT3 N+

Observation Adjuvant
Chemotherapy (seeTable 2.2)

MRF Mesorectal Fascia

Fig. 2.6 Treatment modalities under clinical evaluation

Clinical Local recurrence

stage

No previous RT Previous RT
for the primary for the primary

RT chem Resecability

Primary
treatment Resecability
Yes No

Yes No
Surgery RT chem Chemotherapy RT chem

Chemotherapy B
Resection + IORT Surgery
(see Table 2.2) Adjuvant Resecability
Chemotherapy
(see Table 2.2)
Yes No
adjuvant
chemotherapy
Adjuvant – Adjuvant (see Table 2.2) Surgery Chem
maintenance Chemotherapy B
treatment
Chem

Fig. 2.7 Treatment modalities local recurrence, cM0

14 V. Valentini et al.

Syncronous cancer with

intact primary and R0/R1
resectable metastases
Clinical
stage
< T3 N0
≥ T3 or N+

or
Preop RT (5 × 5) 3 months preop
3 months preop
Primary Or CRT FOLFOX
FOLFOX
treatment

3 months preop Preop RT (5 × 5)

FOLFOX

Resection of primary and met

Pathological Postop CRT if T3, CRM+,

report pN+, perforation

Adjuvant – 6 months postop

maintenance 3 months postop FOLFOX
FOLFOX
treatment

Fig. 2.8 Treatment modalities, cM1, resectable synchronous metastases

Syncronous unresectable met

Clinical with intact primary rectal cancer
stage
Upfront chemotherapy (see Table 2.3)

Primary
Resectability of mets achieved?
treatment

Yes No

< T3 N0 ≥ T3 or N+
Continue/change chemotherapy

Preop CRT or Resectability of mets achieved?

short course RT

Yes No
Resection of primary +
resection of metastases
Avoid radical and mutilating
Adjuvant – Resume initial treatment for a surgery
maintenance total of 6 months RCT or short course RT or brachiterapy
treatment for locally advanced tumors

Fig. 2.9 Treatment modalities, cM1, unresectable synchronous metastases

2 What Is the Ongoing Recommendation in the Management of Rectal Cancer? 15

Clinical Resectable liver/lung metastses

stage

Clearly R0 resectable Boderline/R0 resectable

Intensive chemotherapy
Single, <2 cm FOLFOX
3−4(−6) months
Primary liver met 3 months preop
(see Table 2.3)
treatment

Resection No resection

Adjuvant – R0/1 : complete

R0/1 : FOLFOX R0/1 : FOLFOX Escalate/change
maintenance periop. chemotherapy
6 months postop 3 months postop chemotherapy, than
treatment for total of 6 months resection, if possible

Fig. 2.10 Treatment modalities CM1, non-synchronous

Table 2.1 Chemotherapy-options and doses for concomitant chemotherapy during radiation
Regimen References
5FU 325–350 mg/m2 + LV 20 mg/m2 iv bolus, d1–5, week 1 and 5 [3, 10]
5FU 400 mg/m2 + LV 100 mg iv bolus, d1, 2, 11, 12, 21, 22 [7]
5FU 225 mg/m2 iv continuous infusion, 5 days per week, together [11, 12]
with radiotherapy
5FU 1,000 mg/m2 iv continuous infusion, d1–5, week 1 and 5 [1]
Capecitabine 800–825 mg/m2 bid po continuously, 5–7 days per week, [11, 13, 14]
together with radiotherapy
UFT (300–350 mg/m2/day) and LV (22.5–90 mg/day) po continu- [15–18]
ously, 5–7 days per week, together with radiotherapy
5FU 250 mg/m2 iv continuous infusion on days 1–14 and 22–35 and [19]
oxaliplatin 50 mg/m2 iv d1, 8, 22, 29, only preoperatively

Table 2.2 Standard adjuvant chemotherapy regimens in rectal cancer (number of cycles without chemoradiation are
given in brackets)
Regimen Cycles References
5FU 350–370 mg/m2, + LV 20–25 mg/m2 iv 4 (−6) [3, 20]
bolus, d1–5, q 4 weeks
5FU 500 mg/m2 iv, continuous infusion, d1–5, 4 [1]
q 4 weeks
5FU 500 mg/m2 + LV 100 mg, iv Bolus, d1, 2, 8 [7]
q 2 weeks
Capecitabine 2,000–2,500 mg/m2, po, d1–14, 5–6 (−8) [13, 21]
q 3 weeks
16 V. Valentini et al.

Table 2.3 Choice of first line treatment

2.3 a
Group Clinical presentation Treatment aim Treatment intensity
1 liver and/or lung metastases only
which • maximum upfront most active
• might become resectable after induction chemotherapy tumour combination regimen
• ±limited/localized metastases to other sites, e.g. locore- shrinkage
gional lymphnodes
• physically able to undergo major surgery (biological age,
heart/lung condition)
Group KRAS wildtype Recommenda KRAS mutant Recommenda
1 • FOLFIRI+Cet +++ • FOLFOX/XELOX+Bev +++
• FOLFOX+Pan/Cet +++ • FOLFOXIRI ++(+) b
• FOLFOX/XELOX+Bev ++(+) • FOLFIRI/XELIRI+Bev ++(+) c
• FOLFOXIRI ++(+)b • FOLFOX/XELOX +
• FOLFIRI/XELIRI+Bev ++(+) c • FOLFIRI/XELIRI +
• FOLFOX/XELOX + • IRIS +
• FOLFIRI/XELIRI +
• IRIS +
2.3 b
Group Clinical presentation Treatment aim Treatment intensity
2 multiple metastases/sites, with
• rapid progression and/or • clinically relevant tumour upfront active combination: at
• tumour-related symptoms/risk shrinkage as soon as possible least doublet
of rapid deterioration • at least achieve control of
• co-morbidity allows intensive progressive disease
treatment
Group KRAS wildtype Recommenda KRAS mutant Recommenda
2 • FOLFIRI+Cet +++ • FOLFOX/XELOX+Bev +++
• FOLFOX+Pan +++ • FOLFIRI/XELIRI+Bev ++(+)c
• FOLFOX/XELOX+Bev +++ • FOLFOX/XELOX ++
• FOLFIRI/XELIRI+Bev ++(+)c • FOLFIRI/XELIRI ++
• FOLFOXIRI +(+) b • FOLFOXIRI ++b
• FOLFOX+Cet +(+) • IRIS +
• FOLFOX/XELOX +
• FOLFIRI/XELIRI +
• IRIS +
2.3 c
Group Clinical presentation Treatment aim Treatment intensity
3 multiple metastases/sites, with
• never option for resection • abrogation of further treatment selection according to
• and/or no major symptoms or risk progression disease characteristics and
of rapid deterioration • tumour shrinkage less patients preference re toxicity
• and/or severe comorbidity relevant and efficacy:
(excluding from later surgery and/ • low toxicity most relevant • “watchful waiting”
or intensive systemic treatment, as • sequential approach: start with
for groups 1+2) – single agent, or
– doublet with low toxicity
• exceptional triplets
2 What Is the Ongoing Recommendation in the Management of Rectal Cancer? 17

Group KRAS wildtype Recommenda KRAS mutant Recommenda

3 • FUFOL/Cape (mono) +++ • FUFOL/Cape (mono) +++
• FUFOL/Cape+Bev +++ • FUFOL/Cape+Bev +++
• XELOX/FOLFOX ++ • XELOX/FOLFOX ++
• FOLFIRI/XELIRI ++ • FOLFIRI/XELIRI ++
• IRIS + • IRIS +
• Cet/Pan (mono) (+) • watchful waiting + selected pts.d
• watchful waiting + selected ptsd • triplets (+/-Bev) + option for spec.
triplets (+/-Bev or Cet/Pan) + option for spec. situations e
situationse
a
Rec: consented recommendation, however decision might be modified based on individual objective and subjective
parameters
b
FOLFOXIRI: only 2 (small) phase III trials with contradictory results
c
no randomized data for FOL(XEL)IRI + Bev
d
option in case of low tumor burden, asymptomatic, indolent disease: close control until definitive progression (not until
symptoms!)
e
Patients who are group 3 but deserve (and tolerate) more intensive treatment due to specific reasons

6. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J,

summarize by charts the contents of those two
documents, which largely represent the view of
the experts of the three major European Oncology
Societies (ESTRO, ESMO, and ESSO), to facili-
tate the understanding of the approach to man-
agement of rectal cancer.
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Preoperative radiotherapy with or without concurrent
fluorouracil and leucovorin in T3–4 rectal cancers:
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3. Bosset JF, Collette L, Calais G, Mineur L, Maingon P,
Radosevic-Jelic L, EORTC Radiotherapy Group Trial
22921 et al (2006) Chemotherapy with preoperative
radiotherapy in rectal cancer. N Engl J Med
355:1114–1123
4. Bujko K, Nowacki MP, Nasierowska-Guttmejer A,
Michalski W, Bebenek M, Kryj M (2006) Long-term
results of a randomized trial comparing preoperative
short-course radiotherapy with preoperative conven-
tionally fractionated chemoradiation for rectal cancer.
Br J Surg 93:1215–1223
5. Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg
EK, Putter H, Wiggers T et al (2007) Dutch Colorectal
Cancer Group the TME trial after a median follow-up
of 6 years: increased local control but no survival
benefit in irradiated patients with resectable rectal
carcinoma. Ann Surg 246:693–701
Grieve R, Khanna S et al (2009) Preoperative radio-
therapy versus selective postoperative chemoradio-
therapy in patients with rectal cancer (MRC CR07 and
NCIC-CTG C016): a multicentre, randomised trial.
Lancet 373:811–820
7. Braendengen M, Tveit KM, Berglund A et al (2008)
Randomized phase III study comparing preoperative
radiotherapy with chemoradiotherapy in nonresect-
able rectal cancer. J Clin Oncol 26:3687–3694
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Multidisciplinary Rectal Cancer Management: 2nd
European rectal cancer consensus conference
(EURECA-CC2). Radiother Oncol 92(2):148–163
9. Schmoll HJ, Van Cutsem E, Stein A, Valentini V,
Glimelius B, Haustermans K et al Standards for diagno-
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Improving adjuvant therapy for rectal cancer by combin-
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 Part II
Q&As on Risk Factor Identification
 What Prognostic Clinical Factors
Must Be Considered Before 3
Treatment?

Claus Rödel

Contents 3.1 Patient-Related

3.1 Patient-Related Characteristics: Characteristics: Sex, Age,
Sex, Age, and Body Mass Index ................ 21 and Body Mass Index
3.2 Tumor-Related Characteristics................. 22
3.2.1 Tumor Size and Location ............................. 22 It has been observed in some reports that sur-
3.2.2 Clinical T- and N-Stage ............................... 24 vival after colorectal cancer resection is longer
3.2.3 Distance of the Tumor in women than men. With the use of the
to Mesorectal Fascia .................................... 24
Surveillance, Epidemiology, and End Results-
3.3 Histopathology on Pretreatment Medicare-linked database of a cohort of 30,975
Biopsies ....................................................... 25 colorectal cancer patients (8,350 with rectal can-
3.4 Pretreatment Laboratory Findings .......... 26 cer, treated from 1996 to 2003), one group from
References ................................................................. 26 Philadelphia, Pennsylvania, could show that for
both colon and rectal cancer, women presented
at an older age and underwent less aggressive
therapy but had longer adjusted survival com-
pared with men. In a recent pooled analysis from
five European clinical trials of preoperative con-
ventionally fractionated radiotherapy (with or
without 5-fluorouracil-based concurrent chemo-
therapy), female sex was also associated with a
more favorable overall survival, albeit there was
no difference in local or distant tumor control
between men and women (Table 3.1) [1].
Understanding of this difference is worthy of
further investigation; however, based on these
data, it is unlikely that there are gender-specific
differences in tumor response and rectal cancer-
specific survival rates. Conversely, several
reports have confirmed that acute organ toxicity
C. Rödel during chemoradiotherapy (CRT) is increased in
Department of Radiotherapy and Oncology, women. Gender differences in the dihydropy-
Johann Wolfgang Goethe-University Frankfurt,
rimidine dehydrogenase expression (the initial,
Theodor-Stern-Kai 7, Frankfurt am Main
60590, Germany rate-limiting enzyme in the catabolism of
e-mail: claus.roedel@kgu.de 5-fluorouracil) may contribute to higher toxicity

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 21

DOI 10.1007/978-3-642-25005-7_3, © Springer-Verlag Berlin Heidelberg 2012
22 C. Rödel

Table 3.1 Impact of clinical factors on local and distant control

5-year local 5-year distant 5-year overall
No. control (%) P control (%) P survival (%) P
Total no. of 2,795 87 69 70
patients
Sex
Male 1,961 87 n.s. 68 n.s. 68 <0.001
Female 843 89 72 74
Age
£49 378 85 n.s. 68 n.s. 72 <0.001
50–59 746 87 70 73
60–69 1,131 89 67 67
³70 540 90 73 69
Tumor location
Low 953 86 n.s. 64 0.001 65 0.001
Mid 1,461 88 71 72
High 369 91 75 74
cT stage
cT2 18 95 <0.001 66 n.s. 83 <0.001
cT3 2,228 89 70 71
cT4 275 78 64 57
cN stage
cN0 309 93 n.s. 78 0.009 78 0.006
cN1–2 544 94 72 74
Data from five European randomized trials on preoperative radiotherapy with or without 5-fu-based concurrent
chemotherapy

in women treated with 5-fluorouracil-based CRT.
Furthermore, an increased risk of dyspareunia
and vaginal dryness was observed in women fol-
lowing surgery combined with (chemo-)radio-
therapy compared with women treated with
surgery alone.
There is limited information on how elderly
patients tolerate radiotherapy or combined CRT
for rectal cancer. Recent analyses of the Dutch
TME trial and two large Dutch population-based
registries showed that, unlike younger patients,
patients >75 years of age did not benefit in terms of
overall survival from the introduction of preopera-
tive radiotherapy and TME surgery [2]. Randomized
trials in rectal cancer commonly include few
patients more than 75 years of age. Data from the
pooled analysis of the five European trials
(Table 3.1) do not indicate worse outcome in terms
of local and distant control in the age cohorts from
below 50 years to above 70 years, respectively.
However, several nonrandomized and population-
based datasets indicate higher rates of toxicity and
treatment deviation during CRT among elderly
patients, who may require aggressive supportive
management to complete therapy.
An increased body mass index, particularly in
males, was associated with a decreased likelihood
of sphincter preservation and an increased risk of
local recurrences in a pooled analysis of 1,688
rectal cancer patients treated within postoperative
5-fluorouracil-based CRT trials. Interestingly,
obese patients – both women and men – had a
significantly lower rate of grade 3–4 acute toxic-
ity (mainly leucopenia, stomatitis) when com-
pared to normal-weight individuals, indicating
that actual body weight dosing of 5-fluorouracil
may be justified in obese patients [3].
3.2 Tumor-Related Characteristics
3.2.1 Tumor Size and Location
Through digital rectal examination (DRE, the
average finger can reach approximately 8 cm
above the anal verge), tumors can be assessed for
3 What Prognostic Clinical Factors Must Be Considered Before Treatment?
Table 3.2 Impact of distance from anal verge by univariate analysis on local failure rates
Swedish rectal cancer trial
Local failure rate at 5 years (%)
Preop. RT
High >11 cm 8 12
Middle 6–10 cm 9 26
Low £5 cm 10
Dutch trial
High >10 cm 3.7
Middle 5.1–10 cm 3.7
Low £5 cm 10.7
Medical Research Council MRC CR07
High >10–15 cm 1.2a
Middle >5–10 cm 5.0a
Low 0–5 cm 4.8a
a
Three-year data
size, ulceration, and fixation to surrounding struc-
tures. DRE also permits a cursory evaluation of
the patient’s sphincter function, which is critical
when determining whether a patient is a candi-
date for a sphincter-sparing procedure. Several
studies identified the pretreatment tumor size
(<3 cm) as a significant factor for pathologic
complete response after preoperative chemora-
diotherapy (CRT) in rectal cancer. Other known
risk factors include circumferential lesions, teth-
ered or fixed tumors on palpation, near-obstruct-
ing lesions, and low-lying tumors. Rigid
proctosigmoidoscopy allows direct visualization
of the lesion and provides an estimation of the
size of the lesion and degree of obstruction. This
procedure is used to obtain biopsies and gives an
accurate measurement of the distance of the
lesion from the anal verge.
The rectum is subdivided into three parts
according to the distance of the lower margin of
the tumor from the anal verge: upper third
12–16 cm, middle third 6–£12 cm, and lower
third <6 cm. Alternative definitions (0–5 cm,
>5–10 cm, >10–15 cm) have also been used. The
anterior peritoneal reflexion represents the point
at which the rectum exits the peritoneal cavity
and becomes retroperitoneal (approximately
8–12 cm from the anal verge, extremely variable
between females and males). There are no pro-
spective randomized data examining the impact
of the distance from the anal verge on local recur-
rence. The available data are subset analysis from
23
Surgery P value
n.s.
<0.001
27 0.03
6.2 0.12
13.7 <0.001
12 0.58
6.2a HR 0.19 (0.07–0.47)
9.8a HR 0.50 (0.28–0.9)
10.4a HR 0.45 (0.23–0.88)
randomized trials which were not stratified by
distance. These trials used short-course preopera-
tive radiation and included patients with cT–
–2N0 disease (Swedish Rectal Cancer Trial from
the pre-TME era, Dutch Trial, Medical Research
Council MRC CR07) [4–6]. As seen in Table 3.2,
by univariate analysis, “high” tumors generally
had a lower incidence of local recurrence com-
pared with mid and lower tumors. On multivari-
ate analysis, tumor location was an independent
prognostic variable in the Dutch trial. The MRC
CR07 trial also identified tumors involving the
anterior quadrant as an independent risk factor
for time to local recurrence, whereas distal extent
was not significantly associated with local recur-
rence on multivariate analysis.
It is interesting to note that radiation did
significantly decrease local recurrence for all
tumor positions in the MRC CR07 trial, whereas
this effect was significant only for middle and
low tumors in the Swedish and for middle
tumors only in the Dutch trial, respectively. If
analyzed as a continuous factor (rather than with
arbitrary cutoff points), the benefit of radiother-
apy in the Dutch trial became significant as the
distance from anal verge increased. However, if
patients with positive circumferential resections
margins (which occurs more often in distal rec-
tal cancer) were excluded, the effect of radio-
therapy on reduction of local recurrences was
independent of the distance of the tumor from
the anal verge.
24
3.2.2 Clinical T- and N-Stage
The primary imaging modalities to assess the
extent of the primary tumor (cT-, cN-status) are
endorectal ultrasound (ERUS), multidetector 4–16
slice CT, and phased-array MRI. ERUS is the most
accurate tool in predicting T stage of rectal can-
cers, especially T1 versus T2. Thus, ERUS has
been recommended as the investigation of choice
in selection of potentially curative local excision
which should be restricted to patients with T1
tumors without further risk factors, as well as in
selection of patients with early T3 tumors (vs. T2)
for neoadjuvant treatment. ERUS cannot be reli-
ably used in patients with high or stenosing tumors.
Of note, overestimation of staging with this tech-
nique occurs more often than understaging. In the
German CAO/ARO/AIO-94 study, 18% of patients
in the immediate surgery arm – clinically staged
by ERUS to have cT3–4 and/or cN + disease – had
lymph node negative tumors confined to the rectal
wall (pT1/2 pN0) on pathologic assessment of the
resected specimen. This probably is due to the
inflammatory and desmoplastic processes caused
by the tumor (or by taken tumor biopsy within
1 week before ERUS was performed) but is also
operator dependent. Endorectal coil MRT is an
alternative to ERUS but appears to be not superior
to ERUS for T staging. Because of limited acous-
tic penetration by ERUS, invasion of bulky tumors
into the perirectal fat and adjacent organs and pel-
vic side walls is better evaluated by multislice-CT
scan and phased-array MRI. The involvement of
the anal sphincter and levator ani muscles cannot
be truly seen on CT scans, whereas high-resolu-
tion MRI techniques using phased-array coils have
led to better spatial resolution and particularly
have been shown to identify the anal sphincter,
puborectalis, and particularly the mesorectal fas-
cia. This latter is an important feature to predict
negative circumferential margins between the
tumor and the mesorectal fascia and makes phase
array MRI superior to CT especially for lower
third rectal tumors [7].
The identification of positive lymph nodes is
more difficult. Involvement is mainly assessed by
size criteria (>8 mm), although enlarged lymph
nodes are not pathognomonic of tumor involve-
ment, and morphological features such as the
C. Rödel
presence of mixed signal intensity and irregular-
ity of the borders of the lymph nodes may be more
reliable. However, adequate clinical detection of
lymph node involvement remains a challenge that
is critically important with respect to the increas-
ing use of preoperative treatment strategies.
It is clear that the most important prognostic
factors for survival are the extent of disease as
determined histopathologically after surgery
(with or without neoadjuvant treatment) by the
degree of bowel wall penetration; the presence or
absence of lymph node metastases or distant
metastases, i.e., the (y)pTNM stage, as well as
the tumor resections margins (R0, R1, R2; cir-
cumferential resection margin £1 mm). The prog-
nostic value of the clinically determined cT- and
cN-stage is less validated. Figure 3.1a depicts the
association of the pretreatment, clinical T- and
N-stage with disease-free survival within the
German Rectal Cancer Study [8]. In this trial,
staging procedures included DRE, proctoscopy,
endorectal ultrasound, and a pelvic CT scan (MRI
was not mandatory). Only patients with cT3–4
and/or cN + disease were eligible. Interestingly,
clinical T and N staging was not significantly
associated with long-term outcomes in this trial,
reflecting the inaccuracy of pretreatment staging,
especially with respect to lymph node involve-
ment. Data from the pooled analysis of the five
European trials (Table 3.1), however, indicate
that cT-stage and cN-stage are significantly asso-
ciated with the risk of local and distant failure,
respectively, albeit the absolute difference in out-
comes was only small. Conversely, positive
lymph nodes after preoperative CRT indicate
both an aggressive potential of the malignant
cells to spread to the regional lymph nodes and
the resistance of these cells toward CRT. As a
result, these patients have a very unfavorable
prognosis and ypN0 versus ypN1–2 largely sepa-
rates different prognostic groups (Fig. 3.1b).
3.2.3 Distance of the Tumor
to Mesorectal Fascia
Histopathologic tumor involvement of the mesorec-
tal resection margin is a well-established indepen-
dent predictor of local and distant metastases
3 What Prognostic Clinical Factors Must Be Considered Before Treatment? 25

Fig. 3.1 (a) Impact of clinical a

cT- and cN-stage on disease- 1.0 1.0
free survival after preoperative
chemoradiotherapy. (b) Impact
of pathologic ypT- and .8 cT2 (n=16) .8 cN+ (n=213)
ypN-stage on disease-free

Disease-free survival
survival after preoperative
.6 cT4 cT3 .6
chemoradiotherapy (Data from cN0 (n=154)
the German Rectal Cancer (n=24) (n=268)
Study)
.4 .4

.2 .2
P=0.92 P=0.34

0 0
0 20 40 60 80 100 0 20 40 60 80 100
Months Months
b
1.0 ypT1 1.0
ypT0
ypNO
.8 ypT2 .8
Disease-free survival

ypT3 ypN1
.6
ypT4 .6

.4
.4
ypN2
.2
P=0.001 .2
P<0.0001
0
0
0 20 40 60 80 100 0 20 40 60 80 100
Months Months

both after primary surgery and after preoperative prognostic tumors (e.g.,T4; predicted CRM
CRT/RT plus surgery. High-resolution phased- £1 mm, cN2; extramural venous invasion).
array MRI techniques are highly accurate for the
prediction of the circumferential resection margin
(CRM), especially CRM £1 mm versus >1 mm. 3.3 Histopathology on
Moreover, substaging of T3 tumors (T3a/b with Pretreatment Biopsies
tumor spread £5 mm into the mesorectal compart-
ment) has been validated prospectively by the The majority (over 90%) of rectal cancers are ade-
MERCURY study group and has shown direct nocarcinomas. Some adenocarcinomas have mucin
agreement between pretreatment imaging and which can be extracellular (colloid) or intracellular
corresponding pathology [9]. Both information (signet ring cell). Colloid cancer, which occurs in
may help to stratify patients for preoperative treat- 15–20% of adenocarcinomas, is not an indepen-
ment alternatives, including omission of RT in dent prognostic factor, whereas signet ring cell,
good prognostic tumors (e.g., cT3a/b, cN0, mid- which occurs in 1–2% of adenocarcinomas, is an
dle/upper part of rectum, predicted CRM >1 mm) independent poor prognostic factor for survival.
or short-course RT versus CRT in intermediate Other histological types are rare and include carci-
(e.g., >cT3a/b, predicted CRM >1 mm) and poor noid tumors, leiomyosarcomas, lymphoma, and
26
squamous cell cancers. The grading system used
for adenocarcinomas refers to the degree of dif-
ferentiation. Some institutions use a three-grade
system (well, moderate, poor), and others use a
four-grade system. Despite substantial inter- and
intraobserver variability in tumor grading, poorly
differentiated tumors have consistently found to be
associated with a worse prognosis in multivariate
analysis.
3.4 Pretreatment Laboratory
Findings
Carcinoembriogenic antigen (CEA) is the most
frequently used tumor marker in colorectal can-
cer. An elevated CEA level at the time of presen-
tation has an adverse impact on survival
independent of tumor stage, and a reduction after
radical surgery has been associated with improved
disease-free survival. Prechemoradiotherapy
(CRT) CEA concentrations >5 ng/ml has been
associated with poor tumor response. Another
study found post-CRT CEA concentrations
<5 ng/ml to be associated with increased rates of
complete clinical and pathologic response. Little
is known about the relationship between the
degree of CEA reduction from before to after
neoadjuvant CRT and prognosis. A recent retro-
spective study from Korea suggests that in
patients with elevated CEA levels pre-CRT
(>6 ng/ml), a ³70% reduction in post-CRT levels
predicted for improved disease-free survival [10].
The pretreatment serum hemoglobin level has
also been correlated to pathologic response to
neoadjuvant CRT. According to one study, pre-
treatment anemia (<9.0 g/dl of Hb) was associ-
ated with poor tumor response to CRT, and
correction of anemia for rectal cancer patients
with such low Hb levels was recommended [11].
C. Rödel
References
1. Valentini V, van Stiphout RG, Lammering G et al
(2011) Nomograms for predicting local recurrence,
distant metastases, and overall survival for patients
with locally advanced rectal cancer on the basis of
European randomized clinical trials. J Clin Oncol
29:3163–3172
2. Rutten HJ, den Dulk M, Lemmens VE et al (2008)
Controversies of total mesorectal excision for rectal
cancer in elderly patients. Lancet Oncol 9:494–501
3. Tepper JE, O’Connell M, Niedzwiecki D et al (2002)
Adjuvant therapy in rectal cancer: analysis of stage,
sex, and local control – final report of intergroup 0114.
J Clin Oncol 20:1744–1750
4. van Gijn W, Marijnen CA, Nagtegaal ID et al (2011)
Preoperative radiotherapy combined with total
mesorectal excision for resectable rectal cancer:
12-year follow-up of the multicentre, randomised
controlled TME trial. Lancet Oncol 12:575–582
5. Sebag-Montefiore D, Stephens RJ, Steele R et al
(2009) Preoperative radiotherapy versus selective
postoperative chemoradiotherapy in patients with rec-
tal cancer (MRC CR07 and NCIC-CTG C016): a mul-
ticentre, randomised trial. Lancet 373:811–820
6. Birgisson H, Pahlman L, Gunnarsson U et al (2005)
Adverse effects of preoperative radiation therapy for
rectal cancer: long-term follow-up of the Swedish rec-
tal cancer trial. J Clin Oncol 23:8697–8705
7. Valentini V, Beets-Tan R, Borras JM et al (2008)
Evidence and research in rectal cancer. Radiother
Oncol 87:449–474
8. Sauer R, Becker H, Hohenberger W et al (2004)
Preoperative versus postoperative chemoradiotherapy
for rectal cancer. N Engl J Med 351:1731–1740
9. MERCURY Study Group (2007) Extramural depth of
tumor invasion at thin-section MR in patients with
rectal cancer: results of the MERCURY study.
Radiology 243:132–139
10. Kim CW, Yu CS, Yang SS et al (2011) Clinical
significance of Pre- to post-chemoradiotherapy s-CEA
reduction ratio in rectal cancer patients treated with
preoperative chemoradiotherapy and curative resec-
tion. Ann Surg Oncol 18:3271–3277
11. Lee SD, Park JW, Park KS et al (2009) Influence of
anemia on tumor response to preoperative chemora-
diotherapy for locally advanced rectal cancer. Int J
Colorectal Dis 24:1451–1458
 What Are the Relevant Imaging
Factors to Optimize Treatment 4
Decisions?

Manish Chand and Gina Brown

Contents 4.1 Introduction

4.1 Introduction ................................................ 27
The optimal management of rectal cancer is
4.2 The Common Imaging Modalities ............ 28
influenced by several different factors relating to
4.2.1 Magnetic Resonance Imaging (MRI) .......... 28
4.2.2 Endoanal Ultrasound.................................... 28 the primary tumour. These may be specific char-
4.2.3 Computed Tomography (CT)....................... 29 acteristics of the tumour itself as well as pattern of
4.3 Local Factors Which Influence spread both locally and to distant sites. Identifying
Treatment Decisions................................... 29 these factors at an early stage is beneficial to long-
4.3.1 Circumferential Resection Margin (CRM) .. 29 term outcome and leads to a reduction in the risk
4.3.2 Height of Tumour......................................... 30 of local recurrence and distant spread. The aim of
4.3.3 Extramural Venous Invasion (EMVI) .......... 30
4.3.4 T-Staging ...................................................... 32 treatment must be to alleviate any symptoms, to
4.3.5 Nodal Staging .............................................. 36 deal with the immediate threat of cancer and to
4.4 Distant Factors ........................................... 36
reduce the risk of recurrence. This may involve
4.4.1 Hepatic Metastases ...................................... 36 surgery, radiotherapy and chemotherapy or a com-
4.4.2 Extra-hepatic Disease .................................. 37 bination of all three depending on the prognostic
4.5 Summary..................................................... 38 features of the tumour. Imaging provides an
important role in identifying factors which may
References ................................................................. 38
influence treatment decisions both at the time of
diagnosis and during treatment.
Traditionally, clinicians have relied on a com-
bination of digital rectal examination (DRE),
sigmoidoscopy or colonoscopy and tissue biop-
sies to confirm the diagnosis of rectal cancer.
However, these techniques provided minimal
information on tumour spread and characteris-
tics. Assessment of the surgical specimen would
M. Chand (*) be the basis for decisions on adjuvant therapy
Colorectal Research Fellow
depending on identification of specific prognostic
and Registrar in Colorectal Surgery,
Royal Marsden Hospital, Downs Road, Sutton features on histology. The introduction of increas-
e-mail: mans001@aol.com ingly accurate imaging modalities such as mag-
netic resonance imaging (MRI) and computerized
G. Brown
tomography (CT) have helped identify additional
Consultant Radiologist, Royal Marsden Hospital,
Downs Road, Sutton prognostic information about the tumour pre-
e-mail: gina.brown@rmh.nhs.uk operatively.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 27

DOI 10.1007/978-3-642-25005-7_4, © Springer-Verlag Berlin Heidelberg 2012
28 M. Chand and G. Brown

Optimal treatment strategy must account

for the risk of local recurrence and distant metas-
tases. The decision to offer patients oncologi-
cal therapies such as chemo- and radiotherapy is
now strongly influenced by the results of early
imaging studies – “staging scans”. However, it
is not only important to be able to select patients
who are at a higher risk of poor outcomes for
neoadjuvant therapy but also not to offer
patients such treatment unnecessarily. Therefore,
the role of imaging in adding to management
decisions must be to avoid both under- and
overtreatment.
The current repertoire of imaging modalities
aim to provide detailed information on tumour
size, location and type; pattern and depth of inva-
sion; relationship to mesorectum; nodal involve-
ment and distant metastases; and, most recently,
angiotropism. Ultimately, this information allows
clinicians to risk stratify patients and optimize
treatment decisions.

4.2 The Common Imaging

Modalities
4.2.1 Magnetic Resonance Imaging
(MRI)
The most common MRI techniques for assessing
rectal cancer involve either an endorectal coil or
surface coil. The endorectal coil suffers some of
the drawbacks associated with EAUS, as they
must be positioned in the patient’s anorectum.
This makes it difficult to assess stenosing tumours
and limits visualization of structures immediately
outside the rectum. The imaging field is limited
to a small area, and although the images can be
highly detailed, the external phased-array surface
coil has a greater advantage of providing compa-
rable views of the rectal wall whilst being non-
invasive and able to evaluate the remainder of the
pelvis. Regardless of which coil technique is
used, the protocol may be the same. There have
in the past been wide variations in sequences
used, but all the recently published data have
confirmed the improved accuracy achievable
using high-resolution T2-weighted images. The
use of T1-weighted scans with or without con-
Fig. 4.1 Axial image showing correct field alignment.
The red lines indicate correct alignment so to accurately
measure and stage the tumour
trast enhancement is considered to be far less
reliable.
Correct alignment of the axial images, perpen-
dicular to the long axis of the rectum is essential
for accurate assessment of the tumour. Figure 4.1
shows the normal axis of the rectum. The rectum
angles posteriorly and inferiorly rather than
straight down. Mal-alignment of the imaging
field, for example, perpendicular to the vertical
plane, will lead to inaccurate staging. The field
must be perpendicular to the rectal tube as seen in
Fig. 4.1. Incorrect alignment of the imaging field
can have a major influence on pre-operative deci-
sion making.
4.2.2 Endoanal Ultrasound
Endoanal ultrasound is useful in the local assess-
ment of rectal cancer. A recent review comparing
EAUS to MRI did not find one technique superior
4 What Are the Relevant Imaging Factors to Optimize Treatment Decisions?
over the other when assessing rectal cancer pre-
operatively; rather, they are complimentary tech-
niques [1]. Local staging and the usefulness of
EAUS is discussed below. High spatial resolution of
EAUS images is particularly suited to identification
of the structure of the bowel wall. However, whilst
MRIs drawbacks relate to tolerance and compatibil-
ity with the magnet, EAUS is not reliable for certain
types of tumour morphology. For example, the
endoanal technique produces inaccuracy with
stenosing tumours, polypoidal tumours and high
rectal cancer. In addition, it does not demonstrate
fully the mesorectal fascia and thus the proximity of
tumour to the potential circumferential resection
margin. Peritumoral inflammation, fibrosis and fae-
cal material can give the appearance of artefact or
overcall tumour. Accuracy may be further reduced
due to a combination of technical and user errors
including incorrect field alignment, improper bal-
loon inflation, physical or refraction artefacts and if
the tumour is close to the anal verge [2].
Therefore, EUS is severely limited in support-
ing preoperative treatment decisions on the fol-
lowing basis:
1. Inability to identify patients at risk of local
recurrence based on predicted CRM status
2. Limited assessment of bulky and stricturing
tumours and of identifying disease remote
from the lumen within mesorectum
3. Poor accuracy in reassessment of tumour stage
and safety of surgical margins following
chemoradiotherapy or radiotherapy
4.2.3 Computed Tomography (CT)
The use of CT is mainly that of identifying the
possibility of extra-colonic tumour spread and
metastatic deposits. Although it is not used pri-
marily for local assessment of the tumour, it does
provide information on the tumour relationship to
adjacent organs such as the vagina or bladder and
thus pelvic disease. The main advantage of CT is
in assessment of the common sites of metastases,
i.e. lungs, liver and lymph nodes. It has high sen-
sitivity and specificity for identifying tumour
deposits in the liver and lungs. In the past, involve-
ment of these sites has had a negative effect on
clinical outcome in terms of overall survival.
29
Patients with synchronous metastatic disease now
receive systemic chemotherapy and may be con-
sidered for metastasectomy with consequent
improvements in overall survival.
Limitations of CT include poor spatial resolu-
tion which makes identification of the individual
layers of the bowel wall difficult. Tumour depth is
an important consideration in decision making as
regards neoadjuvant therapy, and accurate local
staging is a must. Recent studies have investigated
the use of multi-detector CT as an alternative to
MRI for local staging of rectal cancer [3, 4].
However, results of these studies have not favoured
CT. Although for “higher” rectal tumours CT is
accurate in identifying a potentially involved
CRM, it has poor accuracy for low rectal cancer.
4.3 Local Factors Which Influence
Treatment Decisions
The main risk factors for local recurrence in
rectal cancer are histopathological involvement
of the circumferential resection margin (CRM)
and height of tumour from anal verge. More
recently, the presence of extramural venous inva-
sion (EMVI) has been shown to be a prognostic
factor for poor outcome in terms of both local
and distant failure [5]. In patients undergoing
TME surgery, nodal status no longer predicts
local failure but remains a risk factor for distant
metastases as well as increasing depth of tumour
spread. All these factors can be most accurately
assessed with MRI, although there may be some
role for CT and endoanal ultrasound (EAUS).
4.3.1 Circumferential Resection
Margin (CRM)
One of the main advantages of MRI is in its abil-
ity to accurately identify the mesorectal fascia
which forms the radial margins of excision and
thus the circumferential resection margin in total
mesorectal excision surgery. Local recurrence of
rectal cancer following surgical resection has
been dramatically reduced by the introduction of
total mesorectal excision (TME). Obtaining a
clear circumferential resection margin following
30
TME is the “gold standard” as CRM involvement
is a positive predictive factor for local recurrence.
Whereas histopathological analysis of the resec-
tion specimen provides confirmation of oncolog-
ically successful surgery, knowledge of the
relationship between the tumour and the mesorec-
tum is a mandatory in treatment planning. MRI
has been shown to accurately predict the rela-
tionship between tumour and mesorectal fascia
with a high degree of concordance (92%) with
histology [6].
Tumour spread which threatens the potential
CRM has been shown to be a predictive factor of
local recurrence [7]. It is now generally accepted
that tumour spread within 1 mm of the potential
CRM is a strong influence in local recurrence.
Recent work by Taylor et al. has shown that rates
of local recurrence decreased from 53% with
tumour less than 1 mm from the potential CRM
to less than 8% when the tumour distance from
the mesorectal fascia was between 1 and 5 mm
[8]. Knowledge of the proximity of the tumour to
the mesorectal fascia at an early stage is impor-
tant when planning treatment.
Involvement of the potential circumferential
resection margin may be subdivided and appears
as distinct entities on imaging (Fig. 4.2). It is
therefore important to define the type of threat to
the potential CRM as not all subtypes may be
prognostic. For example, a local well-encapsu-
lated lymph node lying close to the mesorectal
fascia is not associated with an increased risk in
local recurrence [9] (Table 4.1).
Being able to accurately identify tumour
proximity to the mesorectal fascia within a mil-
limetre on MRI has been a challenge. A mea-
sured distance of 5 mm on MRI has been shown
to strongly correlate with negative CRM on his-
tology, which led to patients being offered
chemoradiotherapy when tumours are within
5 mm of the mesorectal fascia. However, this
results in substantial overtreatment of patients
with safe margins. More recently, the MERCURY
Study Group showed that margins could be
identified more accurately and reproducibly
using a 1-mm cut-off [10]. One recent study has
shown that using MRI-based measurement as a
M. Chand and G. Brown
basis for neoadjuvant therapy for CRM positive
tumours reduced the need for CRT by 35% with-
out compromising outcome [11].
4.3.2 Height of Tumour
Rectal cancer is defined in terms of distance from
the anal verge. The rectum is measured as
12–15 cm from the anal verge, and tumours found
within the distal 6 cm are classified as “low” rec-
tal cancers. The distance from the anal verge or
height of the tumour is important due to its ana-
tomical relationships as the rectum leaves the
peritoneal cavity. It is prognostically significant
for local recurrence [12, 13] and anastomotic leak
following surgery [14, 15].
Traditional assessment of the height of tumour
was done using a combination of digital rectal
examination and rigid sigmoidoscopy. Both these
methods can be greatly inaccurate. The level of the
tumour has implications on surgical planning and
may be the difference between performing an
anterior resection or abdominoperineal resection
or deciding to create a defunctioning stoma. In this
regard, demonstrating the relationship between the
tumour and pelvic floor as well as the sphincter
complex is vital. In the era of laparoscopic surgery,
many surgeons find laparoscopic rectal cancer
resection for low tumours inappropriate, so accu-
rate objective identification of tumour height is
important, particularly the distance between the
distal edge of the tumour and the puborectal sling.
Axial images on MRI can clearly demonstrate
the level and longitudinal spread of the tumour
(Fig. 4.1). However, correct field alignment is
imperative and taking images through a plane
which is not exactly 90° to the long axis of the
rectum and over- or under-call tumour height.
4.3.3 Extramural Venous
Invasion (EMVI)
Invasion of extramural veins has been identified
as a poor prognostic factor for overall survival
and, more recently, local recurrence [1, 2]. This
4 What Are the Relevant Imaging Factors to Optimize Treatment Decisions? 31

a b

Fig. 4.2 (a) Grade 2 EMVI on MRI. (b) Grade 3 EMVI. (c) Grade 4 EMVI. The red arrows indicate the extent of
venous invasion

is independent of tumour stage. The definition
of EMVI is the presence of malignant cells
within the endothelial-lined blood vessels
beyond the muscularis propria. It can occur in
up to 50% of rectal cancer patients. EMVI can
be identified pre-operatively on MRI with great
accuracy [3]. Knowledge of the appearances
and position of normal rectal vasculature is
important to be able to accurately identify
EMVI.
32 M. Chand and G. Brown

Table 4.1 Subtypes of histopathology CRM involvement of the UICC TNM classification. Depth of extra-
Type of spread Frequency (%) mural invasion is recognized as an independent
Direct tumour spread 18–29 prognostic factor [1, 2]. Within the broad T-stage
Discontinuous spread 14–67 classification, there are certain groups of patients
Lymph node metastases 12–14 who are considered high risk and thus may benefit
Venous invasion 14–57 from adjuvant therapy. This has led to a sub-
Lymphatic invasion 9 classification of T-stage. For example, T3 tumours
Perineural spread 7–14 can be further classified according to maximal
tumour invasion beyond the outer border of the
Table 4.2 MRI classification of EMVI muscularis propria – into the mesorectum. T4
MRI- tumours can be further classified depending on
EMVI the presence of invasion into adjacent organs with
score EMVI status Description or without perforation of visceral peritoneum [3].
0 Negative No vessels adjacent to areas A more detailed discussion of T sub-staging will
of tumour penetration be addressed in further chapters.
1 Negative Minimal stranding but well
Accurate assessment of this relies on the
away from vessels
2 Negative Stranding within vicinity of
identification of the layers of the bowel wall. A
vessel but no definite tumour meta-analysis of almost 5,000 patients compar-
signal ing accuracy of T-staging between MRI, CT and
3 Positive Intermediate signal within EAUS showed 84%, 73% and 87%, respectively
slightly expanded vessel [4]. Although this would suggest greater accu-
4 Positive Irregular contour of vessel by racy with EAUS, MRI techniques have improved
definite tumour signal
since, and it has the advantage in being able to
evaluate the peri-rectal structures and not be lim-
Using high spatial resolution MRI, veins are ited by access or user problems. EAUS may be
identified as serpiginous or tortuous linear struc- more useful for T1 and T2 tumours where accu-
tures on T2-weighted images. The depth of inva- rate identification of the mesorectal fascia has
sion of the tumour bears relevance as a tumour less importance, particularly if the lesion is ame-
limited to the muscularis propria will not be able to nable to local resection.
spread into extramural veins. Essentially, this An understanding of the MRI appearances of
means that EMVI positive tumours will be T-stage normal rectal anatomy is essential to appreciate
3 or 4. Assessment of EMVI using MRI must con- tumour depth and spread. MRI can readily iden-
sider the following components: pattern of tumour tify the layers of mucosa and muscle through dis-
margin which gives the appearance of nodularity, tinct signal characteristics. T2-weighted images
location of tumour to relevant vessels which makes are particularly useful for this. The mucosal layer
tumour invasion more likely, calibre of vessel as is seen as a very fine line of low signal intensity
tumour infiltration can cause an increase in lumi- overlying the much thicker and higher signal of
nal size, and vessel border if the tumour disrupts the submucosa (Fig. 4.3). Outside this, the mus-
the vessel itself [4]. Table 4.2 shows classification cularis propria can be seen as a dual layer repre-
of EMVI in rectal cancer. Extension of the primary senting the inner circular and the outer longitudinal
tumour into a vascular structure indicates EMVI. muscle layers. The latter has a typically irregular
appearance due to vessels traversing the rectal
wall. The peri-rectal fat is identified as a high sig-
4.3.4 T-Staging nal with signal void areas surrounding the rela-
tively low signal intensity of the muscularis. This
Staging of rectal cancer involves determining the is all enveloped by the fine layer of low signal
depth of invasion of the tumour in relation to the intensity representing the mesorectal fascia – the
composition of the bowel wall and makes up part defining plane of the TME.
4 What Are the Relevant Imaging Factors to Optimize Treatment Decisions? 33

indicate T3 spread, as this more commonly repre-

sents small vessels penetrating this layer
(Fig. 4.4).
More recently, importance has been given to the
extent of tumour growth beyond the muscularis into
the mesorectal fat. Patients who have tumours

Fig. 4.3 MRI axial image showing tumour relationship to

the mesorectal fascia

Table 4.3 MRI T-staging of rectal cancer

T-stage Description
1 Low signal in submucosal layer but no
signal abnormality in the circular muscle
layer
2 Intermediate signal intensity within muscle.
No extension of signal abnormality into the
peri-rectal fat b
3 Broad based bulge or nodular projection of
intermediate signal intensity projecting
beyond outer muscle coat
4 Extension of abnormal signal into adjacent
organ or peritoneal reflection

The MRI T-staging of rectal cancer is shown

in Table 4.3. Determining the T-stage of the
tumour depends on careful assessment of the
images with respect to the signal characteristics
and correct field alignment. Abnormal or unex-
pected signal intensity in the bowel wall layers
defines the T-stage. Of particular importance are
the characteristics of T3 tumours. A T3 tumour
must demonstrate invasion beyond the muscu-
laris propria into the peri-rectal fat. This is seen
as a bulging projection into the high signal layer
of the peri-rectal fat. Small irregularities along Fig. 4.4 (a) T1 lesion on MRI. (b) T2 lesion on MRI. (c)
the border of the muscularis does not necessarily Subclassification of T3 lesions. (d) T4 tumour
34 M. Chand and G. Brown

70.5

Fig. 4.4 (continued)

4 What Are the Relevant Imaging Factors to Optimize Treatment Decisions? 35

Table 4.4 Bowel wall layers in EAUS

d
Layer of Signal
bowel wall Description characteristic
Superficial The layer between the Hyperechoic
mucosa probe and the superficial
mucosa
Mucosa/ Second layer of bowel Hypoechoic
muscularis wall
mucosae
Submucosa Interface between Hyperechoic
mucosa and submucosa
Muscularis Fourth layer outside Hypoechoic
propria submucosa
Serosa The layer between the Hyperechoic
serosa and peri-rectal fat

Fig. 4.4 (continued)

which show greater invasion into the mesorectum

(>5 mm) have been shown to have lower 5-year sur-
vival and is independent of lymph node involve-
ment [2]. Those patients whose tumours demonstrate
less than 1 mm invasion into the mesorectum have
a favourable prognosis [1]. This has led to a sub-
classification of T3 tumours. Local recurrence rates
are similar in patients staged T2 and T3a, whereas
rates significantly differ between T3a and T3b –
this is independent of lymph node status [5]. MRI is
not particularly accurate in separating T1 and T2
tumours and in distinguishing sessile or polypoid
adenomas from T1 lesions. EAUS in comparison is
highly accurate in assessment of these tumours [6].
Similar to the images produced by MRI,
EAUS identifies different signal characteristics to
correspond to the layers of the bowel wall. Five
alternate layers of hyper- and hypoechoic rings
are produced from the differences in acoustic
impedance. A carcinoma is seen as an irregular
hypoechoic mass which disrupts the normal ana-
tomical layers. The extent of this disruption
determines the depth of invasion and this T-stage.
The normal anatomy is shown in Table 4.4.
EAUS has increased accuracy for defining the
detail of the bowel wall structure which is particu-
Fig. 4.5 Endoanal ultrasound demonstrating layers of
bowel wall
larly useful when planning mucosal resection or
transanal excision. Sensitivity and specificity for
T1 cancers is 87.8% and 98.3%, respectively [7].
As transanal endoscopic microsurgery (TEMS)
and endoscopic submucosal resections become
more popular, greater detail of the bowel wall is
essential to select appropriate patients. Assessing
whether a tumour has breached the submucosa
becomes an important decision, and other imaging
modalities may not be as accurate as EAUS. EAUS
may be particularly useful in distinguishing T2
from T3a tumours, more so than MRI. However,
whether this is relevant in terms of oncological
treatment is debatable. This is discussed in more
detail in future chapters (Fig. 4.5).
36
4.3.5 Nodal Staging
Identifying nodal involvement has traditionally
been a difficult issue. Suspicious appearance of
local nodes can be due to size or differences in
signal characteristics. The problem with using
size is defining a cut-off number. A more sophis-
ticated method may be identifying particular sig-
nal characteristics. MRI criteria involve
identification of spiculated or indistinct lymph
node borders as well as mottled heterogeneous
signal intensity which may predict nodal involve-
ment [8]. More recently, the use of specific par-
ticles unique to normal lymph nodes as compared
with cancerous nodes which are identifiable on
MRI has been used, although further study is
required – Ultra-small Superparamagnetic
Particles of Iron Oxide (USPIO) [9]. As a whole,
MRI, EAUS and CT show sensitivity and
specificity for detection of malignant lymph
nodes to be between 55% and 78%, respectively
[10, 11].
EAUS does not predict lymph node involve-
ment any better. Sensitivity and specificity for
detection of cancerous lymph nodes in rectal
cancer is 73.2% and 75.8%, respectively [12],
although more likely to be accurate in the more
proximal parts of the rectum. Swollen reactive
nodes, small blood vessels and even local struc-
ture such as the seminal vesicles may mimic
malignant nodes.
Fig. 4.6 Nodal assessment on MRI
M. Chand and G. Brown
Location of lymph nodes may be an important
consideration. Lymph nodes distal to the tumour
are rarely involved. Similarly, the sparing of
extra-mesorectal lymph nodes is helpful in under-
standing the signal characteristics of malignant
nodes. A contentious issue has been the relevance
of lymph nodes to the mesorectal fascia. Shihab
et al. showed that a solitary lymph node in close
proximity to the mesorectal fascia and therefore
involvement of the CRM is uncommon [13]
(Fig. 4.6).
4.4 Distant Factors
The presence of distant disease not only has an
implication on oncological therapy but also tim-
ing of treatment. Knowledge of hepatic metasta-
ses may lead to deferral of rectal surgery, for
instance. Common sites of metastases include
liver, lung, bones and adrenal glands. CT exami-
nation of the chest, abdomen and pelvis is man-
datory. For most patients, CT will be sufficient to
examine the extent of extra-abdominal disease.
However, indeterminate lesions of the liver or
lungs may require furthermore detailed imaging
to exclude metastases. Additional anatomical
information may also be needed for surgical plan-
ning of metastasectomy.
4.4.1 Hepatic Metastases
Accurate imaging of the liver is of vital impor-
tance in the optimal management for rectal can-
cer. Metastatic involvement of the liver can have
a profound effect on treatment decisions both in
terms of oncological therapy and surgery. Ideally,
liver imaging should provide the following:
• Accurate delineation of the anatomical distri-
bution of metastases to facilitate planning of
potential surgical resection
• Presence or absence of widespread micro-
metastatic disease within the liver
• Presence or absence of extra-hepatic disease
• Discrimination between benign and malignant
liver lesions
• A method of road mapping lesions to ensure a
margin of greater than 10 mm
4 What Are the Relevant Imaging Factors to Optimize Treatment Decisions?
Fig. 4.7 CT and PET-CT of liver metastases
It is important to appreciate that it is unlikely
that a single imaging modality will be able to
satisfy all the above questions; however, it is impor-
tant to select an appropriate combination of sequen-
tial imaging techniques to optimize outcome.
4.4.1.1 CT
CT exploits the relative hypovascularity of
hepatic metastases compared with normal liver
parenchyma and has accuracy rates of up to 85%
[14]. The use of multi-detector CT can be highly
accurate in demonstrating liver lesions (Fig. 4.7).
The entire liver can be imaged within 10 s during
several phases of hepatic enhancement. Liver
metastases are seen as hypodense lesions with
complimentary rim enhancement. Larger lesions
may exhibit signs of central necrosis such as a
central low density ‘cystic nidus’.
Differentiating metastases from benign lesions
is more straightforward for larger lesions as they
are well defined and lack rim enhancement. Smaller
lesions, particularly less than 10 mm, are more
difficult to characterize, but the same principles of
37
Fig. 4.8 MR image showing same liver metastases
margin definition and rim enhancement apply [15].
Haemangiomas enhance peripherally in a nodular
fashion and persistence of enhancement [16].
Artefact can produce occasional wedge-shaped
defects; however, assessment of these areas on the
pre-contrast images can usually avoid confusion.
4.4.1.2 MRI
MRI assessment includes T1- and T2-weighted
images with a contrast medium such as gadolin-
ium providing sufficient anatomical detail, delin-
eating perfusion defects seen on CT images from
fatty infiltration. Differentiating benign liver
lesions from malignant ones is an important abil-
ity of MRI. Specific contrast agents are taken up
by functioning Kupffer cells and are seen as dark-
ened areas on MR imaging. Mangafodipir triso-
dium (Mn-DPDP) is taken up by functioning
hepatocytes and leads to an elevation in signal
intensity of T1-weighted images of normal liver
parenchyma within 10 min of injection. There is
a 400% increase in conspicuity between the
hypointense hepatic metastases and the surround-
ing normal liver tissue [17]. It is important to be
able to distinguish metastases from haeman-
giomas, fatty infiltration and cysts (Fig. 4.8).
4.4.2 Extra-hepatic Disease
Patients who demonstrate single metastases in
one lobe only are much less likely to have
unrecognized irresectable disease when
38
compared with those patients with multi-lobar
metastases [18]. Although laparoscopy may be
a useful tool in assessing the presence of extra-
hepatic disease, a combination of CT and PET
scanning are more common.
PET imaging with 18-fluoro-2-deoxyglucose
(FDG) has been shown to have the greatest poten-
tial in detecting extra-hepatic disease not found
on conventional imaging [19]. Tumour tissue can
be detected on the basis of its increased glucose
utilization which is characteristic of malignant
cells. Sensitivity to tissue glucose metabolism
allows differentiation from equivocal lesions.
Upstaging of disease resulting in a change in sur-
gical management can be seen in up to 40%, and
this is more sensitive than contrast-enhanced CT
[20]. Its role in the evaluation of liver disease is
well defined, but it remains inferior to MRI,
which is the most effective imaging modality for
liver anatomy [21]. One of the drawbacks of PET
imaging has been its lack of spatial resolution
and anatomical detail. The solution to this has
been a single examination combining PET and
CT. PETCT is most useful in detecting small
mesenteric or peritoneal disease not apparent on
CT. It has been shown to reduce the rate of recur-
rence in patients undergoing hepatic resection for
colorectal metastases [12].
One of the limitations of PET is the false-pos-
itive rate. This is particularly the case with granu-
lomatous disease and inflammatory processes of
the lung. False-negatives can be diagnosed in
lesions less than 1 cm in size, as well as micro-
metastatic disease in lymph nodes.
4.5 Summary
A shift of strategy has become apparent in recent
years with more efforts being concentrated on
pre-operative rather post-operative oncological
therapy. Implementing successful neo-adjuvant
treatment relies on prognostic and predictive
factors of outcome being known early in diagno-
sis. This has led to increased importance in
accurately identifying these factors at an early
stage. An improvement in the quality of imaging
modalities has led to increasingly more subtle
M. Chand and G. Brown
tumour features being identified, thus giving cli-
nicians more information to base treatment deci-
sions. This also highlights the advantages of a
multi-disciplinary approach to cancer.
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factors – the circumferential resection margin and nodal
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assessment of lymph node involvement with endolu-
minal US, CT, and MR imaging – a meta-analysis.
Radiology 232(3):773–783
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sound to diagnose nodal invasion by rectal cancers: a
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detected lymph nodes close to the mesorectal fascia
are rarely a cause of margin involvement after total
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tern-based classification scheme for enhancement at
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17. Young SW et al (1990) Detection of hepatic malig-
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 What Biochemical and Molecular
Biological Factors Have Greater 5
Relevance to Treatment Decisions?

Guido Lammering and Jeroen Buijsen

Contents 5.1 Introduction

5.1 Introduction ................................................... 41
The current standard therapy for rectal cancer in
5.2 Biochemical and Molecular Biological
Factors for Radiochemotherapy .................. 42
most countries around the world consists of a pre-
operative treatment either with long-term radio-
5.3 Biochemical and Molecular Biological
therapy (RT) and a 5-FU-based chemotherapy
Factors for Surgical Decisions...................... 44
(CT) or a short course RT followed by
5.4 Biochemical and Molecular surgery or surgery alone, depending on the pre-
Biological Factors for Adjuvant
and Systemic Therapy .................................. 45 therapeutic staging resulting in a 5-year cumula-
tive rate of local relapse of less than 10% and an
References ................................................................. 47
incidence of distant metastases of about 35%
[2, 27]. The preoperative treatment has a major
impact on local control, however, with only mini-
mal impact on survival and disease-free survival.
So far, no clear evidence has been produced for
the benefit of adjuvant chemotherapy, leading to
different protocols in different countries and
regions around the world. Generally, all parts of
the current standard treatment of rectal cancer
have its toxicity profiles. Preoperative chemora-
diotherapy (CRT) can lead to diarrhoea, radiation
dermatitis and increased risk for anastomotic
leakage and perineal wound complications [29],
while short course radiotherapy generally
increases the risk for faecal incontinence, anal
blood loss, mucus loss and erectile dysfunction
[18, 28]. The surgical treatment itself is generally
accompanied with an increased risk for urinary,
bowel and erectile dysfunction, anastomic leak-
age, perineal wound complications and a mortality
G. Lammering (*) • J. Buijsen rate of 4–11%, depending on age and co-morbid-
Maastro Clinic, 1345, 6201 BH,
ity [12, 21]. Thus, all treatments come with a
Maastricht, The Netherlands
e-mail: guido.lammering@maastro.nl; price to pay, namely, the risk for over- or under-
jeroen.buijsen@maastro.nl treatment based on the current imaging-related

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 41

DOI 10.1007/978-3-642-25005-7_5, © Springer-Verlag Berlin Heidelberg 2012
42
treatment decisions leading to probably unneces-
sary toxicities and subsequently impact on quality
of life [8, 26]. However, rectal cancer is a biologi-
cal tumour, characterized by several biological
features, which are nowadays better and better
understood. Dramatic technical improvements in
detection assays have made it possible to charac-
terize more and more biochemical and biological
features and phenotypes related to individual rec-
tal cancer patients. Thus, biological markers
might be able to better tailor the treatment of rec-
tal cancer, thereby minimizing the risk for over-
and undertreatment with also an improvement in
outcome and quality of life. However, this needs
prospective evaluation and stringent validation. It
is clear that there is a biological basis for the dif-
ferent responses of individual tumours to certain
treatments, like CRT, RT and CT. The tumour
microenvironment, e.g. angiogenesis and hypo-
xia, repopulation and the intrinsic radiosensitivity
are currently the best known biological tumour
phenotypes, which undoubtedly have an impor-
tant impact on the degree of response to anti-
tumour treatments [11].
This chapter will focus on the question where
we are now in the detection and analysis of bio-
chemical and biological factors influencing treat-
ment decisions and how far we have already
come in our attempts to better individualize treat-
ment based on biomarkers.
Section 5.2 will give an update on the current
knowledge on biomarkers in treatment deci-
sions for neoadjuvant RT and CRT. Section 5.3
will focus on biomarkers for surgical treatment
decisions, while Sect. 5.4 will discuss the bio-
markers known to influence decisions for the
adjuvant and systemic treatment of rectal can-
cer. Finally, Sect. 5.5 will provide a conclusion
and a perspective.
5.2 Biochemical and Molecular
Biological Factors for
Radiochemotherapy
The combination of chemotherapy and radiother-
apy leads to some degree of pathological down-
staging in approximately 40–60% of patients.
G. Lammering and J. Buijsen
The percentage of patients developing a patho-
logical complete response (pCR) varies, but lies
typically around 20%. In treatment decision mak-
ing, it would be very helpful to identify good and
poor responders in order to give a tailored treat-
ment. Until now, the predictive value of several
biomarkers has been studied. In these studies,
various endpoints have been used, but the most
common endpoints are overall survival, tumour
regression grade (TRG), pCR and downstaging.
Kuremsky et al. published a review evaluating
the potential of genetic biomarkers in predicting
the outcome of locally advanced rectal cancer
patients treated with chemoradiation [9]. In their
review, they focused on gene products with more
than five studies in the literature. The six bio-
markers that met this criterion were p53, epider-
mal growth factor receptor (EGFR), thymidylate
synthase (TYMS), Ki-67, p21 and bax/bcl-2.
The most studied marker is p53, a gene that
plays a key role in apoptosis, tumorigenesis and
sensitivity to chemotherapeutic agents. Twenty-
one studies studying the predictive value of p53
status were identified. Seventeen of these stud-
ies could not identify a correlation between p53
expression and tumour response. Of the four
studies that did show a relationship between
p53 and outcome, three identified a p53 muta-
tion as a predictor of poor response, whereas the
other study found a positive predictive value for
mutated p53. Therefore, p53 does not seem to
be a good predictor for tumour response to
chemoradiation.
EGFR is important in the regulation of various
cellular responses, like proliferation, apoptosis
and differentiation. Overexpression of EGFR has
been shown in 60–80% of all colorectal cancers
and has been associated with a poor prognosis
independent of lymph node status. Five studies
have been published studying the value of EGFR
expression as response predictor. These were
studies looking at chemoradiation only, without
addition of EGFR inhibitors. Although these
studies looked at different endpoints, the studies
that found a correlation all point towards a better
response to chemoradiation in tumours with low
EGFR expression. It seems to be more important
to quantify the level of EGFR expression rather
5 What Biochemical and Molecular Biological Factors Have Greater Relevance to Treatment Decisions?
Good-risk group
TYMS
*2/*2,*2/*3,
*2/*4
T3/T4
Rectal TYMS genotyping
Cancer
TYMS
*3/*3,*3/*4
Staging
Poor-risk group
(TRUS, CT, MRI)
Biopsy
Fig. 5.1 Design of a phase II trial stratifying rectal cancer patients in good- and poor-risks according to TYMS status
than divide tumours into positive or negative. One
study identified a single nucleotide polymorphism
that may be useful as a biomarker for response.
Thymidylate synthase is an important enzyme
in DNA synthesis and is the main target of
5-fluorouracil (5-FU). Overexpression of this
enzyme leads to 5-FU resistance. Nine studies
were identified in the Kuremsky review analysing
the influence of TYMS expression and SNPs in
the TYMS enhancer region on tumour response,
and very recently, two additional studies have
been published. Four studies used immunohis-
tochemical staining, and five studies used PCR
for genotyping. Three studies did not show a cor-
relation between TYMS and tumour response.
The remaining six studies found in general a bet-
ter response to chemoradiation in tumours with
low TYMS expression. Two studies also included
a group of patients treated with radiotherapy only,
and as could be expected in this group, no corre-
lation between TYMS expression and response
was observed. Only one study found an inverse
correlation; however, this was a small study with
only 19 patients, who received both 5-FU and
oxaliplatin, which could have confounded the
results. Recently, however, two studies found a
correlation between high expression of TYMS
and better response after CRT for rectal cancer
[10, 17]. Although there is not enough evidence
to use TYMS in daily practice, incorporation of
TYMS expression measurements in chemoradio-
therapy trials would be worthwhile. Recently, the
results of a phase II study have been published in
which patients were stratified in a good-risk
group (no TYMS overexpression) and a poor-risk
43
Surgical Resection
RT 45 Gy
FU 225 mg/m2/day
RT 45 Gy
FU 225 mg/m2/day
Cpt-11 50 mg/m2
q wk × 5
Staging
(TRUS, CT, MRI)
group (TYMS overexpression) (Fig. 5.1) [31].
The good-risk group was treated with standard
chemoradiation consisting of radiotherapy and
continuous 5-FU infusion, while the poor-risk
patients received weekly irinotecan in addition to
standard chemoradiation. A pCR and tumour
downstaging was found in 18.9% and 64.4% of
good-risk patients, respectively, and in 35.5%
and 64.5% of poor-risk patients. However, the
combination with irinotecan turned out to cause
more toxicity. RFS and OS were comparable
between both risk groups. This study is the first
attempt to stratify the treatment of rectal cancer
patients according to TYMS status. Although
further phase III trials are needed, it was remark-
able that the proportion of patients showing
downstaging was comparable between the good-
and poor-risk group and the percentage that
developed a pCR was higher in the poor-risk
group.
Ki-67 is a proliferation marker which has not
shown a clear relationship with chemo- or radio-
sensitivity. Thirteen articles have been published
about the predictive value of Ki-67, of which
only 2 showed a correlation. One study found a
better response in tumours with high Ki-67 stain-
ing; the other showed an association between low
Ki-67 expression and response. Therefore, Ki-67
is not a good biological marker in rectal cancer.
The tumour suppression gene p21 is activated
by DNA damage and causes cell cycle arrest. Four
of eight studies found a correlation between p21
expression and response to chemoradiation.
However, the results of these four studies are
conflicting. Two studies found better responses or
44
survival in patients with low or negative p21
expression, while the other two studies found the
opposite. Based on in vitro studies, one would
expect better results in tumours with low p21
expression because p21 suppresses apoptosis in
case of DNA damage. The two studies which
showed better results in positive p21 tumours used
other treatments in addition to radiotherapy and
5-FU which may have confounded the results.
The bax and Bcl-2 proteins are involved in
apoptosis. Loss of bax function is correlated with
chemoresistance in colorectal cancer, and Bcl-2
overexpression has been linked with resistance to
different chemotherapeutic agents and inhibition
of radiation-induced apoptosis. Three studies
evaluated the role of bax expression in response
to chemoradiation. Only one study found a
significant correlation. In that study, the percent-
age of bax-positive tumours was significantly
higher in the complete-response group than in the
partial-response group (54% vs. 29%). Bcl-2 was
analysed in 12 studies, but a correlation with
response was found in only one study including
only 17 patients.
Two rather small studies have tested the value
of microarray in prediction of response. The first
study tested 54 genes in 23 patients. A different
expression pattern was found between respond-
ers and non-responders based on downstaging,
but this difference was no longer significant if
response evaluation was based on TRG. The neg-
ative predictive value (NPV) was 86%, and the
positive predictive value (PPV), 78%. The second
study included 43 patients and found 42 genes that
were differentially expressed between respond-
ers and non-responders based on TRG. The PPV
using this gene set was 71% and the NPV 86%.
Although these studies show for the first time
that gene expression profiles may be helpful in
response prediction, they certainly need further
validation with larger patient groups.
Quite recently, X-ray repair cross-comple-
menting 1 (XRCC1) has been identified in three
studies as a potential useful marker for response
prediction in rectal cancer [4, 10, 17]. XRCC1
plays an important role in DNA repair as it is
involved in the base excision repair (BER) path-
way. One polymorphism, A399G, has been
G. Lammering and J. Buijsen
shown to have a predictive role in radiosensitivity
of malignant tumours. The first study included 81
patients with locally advanced rectal cancer
treated with chemoradiation. Of the patients with
an AG phenotype, 47% showed a major response,
as compared to 22% in the AA and GG pheno-
type group. The second study analysed 93 patients
treated with chemoradiation for rectal cancer.
Genotyping was done on peripheral blood mono-
cytes. They found a better response in G/G carri-
ers as compared with G/A carriers (OR 4.180;
p = 0.003). In the third study, DNA from mono-
cytes of 128 rectal cancer patients was analysed.
In this study, no statistical significant association
with tumour response was found. In conclusion,
results of XRCC1 as a predictor of response in
rectal cancer are conflicting.
Another protein that attracted interest in the
past years is survivin, an inhibitor of apoptosis
[7, 16, 25]. Again, results are conflicting. Two
recent studies reported a correlation between sur-
vivin expression and tumour response. Higher
survivin expression correlated with worse
response to chemoradiation. One of these studies
compared survivin expression in pretreatment
biopsies and surgical resection specimens and
found a worse survival in patients with tumours
expressing high levels of survivin after chemora-
diation. However, other studies could not find a
correlation between survivin expression and clin-
ical outcome, which underlines the need for fur-
ther studies.
5.3 Biochemical and Molecular
Biological Factors
for Surgical Decisions
The surgical treatment strategy for rectal cancer
has dramatically changed over the last years.
Coming from a standard radical surgical proce-
dure performed in strictly defined TME protocols
with only radicality being the primary goal, it
nowadays changes to a more tailored approach
with also the aim to reduce toxicity with better
quality of life. The surgical treatment usually
takes place initially after diagnosis in early stage
cancer or after a neoadjuvant treatment consisting
5 What Biochemical and Molecular Biological Factors Have Greater Relevance to Treatment Decisions?
of either radiotherapy alone (5 × 5 Gy) or RCT. In
case of a neoadjuvant treatment, a short-course
radiotherapy will usually be followed within
1–3 days by an immediate surgical resection of
the TME, as has been published by the DUTCH
TME trial [6]. Thus, the short-course radiother-
apy does not induce any downsizing or down-
staging, since the timing of the followed surgical
replacement of the rectum tumour does not allow
any tumour shrinkage [15]. However, newer trials
have suggested that the short-course preoperative
radiotherapy indeed could be used to also down-
size and downstage the tumour, if the surgical
treatment is postponed by at least 6–8 weeks after
radiotherapy [19, 22]. This strategy might
increase the potential for better sphincter- and
even organ-sparing surgical treatment techniques,
etc., as has been already proposed after neoadju-
vant chemoradiotherapy in selected patients [14].
However, accurate tumour response assessment
is crucial in these modern adaptive surgical strat-
egies after neoadjuvant radio- or radiochemo-
therapy. Biomarkers could help in the treatment
decisions for less aggressive conservative surgi-
cal treatments, beside modern imaging and clini-
cal examinations. This applies not only for
preoperatively pretreated rectal cancer patients
but also for initially diagnosed patients, in which
early stage disease is suggested. These patients
could benefit from conservative surgery (e.g.
TEM) instead of radical surgery, if accurate bio-
markers associated with disease progression, par-
ticularly mesorectal nodal metastasis, would
become available.
One recently published study compared pat-
terns of gene-specific hypermethylations in radi-
cally excised rectal cancers with histopathological
stage and came to the conclusion that locus-
specific hypermethylation was more prevalent in
early- than late-stage disease and that the hyper-
methylation of two or more of a panel of five
tumour suppressor genes was associated with
localized disease [13]. Another study by Rasheed
et al. assessed the microvessel density (MVD)
and the CA9 expression in more than 100 rectal
cancer specimen and came to the conclusion that
the MVD was higher in more advanced T and N
stages, whereas the CA9 expression was generally
45
higher in earlier stages [23]. This however has
not been validated yet and warrants further evalu-
ation. Generally, the only molecular markers
being currently prognostically relevant in rectal
cancer are the deficient mismatch repair and pos-
sibly the KRAS mutation and the BRAF muta-
tions. All else, like expression assays, copy
number variation tests and even proteomics is
experimental and have not shown any validated
correlation with prognosis yet. The recently
published analysis of the QUASAR study, which
mainly analysed stage II cases, showed MMR,
KRAS or BRAF abnormalities in rectal cancer in
1–4%, 30–35% and 2–3%, respectively [5]. All
three abnormalities had prognostic impact at dif-
ferent levels, with MMR being the strongest
marker for prognostic impact. The defective
MMR genes were hMLH-1, hMSH-2 PMS-2 and
hMSH-6, detected by either immunohistochem-
istry or microsatellite testing. However, up until
now, no biomarkers have reached the level of
clinical relevance which would allow inclusion in
surgical decision making. Recently, the first
cohort analysis of 20 patients selected for a non-
surgical wait-and-see strategy after RCT has been
published with very promising local and distant
controls [14]. The decision making for such a
non-surgical approach in patients with good to
complete clinical response after RCT, which is
currently only based on clinical and imaging
parameters due to the lack of sufficient biomark-
ers, should be stepwise improved with also bio-
chemical and molecular markers, as soon as they
have been approved and validated.
5.4 Biochemical and Molecular
Biological Factors for Adjuvant
and Systemic Therapy
The value of adjuvant chemotherapy in node-pos-
itive colon cancer is clear. Since rectal tumours
originate in an organ that is in anatomic continuity
with the colon and tumours show a similar histol-
ogy, it is often argued that results of adjuvant trials
in colon cancer can be translated to rectal can-
cers. However, until now, randomized trials in
rectal cancer have failed to show a clear benefit of
46
adjuvant chemotherapy [3]. Especially in patients
who have a good response after preoperative
chemoradiation, the expected gain of adjuvant
treatment is small. Recently, data of five large rec-
tal cancer trials including chemoradiation have
been pooled to build nomograms for the prediction
of local and distal recurrence as well as survival.
This analysis confirms that in patients showing a
good response after chemoradiation, the added
benefit of adjuvant chemotherapy is small [32].
Biomarkers could be helpful to identify
patients who are at higher risk for recurrent dis-
ease. When looking at the value of biomarkers, it
is important to distinguish prognostic from pre-
dictive factors. A prognostic factor gives infor-
mation about the risk of recurrence of disease
irrespective of a certain treatment, while a predic-
tive factor predicts the chance that a patient will
benefit from a treatment. Of course, a marker can
be both prognostic and predictive.
In colorectal cancer, most evidence is available
for the prognostic value of mismatch repair (MMR)
gene status. Tumours that are MMR deficient have
a better prognosis. There is some debate whether
MMR status also has a predictive value. However,
the proportion of rectal tumours that is MMR
deficient is small (around 1%). Therefore, it is not
a useful marker for rectal cancer.
The role of BRAF status seems to have a pre-
dictive value, but the debate is going on about a
possible predictive role. Because the proportion of
rectal tumours carrying a BRAF mutation is very
low, BRAF does not seem to be a very important
biomarker in rectal cancer.
KRAS status also has been shown to be of prog-
nostic value. In about 40% of all rectal tumours,
KRAS is mutated. KRAS mutant tumours have a
poor prognosis and a higher chance of recurrence.
In the QUASAR trial, this difference was even
more pronounced for tumours located in the rec-
tum as compared to tumours in other parts of the
colon. In this trial, the reduced risk of recurrence
with chemotherapy was comparable between
KRAS wild-type and KRAS-mutated tumours.
Other studies also found that KRAS has a prognos-
tic but not predictive value [30]. However, for the
prediction of response to EGFR inhibitors, KRAS
status has a predictive value. This has been
G. Lammering and J. Buijsen
confirmed for metastatic colorectal cancer in a
recent meta-analysis [1].
Conclusion and Perspective of Biomarkers for
Treatment Decisions
Biochemical and molecular biological factors
could help in treatment decision making along
the different treatment steps in the treatment of
rectal cancer. This would allow more tailored
treatment approaches, thereby improving qual-
ity of life with even the benefit of more effec-
tive treatments. When analysing the current
value of these biomarkers in treatment decision
making, it is important to identify markers as
being prognostic or predictive or even both. In
rectal cancer, the only markers reaching clini-
cal relevance in prognosis so far are deficient
MMR, KRAS and BRAF; however, its fre-
quency in rectal cancer is rather low with only
1–4% deficient MMR, 30–35% KRAS muta-
tion and 2–3% BRAF mutation (QUASAR).
The defective MMR genes hMLH-1, hMSH-2,
PMS-2 and hMSH-6, detected by immunohis-
tochemistry or by microsatellite testing,
showed a prognostic value in a meta-analysis
[20], in the PETACC trial [24], the QUASAR
and numerous single-centre studies, which
might lead to MMR-related treatment deci-
sions in the near future. KRAS status has also
been shown to be of prognostic value. KRAS
mutation tumour has a worse prognosis and a
higher chance of recurrence. For EGFR-
inhibitor therapy, the KRAS status even reaches
a predictive value.
With regard to prediction, six genetic bio-
markers were identified with the potential of
being predictive in the outcome of locally
advanced rectal cancer after CRT. These were
p53, EGFR, TYMS, Ki-67, p21 and bax-bcl-2.
While EGFR expression levels seem to pro-
vide some prediction to CRT response, p53
does not seem to serve as a good predictor, nei-
ther does Ki-67 or p21 nor bax and Bcl-2.
TYMS expression measurements are worth-
while to further study in future trials, while
survivin showed mostly conflicting results and
gene expression profiles with microarrays need
further validation with larger patient groups.
5 What Biochemical and Molecular Biological Factors Have Greater Relevance to Treatment Decisions?
Taken together, the current value of bio-
chemical and molecular biological factors in
treatment decision making is rather low, how-
ever, with many promising developments in
the pipeline. Especially whole genome DNA
or RNA analysis with copy number variation,
multiple mutation testing, full sequencing and
the association of genotype with phenotype,
will ultimately lead to more biomarker-based
treatment decisions in rectal cancer. However,
successful biomarker development needs col-
laboration, external validation and meta-analy-
ses to reach the level of accuracy necessary to
base treatment decisions on these markers.
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 Do Different Populations of Rectal
Cancer Exist? 6
Vincenzo Valentini, Francesco Cellini,
Maria Cristina Barba, and Ruud van Stiphout

Contents The impact of new treatments for rectal cancer

6.1 Is It Possible to Obtain an Adequate has substantially improved patients clinical out-
Characterization of Tumour comes in the last years, but still worldwide col-
Heterogeneity, Based on Biological orectal cancer remains the third most common. In
Evidences?..................................................... 50 2000, colorectal cancer was responsible for 7.9%
6.2 Is It Possible to Obtain an Adequate of the world’s cancer deaths, with 492,000 deaths;
Characterization of Tumour it accounted for 9.4% of the world’s new cancers
Heterogeneity, Based on Clinical
Observation?................................................. 50
registered, with 945,000 cases diagnosed [1, 2].
Still remaining fundamental the role of surgery
6.3 Is It Possible to Identify These
for the curative approach to rectal cancer, the pub-
Different Groups Using Surrogate
Endpoints? .................................................... 52 lished clinical evidences of the last two decades
moved the management of such disease towards a
6.4 What Could Be a Methodology
That Provides Good Prediction multidisciplinary integrated treatment. In the
of Tumour Behaviour Basing frame of long course preoperative radiochemo-
on Surrogate Endpoints? ............................. 54 therapy, there are strong evidences that pathologi-
References ............................................................... 55 cal stage better discriminates different survivals in
a uniform patient population of locally advanced
presentations accrued in randomized clinical tri-
V. Valentini (*) • M.C. Barba als published after 2000. It supports the assump-
Department of Radiotherapy, tion that different populations of patients have
Università Cattolica Sacro Cuore, different sensibility to the same treatment [3].
Rome, Italy
All of these studies were based on the combi-
Policlinico Universitario ‘A. Gemelli’, nation of preoperative treatment and surgery, but
L. go Gemelli 8, Rome 00168, Italy
also, in series with patients treated with radiother-
e-mail: vvalentini@rm.unicatt.it; crissile@libero.it
apy alone, it is possible to observe the same het-
F. Cellini
erogeneity. Between 1978 and 1997, a group of
Radioterapia Oncologica,
Università Campus Biomedico, 271 patients affected by locally advanced rectal
Via E. Longoni 47, Rome 00155, Italy cancer underwent to primary radical external beam
e-mail: f.cellini@unicampus.it radiotherapy and was observed with long-term
R. van Stiphout follow-up. Patient received primary radical radio-
Department of Radiation Oncology (MAASTRO), therapy alone (without induction or concomitant
GROW – School for Oncology and Developmental
chemotherapy): treatment-administered doses
Biology, Maastricht University Medical Centre+,
Dr. Tanslaan 12, Maastricht 6201 BN, The Netherlands ranged from 40 to 60 Gy [4]. The 5-year cancer-
e-mail: ruud.vanstiphout@maastro.nl specific survival for the subgroup presenting a

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 49

DOI 10.1007/978-3-642-25005-7_6, © Springer-Verlag Berlin Heidelberg 2012
50
mobile lesion was 59% (95% CI 49–70%), for that
with partially fixed it was 33% (95% CI 21–54%),
and for the fixed tumour presentations was 9%
(95% CI 4–20%). Even if tumour spread through
rectal wall is prognostically significant for sur-
vival, each of the tumour presentation reported
subset (i.e., mobile, partially fixed and fixed)
showed a rate of long-surviving patients (varying
according to the extension of the tumour): for the
locally advanced lesions, up to 33% were cured by
only intermediate dose of radiotherapy. This
behaviour highlights a different sensibility to the
same treatments that is irrespective of the macro-
scopic initial presentation and based on intrinsic
tumour heterogeneity, supporting the concept that
biological tumour heterogeneity leads to different
clinical patterns of responses and tumour progres-
sion. As Mohiuddin et al. highlighted, indeed rec-
tal cancer represents a broad spectrum of diseases
requiring tailored treatment regimens to maximize
the outcome [5]. It aims to use the most aggressive
therapies only for the high-risk-featured presenta-
tions, avoiding the less biologically aggressive
tumours from the more intense treatment sched-
ules. To tailor treatments, there are some questions
which have to be considered in the multidisci-
plinary management of rectal cancer.
6.1 Is It Possible to Obtain an
Adequate Characterization
of Tumour Heterogeneity,
Based on Biological Evidences?
There is nowadays a great expectation about the
likelihood to determine tumour heterogeneity bas-
ing on biological evidences. From the main clinical
evidences on biomarkers associated to rectal can-
cer heterogeneity, we could summarize that EGFR
expression have shown a role in the prediction of
the response, as well as mutation status of BRAF,
dMMR and KRAS (even if only in a reduced pro-
portion of cases for the last). However, since many
studies available in literature seem promising, the
identification of a validated and well correlated to
the clinical outcomes biological marker cluster
needs yet a lot of investigation and is still lacking
[6]. Some studies obtained controversial results,
and it is still also difficult to handle the importance
V. Valentini et al.
of each evidence, understanding not only its
specific strength but also how the main evidences
mutually correlate. A detailed analysis is reported
in the chapter dealing with this issue [7].
6.2 Is It Possible to Obtain an
Adequate Characterization
of Tumour Heterogeneity,
Based on Clinical Observation?
On the basis of the data reported by a recent study
on pooled data from five large European random-
ized trials about the clinical behaviour of the differ-
ent populations in locally advanced rectal cancer,
the four subgroups [8] identified are as follows:
• Very good (15–20%): curable patients, highly
sensible to radiation, in whom organ preserva-
tion is to be pursued
• Good (40–50%): curable patients, who require
good local treatment and could have some
benefit by adjuvant chemotherapy
• Bad (10%): patients with late recurrent dis-
ease, who require radical treatment when
tumour recurs
• Ugly (15–20%): patients with early metasta-
ses onset, whom ongoing chemotherapy has
still not been able to cure
The analysis of overall risk ratio between DM
rate and LR rate (Fig. 6.1) reveals that at the start
6
5.5
5
DM rate/LR rate [−]
4.5
4
3.5
3
2.5
2
0 2 4 6 8 10
Time of follow− up [years]
Fig. 6.1 Ratio of distant metastasis rate and local recur-
rence rate over the time of follow-up in years
6 Do Different Populations of Rectal Cancer Exist? 51

Fig. 6.2 Percentages of the 40

outcomes LR, DM and death
over the follow-up time as a
total of the outcome events 30

LR [% of total LR]
20

10

0
1 2 3 4 5 6 7 8 9 10

40
DM [% of total DM]

30

20

10

0
1 2 3 4 5 6 7 8 9 10

40

30
Death [% of total]

20

10

0
1 2 3 4 5 6 7 8 9 10
Time of follow-up [years]

of follow-up, there are six times more metastases
than local recurrences. This number decreases to
around 2.5 in the first 2 years and remains con-
stant afterwards. Figure 6.2 shows that around
80% of the recurrences occur within the first
4 years, while the occurrence of death is more
frequent from the second to the fourth year
consequently.
Overall, in recurrent patients, two typologies
of behaviour are identified: that can occur early
for the most aggressive or late for the less
aggressive but still bad prognosis associated
tumours.
Early recurrent patients (ugly), which are
affected by highly aggressive tumour. This group
affects 15–20% of locally advanced tumour pre-
sentations. They do not seem to get benefit from
the current treatment intensification and chal-
lenge clinicians for better strategies.
Late recurrent patients (bad) probably with
slightly better pattern of features respect the pre-
vious one and late onset as for a slow growth, but
although aggressive on itself. This presentation
occurs in at least 10–15% of patients, and it
benefits from aggressive approach by integrated
treatment to optimize the curative chance.
52
On the other hand, two typologies of behav-
iour are both characterized by chance of cure: the
good are patients for whom the cure is achievable
by the use of the fully integrated treatment, as
neoadjuvant chemoradiation or radiation alone
followed by surgery ± adjuvant chemotherapy.
They represent 40–50% of locally advanced rec-
tal cancer patients.
Finally, there is a group of patients in locally
advanced presentations undergoing to the inte-
grated schedule that shows a high response to
neoadjuvant therapy (the best), suggesting that
are potentially curable also avoiding surgery.
The random distribution of these four groups
of patients in the different series could justify the
missing of evidences of clinical benefit for the
treatment strategies when they are addressed to
one of them, namely, but applied to the whole
cohort of patients; all single trials of neoadjuvant
chemoradiotherapy followed by surgery failed to
show a 5-year survival benefit because the ugly
and bad component hid the benefit of this treat-
ment modality in the good and the best ones. The
main problem is how to distinguish them to tailor
treatment properly.
6.3 Is It Possible to Identify These
Different Groups Using
Surrogate Endpoints?
In a time of limited sources, there is a need to
have fast validation of new hypotheses to improve
cancer treatment. One way is to have reliable sur-
rogate endpoints, for example, prostate-specific
1.0
0.9
0.8
DC (-)
LC (-)
0.7
0.6
0.5
0.00 60.00 120.00 180.00
Time of follow−up [months]
Fig. 6.3 Outcome rates local control (LC), distant control (DC) and overall survival (OS) for pCR subpopulation
(green) versus the non-pCR population (blue)
V. Valentini et al.
antigen (PSA) as a surrogate endpoint for sur-
vival in prostate cancer. In colon cancer, 2–3 years
of disease-free survival (DFS) correlated better
with 6-year overall survival after adjuvant che-
motherapy in an analysis of a large pooled data-
base from randomized trials [9].
For rectal cancer, pathologic complete response
(pCR) was argued to identify this more favour-
ably in population with less local recurrences
(LR) and distant metastases (DM) and better
overall survival (OS) [10, 11]. Anyway, no ran-
domized studies showed a significant benefit for
survival for increasing pCR rates [12], which
questions the role of promoting pCR in preopera-
tive approaches.
In a recent analysis of a pooled database of
five randomized trials, the comparison between
the pCR and non-pCR population with respect to
long-term outcome, all KM curves differed
significantly (Fig. 6.3). After 10 years, the pCR
population had 11% more local control than the
non-pCR population (96% vs. 85%). For DM and
OS, these numbers are 18% (82% vs. 64%) and
16% (73% vs. 57%).
There are evidences that pCR patients have a
better outcome, but this marker does not have an
impact on the outcome of any single randomized
trial, and the relative small benefit in survival
(16%) support the value of this surrogate end-
point in identifying only a group of patients with
favourable outcome, for whom surgery could be
avoided, but not in providing a reliable prediction
for the whole cohort of locally advanced rectal
cancer patients and, namely, about the impact of
each treatment in the ugly ones.
1.0 1.0
0.9 0.9
0.8 0.8
OS (-)
0.7 0.7
0.6 0.6
0.5 0.5
0.00 60.00 120.00 180.00 0.00 60.00 120.00 180.00
Time of follow−up [months] Time of follow−up [months]
6 Do Different Populations of Rectal Cancer Exist? 53

1.0 1.0

0.8 pCR 0.8

Disease free at 2 years

0.6 0.6
OS (–)

Non−pCR
0.4 0.4

0.2 0.2

Recurrence within 2 years

0.0 0.0
0.00 50.00 100.00 150.00 0.00 50.00 100.00 150.00

Fig. 6.4 Comparison between the status of pCR and disease free at 2 years for overall survival (OS)

Fig. 6.5 Overall survival rate

(OS) over time for subpopula- 1.0
tions having different status pCR+disease free
for pCR and disease free at
2 years
0.8
Non−pCR+disease free

0.6
OS (–)

0.4

pCR+recurrence
0.2

Non−pCR+recurrence
0.0

0.00 50.00 100.00 150.00

Time of follow−up [months]

In the same study, a further analysis compared
overall survival of the populations of pCR and
disease free after 2 years (Fig. 6.4). Disease free
after 2 years is more beneficial than having just a
pCR. A recurrence within 2 years results in 13%
chance of survival within 10 years, while having
no PCR results in 58% chance of survival after
10 years. The p value between disease-free +
pCR versus disease-free + non-PCR is 0.396, and
the p value between recurrence + pCR versus
recurrence + non-pCR is 0.083, which means that
being disease free after 2 years can be used as a
surrogate endpoint for pCR, since knowing the
pCR status does not change overall survival
significantly when knowing the recurrence state
after 2 years (Fig. 6.5).
Two-year disease-free survival as an endpoint
may however be useful to predict survival for the
subpopulations in the group of more aggressive
tumours. This endpoint may promote different
54 V. Valentini et al.

chemotherapy regimens to reduce distant metas-
tases rates for this subpopulation, but could hide
the overtreatment for the best and the good
patients when all are treated by the same approach.
Diversifying the options to personalize treatment
is essential with the current increasing complex-
ity of clinical decision making. These hypotheses
require finalized analyses based on large database
with pooled individual patients, namely, from
randomized trials, to identify the different patient
population by reliable and validate predictive
models as early as possible along the multiphase
treatment programmes.
6.4 What Could Be a Methodology
That Provides Good Prediction
of Tumour Behaviour Basing
on Surrogate Endpoints?
The presented patient and tumour heterogeneity
allows prediction of primary and surrogate end-
points with the aim of individualizing cancer
treatment. Statistical prediction models able to
find multivariate correlations between patient and
tumour characteristics and outcome are available
in many forms [13]. Interpretation of the model
results is very much dependent on model
representation. One highly interpretable way
to represent a prediction model is the nomogram.
A nomogram is nothing more than a visual repre-
sentation of mathematical equations involving
variables, weights and constants. An example for
rectal cancer is given in Fig. 6.6. In the example,
nomogram six variables were found to be predic-
tive for the outcome local control. Each of these
predictors is represented by a scale with possible
values. When using the nomogram to make a pre-
diction for a single patient, one may fill in each of
the values for the predictors and read out the score
scale on top by drawing a vertical line between the
scales. These scores need to be summed and filled
in on the scale ‘total score.’ Subsequently, this
final score corresponds to a probability for the
outcome by reading out the bottom scale. Often,
risk groups are defined or calculated based on this
probability, even if the prediction gives a continu-
ous probability score, because in this way patients
are assigned to a certain subgroup which could be
treated less or more aggressive. Trials could be
designed based on these developed prediction
models to encourage treatment individualization.

Single score
−2 −1 0 1 2
pT-stage
0 1 2 3 4
pN-stage
0 1 2
Concomitant chemo
Yes No
Adjuvant chemo
Yes No
Radiotherapy dose [Gy]
>45 45 <45
Tumor location
High Mid Low

Total score
−3 −2 −1 0 1 2 3 4 5
Low Medium High
Probability of LR [−]
0.05 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0.95

Fig. 6.6 Example of a nomogram for locally advanced rectal cancer; prediction of local recurrence (LR) probability
based on clinicopathological data. Three risk groups were defined based on the outcome probabilities
6 Do Different Populations of Rectal Cancer Exist?
High prediction accuracy is however a necessity
which can only be achieved with high-quality,
unbiased data from different origins.
Conclusions
It is a priority to take in the right account that
a strong component of heterogeneity exists in
rectal cancers: that implies the needing to per-
sonalize treatments. The correct use of surro-
gated endpoints and nomograms can aid to
tailor the treatments.
References
1. Parkin DM (2001) Global cancer statistics in the year
2000. Lancet Oncol 2(9):533–543
2. National Cancer Institute: PDQ® Rectal Cancer
Treatment. Bethesda, MD: National Cancer Institute.
(2011) http://cancer.gov/cancertopics/pdq/treatment/
rectal/HealthProfessional
3. Valentini V, van Stiphout RG, Lammering G,
Gambacorta MA, Barba MC et al (2011) Nomograms
for predicting local recurrence, distant metastases,
and overall survival for patients with locally advanced
rectal cancer on the basis of European randomized
clinical trials. J Clin Oncol 29:3163–3172
4. Wang Y, Cummings B, Catton P et al (2005) Primary
radical external beam radiotherapy of rectal adenocar-
cinoma: long term outcome of 271 patients. Radiother
Oncol 77:126–132
5. Mohiuddin M, Ahmad N, Marks G (1993) A selective
approach to adjunctive therapy for cancer of the rec-
tum. Int J Radiat Oncol Biol Phys 27(4):765–772
6. Schwaab J, Horisberger K, Ströbel P (2011)
Expression of transketolase like gene 1 (TKTL1)
55
predicts disease-free survival in patients with locally
advanced rectal cancer receiving neoadjuvant chemo-
radiotherapy. BMC Cancer 11:363
7. Lammering G, Buijsen J (2012) What biochemical
and molecular biological factors have greater rele-
vance to treatment decisions? In: Multidisciplinary
management of rectal cancer – questions and
answers
8. Valentini V, van Stiphout R, Lammering G et al
2-Year Disease Free vs Pathological Complete
Response as a Surrogate Endpoint by using Pooled
Data of Randomized Trials for Locally Advanced
Rectal Cancer. In Press
9. Sargent D, Shi Q, Yothers G (2011) Two or three year
disease-free survival (DFS) as a primary end-point in
stage III adjuvant colon cancer trials with fluoropy-
rimidines with or without oxaliplatin or irinotecan:
data from 12,676 patients from MOSAIC, X-ACT,
PETACC-3, C-06, C-07 and C89803. Eur J Cancer
47(7):990–996, Epub 2011 Jan 21
10. Valentini V, Coco C, Picciocchi A (2002) Does down-
staging predict improved outcome after preoperative
chemoradiation for extraperitoneal locally advanced
rectal cancer? A long-term analysis of 165 patients.
Int J Radiat Oncol Biol Phys 53(3):664–674
11. Capirci C, Valentini V, Cionini L (2008) Prognostic
value of pathologic complete response after neoadju-
vant therapy in locally advanced rectal cancer: long-
term analysis of 566 ypCR patients. Int J Radiat Oncol
Biol Phys 72(1):99–107, Epub 2008 Apr 11
12. Sebag-Montefiore D, Bujko K, Valentini V (2009)
Rectal cancer multidisciplinary management: evi-
dences and future landscape. Radiother Oncol
92(2):145–147, Epub 2009 Jul 10
13. van Stiphout R, Roelofs E, Dekker A (2012) How to
share data and promote a rapid learning health
medicine? In: Multidisciplinary management of rectal
cancer – questions and answers
 Part III
Q&As on Imaging
 How Can We Identify Tumour
Penetration? 7
Manish Chand and Gina Brown

Contents 7.1 Introduction

7.1 Introduction .....................................................
7.2 Endoanal Ultrasound (EAUS) ........................
7.3 Magnetic Resonance Imaging (MRI) ............
7.4 Extent of Mesorectal Spread ..........................
7.5 CRM Involvement ...........................................
7.6 Summary ..........................................................
References .................................................................
M. Chand (*)
Colorectal Research Fellow
and Registrar in Colorectal Surgery,
Royal Marsden Hospital, Downs Road, Sutton
e-mail: mans001@aol.com
G. Brown
Consultant Radiologist, Royal Marsden Hospital,
Downs Road, Sutton
e-mail: gina.brown@rmh.nhs.uk
59
Tumour penetration is seen as the depth of inva-
61
sion through the layers of the bowel wall and into
61 the surrounding mesorectum. It is an important
62 component of the staging system during assess-
ment of rectal cancer. Historically, the Duke’s
63
staging system has been used to risk-stratify
65 patients and influence treatment decisions. In
65 addition to tumour depth, it includes assessment
of local lymph node infiltration. In recent years
with increasing use of oncological therapy to
accompany surgical treatment of rectal cancer,
traditional staging systems have been found lack-
ing in detail. The UICC TNM classification has
largely replaced the Duke’s staging system,
although many pathologists still report both.
Stage at presentation strongly influences progno-
sis and in particular tumour depth. The risk of
recurrence for stage T1, T2 and T3 independent
of lymph node involvement is 5%, 10% and 25%,
respectively [1]. As the trend has shifted away
from adjuvant therapy to neoadjuvant therapy
due to improved outcomes and less morbidity,
staging information on the tumour is ideally
needed at an early stage in the diagnosis. Accurate
tumour stage is important in determining the
appropriateness of preoperative chemoradiother-
apy (CRT), which has been shown to improve
overall outcomes in more advanced tumours.
Sufficient detail cannot be obtained from biop-
sies alone.
Dukes originally noted the link between
increasing depth of spread and risk of nodal

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 59

DOI 10.1007/978-3-642-25005-7_7, © Springer-Verlag Berlin Heidelberg 2012
60 M. Chand and G. Brown

Table 7.1 Standard TNM classification of rectal cancer

Primary tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour invades submucosa
T2 Tumour invades muscularis propria
T3 Tumour invades through muscularis propria into the subserosa
T4 Tumour directly invades other structures and/or perforates
visceral peritoneum
Regional lymph nodes (N)
NX Regional nodes cannot be assessed
N0 No node metastases
N1 Metastases in 1–3 regional nodes
N2 Metastases in four or more nodes
Distant metastases (M)
MX Distant metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases

involvement and the importance of tumour spread
in millimetres beyond the muscularis propria –
extramural spread. It has been further noted in
several histopathology studies. As a result,
Hermanek proposed a modification of the TNM
classification to take into account the survival
variation amongst patients with T3 tumours
according to depth of extramural spread.
The single-most important factor which has
led to reduction in local recurrence rates is the
acceptance of total mesorectal excision (TME)
as the ‘gold-standard’ surgical technique for
rectal cancer surgery. Sharp, precision dissec-
tion along the mesorectal fascia ensures that
the tumour and all local draining lymph nodes
are excised in a single package. Knowledge of
the relationship between the tumour edge and
the mesorectal fascia is essential to facilitate a
successful dissection and give a tumour-free
resection margin.
As imaging modalities have improved, prog-
nostic risk factors in rectal cancer can be demon-
strated with much greater accuracy. Tumour
depth or T-stage is one such factor; however,
there is no single optimal staging classification
which can be applied to the entire spectrum of
T-stage. Tumour spread can be measured to
within millimetres beyond the layers of the bowel
wall and surrounding mesorectum, and this has
significant bearing on treatment decisions. The
only preoperative modality that has been shown
to measure depth of tumour spread with precision
is high-resolution MRI (Table 7.1).
Accurate preoperative identification of tumour
depth is required for:
1. Successful TME surgery
2. Patient selection for neoadjuvant CRT
3. Limiting overtreatment of patients with CRT
The importance of accurate identification of
T-stage relates to its treatment implications and
prognosis. In essence, tumours which are confined
to the bowel wall, that is, T1 and T2 tumours, are
referred for immediate surgery and do not need
preoperative chemoradiotherapy. In comparison,
tumours which penetrate beyond the bowel wall
into the surrounding mesorectum and beyond,
e.g. T3 and T4 tumours, are considered for pre-
operative chemoradiotherapy to improve overall
outcomes. Furthermore, distinguishing early
T-stage tumours has implications in the type of
surgery. For example, T1 lesions may be suitable
for a less traumatic local excision such as an
endoscopic mucosal resection rather than ante-
rior resection and total mesorectal excision.
Clearly, accurate T-staging is essential so not to
over- or undertreat patients.
7 How Can We Identify Tumour Penetration?
7.2 Endoanal Ultrasound (EAUS)
Endoanal ultrasound is considered as the modality
of choice in the local assessment of early rectal
cancer by many clinicians. Its suitability for early
lesions relates to identification of those patients
where local resection may be more appropriate
rather than TME surgery. This is because it has
greater accuracy than MRI in visualizing the sub-
mucosa which is essential in planning local resec-
tion. However, its main limitation is its inability to
define the mesorectal facia accurately and thus
identify whether the circumferential resection mar-
gin is threatened. In a large multi-centre trial, EAUS
was shown to substantially over-stage patients and
thus over-treat patients with preoperative CRT [2].
Involvement of the circumferential resection mar-
gin is known to be a significant factor in local recur-
rence and is essential in surgical planning.
Fig. 7.1 MRI axial image
showing a rectal cancer and
the different signal character-
istics of the rectal wall and
surrounding tissues
61
7.3 Magnetic Resonance
Imaging (MRI)
MRI is the optimal method for local assessment of
primary rectal cancer as a whole. Technique is
important to obtain accurate images and not under-
or over-stage tumours. This requires correct field
alignment in relation to the long axis of the rectum.
The structure of the rectal wall can be readily
identified on MRI. T2-weighted images are most
suitable for distinguishing the layers of the bowel
wall. The different layers of the bowel wall are
identified from their unique signal characteristic.
An appreciation of the normal anatomy is essential
for accurate identification of tumour invasion.
Disruption through the normal signal characteristic
pattern determines the depth of invasion (Fig. 7.1).
As mentioned, the main advantage over EAUS
is that MRI can accurately delineate the mesorectal
62
fascia. The circumferential resection margin is
defined by the relationship between the tumour
edge and the mesorectal fascia. It is known to be an
independent risk factor for local recurrence. In
those patients where the CRM is threatened, neo-
adjuvant aims to downsize the tumour to obtain
tumour-free resection margins following TME sur-
gery. Accurate identification and definition of the
mesorectal fascia is therefore mandatory in plan-
ning optimal treatment.
Brown et al. first demonstrated the accuracy
of high-resolution MRI in preoperative predic-
tion of rectal cancer stage [3]. In their study of
28 patients, they not only correlated tumour
stage on MRI with histological analysis but
showed that MRI can accurately identify extent
of extramural spread. One of the difficulties in
predicting tumour stage on MRI is distinguish-
ing between T2 and T3 tumours. The patho-
logical difference between T2 and T3 tumours
is invasion of the mesorectal fat. Defining the
MR characteristics for T3 tumours is therefore
important so to avoid over-staging. The pres-
ence of spiculation within the extramural fat
can lead to misinterpretation and over-staging
of tumours. Both the tumour itself and the
effects of radiotherapy can produce a host des-
moplastic reaction resulting in fibrosis. This
fibrotic reaction can cause spiculation into the
mesorectal fat and should not be confused with
tumour. Through careful correlation with his-
topathology whole-mount sections, Brown
et al. defined T3 tumours by the presence of
tumour signal intensity permeating into the
mesorectal fat with a ‘broad-based’ or nodular
configuration and in continuity with the intra-
mural portion of the tumour. Such features
could only be appreciated on small field of
view high-resolution imaging (3-mm slices,
16 cm field of view). Further study of prognos-
tic factors using high-resolution MRI by Brown
and colleagues demonstrated 94% concordance
between MRI and histology in terms of T-stage
in addition to 92% agreement in prediction of
the CRM [4].
Figure 7.2 shows the difference between
fibrotic T2 lesions and actual T3 lesions. However,
as we shall see, distinguishing T2 cancers, which
would normally not need preoperative CRT, and
M. Chand and G. Brown
early T3 tumours may not actually be as clini-
cally relevant as first thought.
7.4 Extent of Mesorectal Spread
The mesorectum is the lymphovascular enve-
lope which surrounds the rectum to varying
degrees. It completely surrounds the middle
third of the rectum but is virtually absent in the
lower third and only covers the posterior aspect
of the upper third of the rectum. The extent to
which tumour penetrates the mesorectal fat is an
independent risk factor for recurrence. This is
not adequately represented in the traditional
staging classifications as the level of penetra-
tion into the mesorectum has prognostic
implications.
As described above, total mesorectal exci-
sion (TME) involves excision of the rectum
along with the mesorectum. T3 tumours are
those which have traversed the bowel wall and
penetrated into the mesorectum. The majority
of patients present with T3 tumours; however,
there is wide variety in survival rates of these
patients. Jass and colleagues were the first to
describe the importance of the extent of
mesorectal invasion on prognosis [5]. Further
work by Cawthorn and Merkel demonstrated an
improvement in 5-year survival in patients who
had ‘slight’ mesorectal invasion. Cawthorn
described ‘slight’ mesorectal invasion as 4 mm
or less and found 5-year survival to be 55%
compared to 25% when more than 4 mm [6].
Another study by Merkel et al. studied patient’s
survival characteristics with T3 tumours. Those
patients with extramural spread of more than
5 mm had 5-year survival rate of 54% compared
with 85% for those patients whose tumours had
extramural spread of less than 5 mm [7]. These
results were independent of lymph node involve-
ment. These early studies highlight the impor-
tance of accurate measurement of tumour
penetration into the mesorectum and those
tumours with a worse prognosis, namely, T3c
and T3d. Therefore, the distinction between T2
and T3 tumours with less than 5-mm mesorectal
spread – T3a and T3b – becomes irrelevant as
these patients will have minimal benefit from
7 How Can We Identify Tumour Penetration? 63

Fig. 7.2 (a) This shows the baseline MRI axial image red arrow indicates an example of fibrosis which may be
before chemoradiotherapy and the same patient following mistaken for tumour thus overstaging. (b) MRI axial
chemoradiotherapy. The low signal represents the fibrosis image of a T3 tumour
that has taken place but the actual tumour remains T2. The

CRT. The accuracy of MRI in delineating the 7.5 CRM Involvement

mesorectal fascia and producing comparable
results to histological analysis has been shown The importance of TME surgery in the reduction in
by the MERCURY Study Group (Table 7.2 and risk of local recurrence has been mentioned above.
Fig. 7.3). Key to a successful resection is obtaining tumour-free
64 M. Chand and G. Brown

circumferential margins. Tumour cells identified at to the mesorectal fascia. Stratifying T3 tumours
the circumferential resection margin is known to con- through the sub-classification described above is
fer poor prognosis in terms of local recurrence and important when deciding preoperative oncological
overall survival. This is related to the depth of inva- therapy. However, identification of those patients in
sion into the mesorectum and proximity of the tumour whom the CRM would be involved is equally impor-
tant in surgical planning. These patients with threat-
ened CRM have been shown to benefit from
Table 7.2 T3 sub-classification
neoadjuvant chemoradiotherapy to downstage the
T-stage Depth of extramural spread tumour and thus allowing for a clear resection
T3a <1.00 mm margin.
T3b 1.01–5.00 mm MRI has been the most useful imaging modal-
T3c 5.01–15.00 mm
ity in identifying the mesorectal fascia. Early
T3d >15.00 mm
studies correlating MRI’s accuracy in identifying

a b

c d

Fig. 7.3 (a–d) Subclassification of T3 tumours – T3a–d

7 How Can We Identify Tumour Penetration?
the mesorectal fascia and a subsequent negative
CRM on histology have led to patients in whom
tumour extends to within 5 mm of the mesorectal
fascia to be given preoperative CRT [8]. Although
detailed staging is important to identify patients
who would most benefit from preoperative onco-
logical therapy, it is also important not to offer
patients CRT where there is no proven benefit.
The MERCURY Study Group showed that it is
possible to predict negative CRM histologically
using a 1 mm cut-off on MRI. Further analysis
using different cut-offs (1, 2 and 5 mm) did not
show any increase in risk of local recurrence [9].
Thus, a distance of 1 mm from the mesorectal
fascia on MRI is the optimal cut-off to identify
patients who may have positive resection margins
following surgery. It is important to state that a
certain proportion of patients who have negative
CRM will still suffer a local recurrence. This sug-
gests that there are additional phenotypical fac-
tors which remain important in the local
recurrence and may be able to be identified on
pretreatment imaging.
7.6 Summary
In summary, preoperative MRI measurement of
the extramural depth of spread and assessment of
tumour to the potential CRM enables the selec-
tion of good prognosis rectal cancer patients. In
clinical practice, this can account for at least one-
third of the patients with rectal cancer. With opti-
mal preoperative selection and good quality TME
surgery, local recurrence rates of 1.7% are achiev-
able in MRI-defined T3a/b. This is regardless of
65
nodal status and is independent of known vari-
ables such as type of surgery and height of
tumour. Conversely, patients with more extensive
tumour spread of 5 mm or more beyond the mus-
cularis propria are at increased risk of local recur-
rence and distant failure, and therefore,
preoperative identification of such patients will
lead to appropriate intensification of preoperative
therapy aimed at reducing such risks.
References
1. Sobin LH, Wittekind C, International Union against
Cancer (1997) TNM classification of malignant
tumours, 5th edn. Wiley, New York, p xxiii, 227 p
2. Sauer R et al (2004) Preoperative versus postoperative
chemoradiotherapy for rectal cancer. N Engl J Med
351(17):1731–1740
3. Brown G et al (1999) Rectal carcinoma: thin-section
MR imaging for staging in 28 patients. Radiology
211(1):215–222
4. Brown G et al (2003) Preoperative assessment of prog-
nostic factors in rectal cancer using high-resolution
magnetic resonance imaging. Br J Surg 90(3):355–364
5. Jass JR, Love SB, Northover JM (1987) A new prog-
nostic classification of rectal cancer. Lancet 1(8545):
1303–1306
6. Cawthorn SJ et al (1990) Extent of mesorectal spread
and involvement of lateral resection margin as prog-
nostic factors after surgery for rectal cancer. Lancet
335(8697):1055–1059
7. Merkel S et al (2001) The prognostic inhomogeneity in
pT3 rectal carcinomas. Int J Colorectal Dis 16(5):
298–304
8. Beets-Tan RG et al (2001) Accuracy of magnetic reso-
nance imaging in prediction of tumour-free resection
margin in rectal cancer surgery. Lancet 357(9255):
497–504
9. Taylor FG et al (2011) One millimetre is the safe cut-off
for magnetic resonance imaging prediction of surgical
margin status in rectal cancer. Br J Surg 98(6):872–879
 How Can We Identify Mesorectal
Fascia Involvement? 8
Regina G.H. Beets-Tan

Contents
8.1 Introduction .....................................................
8.2 What Is the Mesorectal Fascia? .....................
8.3 Why Do We Need to Evaluate
Involvement of the Mesorectal Fascia
Preoperatively?................................................
8.4 Can EUS Visualize the Mesorectal
Fascia and Its Involvement? ...........................
8.5 How Accurately Can CT Identify
Advanced Tumors, Threatening
or Invading the Mesorectal Fascia? ...............
8.6 Is MRI an Accurate Imaging Method to
Visualize the Mesorectal Fascia and Its
Involvement?....................................................
8.7 Can a Restaging MRI After
Preoperative Chemoradiotherapy
Help in Identifying Tumor Regression
from the Mesorectal Fascia? ..........................
References .................................................................
67 8.1 Introduction
67
The circumferential resection margin (CRM) is
the lateral or radial resection margin created by the
surgeon at the total mesorectal excision. A positive
68
CRM is defined as a closest distance of 1 mm or
less between tumor and resection margin, as this
68
represents the optimal prognostic cutoff point. The
importance as a prognostic factor and as a param-
68
eter of surgical quality has been recognized and
confirmed in the past 20 years [1]. Because the
ideal plane of resection in a total mesorectal exci-
69 sion is just outside the mesorectal fascia, a relevant
question in rectal cancer surgery which is addressed
in this chapter is “How can we identify mesorectal
fascia involvement?”
69
71
8.2 What Is the Mesorectal Fascia?

The mesorectal fascia, anatomically known as

the fascia propria is a continuous fascial sleeve
surrounding the rectum and mesorectum that can
be dissected as a complete sock off a fresh extra-
fascial specimen. It is 154 (±1 standard devia-
tion = 61–391) mm thick, is thinner anteriorly than
posteriorly (P < 0.05), and is composed predomi-
R.G.H. Beets-Tan nantly of collagen. It can be identified surgically
Department of Radiology,
at the pelvic brim as a shiny membrane and lies
Maastricht University Medical Centre,
5800, Maastricht, 6202 AZ, The Netherlands inside the hypogastric nerves and the pelvic plex-
e-mail: r.beets.tan@mumc.nl uses [2].

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 67

DOI 10.1007/978-3-642-25005-7_8, © Springer-Verlag Berlin Heidelberg 2012
68
8.3 Why Do We Need to Evaluate
Involvement of the Mesorectal
Fascia Preoperatively?
A positive circumferential resection margin
(CRM) can be the result of inadequate total
mesorectal excision (TME) surgery or of an
advanced tumor that comes close to or invades
the mesorectal fascia. The first problem is one
of surgical technique, whereas the second is a
matter of preoperative identification and ade-
quate neoadjuvant treatment of advanced tumors.
For centers that use only a long course of chemo-
radiation as a neoadjuvant treatment, the dis-
tance of the tumor to the mesorectal fascia is
usually not very important in the preoperative
decision process, as all tumors that extend
beyond the muscular wall are considered candi-
dates for a long course of chemoradiation, pro-
viding an opportunity for downsizing. For
centers that also use a short course of 5 × 5 Gy
and immediate surgery, this is different. Although
it has been shown that 5 × 5 Gy is a very efficient
and cost-effective way to prevent local recur-
rences in many patients, it is much less effective
when the tumor comes close to or invades the
mesorectal fascia [3]. These tumors should be
identified and treated with a long course of
chemoradiation and a long interval to provide
downsizing.
Regardless of the neoadjuvant treatment strat-
egies, it is important for the surgeon to know the
exact anatomic relation of the tumor to the
mesorectal fascia and the surrounding structures
to obtain a complete resection, and in advanced
cases, it can be very valuable to have the images
available in the operating room.
8.4 Can EUS Visualize the
Mesorectal Fascia and Its
Involvement?
Endorectal ultrasonography (EUS) is inaccurate
in identifying patients with a “threatened or
involved mesorectal fascia,” because the
mesorectal fascia is not well visualized by EUS.
The inherent low soft-tissue contrast resolution
R.G.H. Beets-Tan
hampers the visualization of the ultrathin
mesorectal fascia. Furthermore, because of its
limited field of view, evaluation of tumor involve-
ment of anatomical structures outside the scope
of the probe is a challenging and often a difficult
task. This is especially true in high rectal tumors
that have extended to the dorsal pelvic wall. But
when it comes to identifying tumor involvement
of the anterior mesorectal fascia including the
assessment of anterior organ invasion (vagina,
prostate, or seminal vesicles), EUS is as accurate
as MRI.
8.5 How Accurately Can CT Identify
Advanced Tumors,
Threatening or Invading the
Mesorectal Fascia?
A Dutch prospective multicenter study investi-
gated the role of 16-slice CT (MSCT) for the pre-
diction of an involved mesorectal fascia in 250
patients [4]. The results show that MSCT was
especially accurate in high tumors that have a
large distance of the tumor to the mesorectal fas-
cia with a sensitivity, specificity, PPV, and NPV
of 70%, 96%, 85%, and 92% for the prediction of
an involved mesorectal fascia. For low rectal
tumors, the accuracy was only moderate. Another
study confirmed the high negative predictive
value for the prediction of an involved mesorectal
fascia and considerable overstaging for CT [5].
The inherent low contrast resolution of CT
together with the complex tapered anatomy of
the mesorectum with little or no fat between
tumor and pelvic structures low down in pelvis
all contribute to the inaccuracy of CT in this
area (Fig. 8.1). The poor accuracy of CT in low
anteriorly located tumors was confirmed by a
study that also demonstrated a high variability
among observers for prediction of an involved
mesorectal fascia [6]. The role of new-genera-
tion multidetector-row CT has been addressed
in one study that showed a reasonable agree-
ment between CT and MRI but not for predic-
tion of tumor involvement in the mesorectal
fascia in low tumors. Therefore, CT cannot
replace MRI in rectal cancer staging [7].
8 How Can We Identify Mesorectal Fascia Involvement?
Fig. 8.1 (a, b) Axial CT and T2 weighted MRI of a patient
with rectal cancer. On CT a low rectal tumor mass is visual-
ized invading the anterior mesorectal fascia (white arrows)
8.6 Is MRI an Accurate Imaging
Method to Visualize the
Mesorectal Fascia and Its
Involvement?
Magnetic resonance imaging (MRI) is the method
of first choice to identify the mesorectal fascia
because of its inherent superior contrast resolu-
tion as compared to EUS or CT. The ultrathin
fascia can be sharply delineated within the high-
intensity pelvic fat tissue on T2-weighted MR
images (Fig. 8.2). A standard rectal cancer MR
scan protocol should therefore include sequences
with a bright signal of fat, T2W FSE sequences.
If fat-suppressed sequences are applied, the con-
trast between fascia and surrounding fat tissue
diminishes and mesorectal fascia involvement
will be difficult to determine. Many expert sin-
gle-center studies have shown that MRI is highly
accurate for predicting an involved mesorectal
fascia (see Fig. 8.3a) [2, 8–10].
The results of a systematic review of all pub-
lished single-center studies confirm the high per-
formance of MRI, showing a sensitivity for the
prediction of an involved mesorectal fascia vary-
ing between 60% and 88% and specificity
between 73% and 100% [11].
69
while on the corresponding MRI the tumor is not adjacent
to the mesorectal fascia but can be delineated at short dis-
tance from the anterior mesorectal margin (black arrows)
A subsequent large European multicenter
Mercury study showed an accuracy of 91% with
a negative predictive value of 93% for patients
who underwent immediate surgery [12].
Two European centers that use a short course
of radiotherapy as a treatment option report a
decrease in the number of positive margins after
the incorporation of MRI in the discussion of all
patients with rectal cancer in multidisciplinary
meetings [13, 14].
8.7 Can a Restaging MRI After
Preoperative
Chemoradiotherapy Help in
Identifying Tumor Regression
from the Mesorectal Fascia?
A restaging MRI, performed 6–8 weeks after
completion of chemoradiotherapy is useful for
evaluation of response to neoadjuvant treatment.
There is evidence that MRI can predict tumor
regression of locally advanced primary rectal
cancer that has undergone preoperative chemora-
diotherapy [15]. MRI after chemoradiation has a
sensitivity of 54%, specificity of 87%, PPV of
44%, and NPV of 91% for predicting invasion of
the MRF [16]. A restaging MRI can therefore
70 R.G.H. Beets-Tan

Fig. 8.2 (a, b) Axial and coronal T2 weighted MRI of a patient with rectal cancer. The mesorectal fascia (black arrows)
can be clearly delineated, enveloping the mesorectum

Fig. 8.3 (a) Axial T2 weighted MRI of a patient with
locally advanced rectal cancer, before chemoradiotherapy.
The tumor (asterisk) is invading the mesorectal fascia ante-
riorly (black arrows). Note a suspected node close to the
mesorectal fascia (black arrowhead). (b) Axial T2 weighted
MRI of the same patient with locally advanced rectal cancer,
6 weeks after completion of chemoradiotherapy. The tumor
(asterisk) has been downsized and has turned fibrotic but the
fibrosis is still invading the anterior mesorectal fascia (white
arrow). In this patient one must be reluctant to predict a free
anterior margin, because the fibrosis may still contain tumor
and the mesorectal fascia may still be involved
8 How Can We Identify Mesorectal Fascia Involvement?
reliably identify those tumors that have regressed
from the mesorectal fascia. False positivity still
occurs in around 50%. These false positives occur
in tumors that show fibrosis after chemoradiation
and where the fibrosis has not retracted from the
mesorectal fascia. In 50%, the fibrosis may still
contain tumor (Fig. 8.3b). In order not to under-
treat, it is better to err on the safe side and overes-
timate an involved margin.
Conclusion
Rectal cancer involvement of the mesorectal
fascia can be well anticipated by imaging. MRI
is the most reliable technique in all rectal can-
cers, while modern multidetector CT could be
an alternative mainly in mid and high rectal
tumors. In low tumors, CT cannot replace MRI.
Therefore, MRI remains the preferred (re-)
staging method in rectal cancer. Although EUS
is accurate in assessing tumor ingrowth into the
vagina or prostate, it is unable to identify tumor
involvement in the mesorectal fascia.
References
1. Nagtegaal ID, Quirke P (2008) What is the role for the
circumferential margin in the modern treatment of
rectal cancer? J Clin Oncol 26(2):303–312
2. Bissett IP, Fernando CC, Hough DM et al (2001)
Identification of the fascia propria by magnetic reso-
nance imaging and its relevance to preoperative
assessment of rectal cancer. Dis Colon Rectum
44(2):259–265
3. Peeters KC, Marijnen CA, Nagtegaal ID et al (2007)
The TME trial after a median follow up of 6 years:
increased local control but no survival benefit in irra-
diated patients with resectable rectal carcinoma. Ann
Surg 246(5):693–701
4. Wolberink SV, Beets-Tan RG, de Haas-Kock DF et al
(2009) Multislice CT as a primary screening tool for
the prediction of an involved mesorectal fascia and
distant metastases in primary rectal cancer: a multi-
center study. Dis Colon Rectum 52(5):928–934
71
5. Taylor A, Slater A, Mapstone N et al (2007) Staging
rectal cancer: MRI compared to MDCT. Abdom
Imaging 32(3):323–327
6. Vliegen R, Dresen R, Beets G et al (2008) The accu-
racy of multi-detector row CT for the assessment of
tumor invasion of the mesorectal fascia in primary
rectal cancer. Abdom Imaging 33(5):604–610
7. Maizlin ZV, Brown JA, So G, Brown C, Phang TP,
Walker ML, Kirby JM, Vora P, Tiwari P (2010) Can
CT replace MRI in preoperative assessment of the cir-
cumferential resection margin in rectal cancer? Dis
Colon Rectum 53(3):308–314
8. Beets-Tan RG, Beets GL, Vliegen RF et al (2001)
Accuracy of magnetic resonance imaging in predic-
tion of tumour-free resection margin in rectal cancer
surgery. Lancet 357(9255):497–504
9. Blomqvist L, Machado M, Rubio C et al (2000) Rectal
tumour staging: MR imaging using pelvic phased-
array and endorectal coils vs endoscopic ultrasonog-
raphy. Eur Radiol 10(4):653–660
10. Peschaud F, Cuenod CA, Benoist S et al (2005)
Accuracy of magnetic resonance imaging in rectal
cancer depends on location of the tumor. Dis Colon
Rectum 48(8):1603–1609
11. Lahaye MJ, Engelen SM, Nelemans PJ et al (2005)
Imaging for predicting the risk factors – the circum-
ferential resection margin and nodal disease – of local
recurrence in rectal cancer: a meta-analysis. Semin
Ultrasound CT MR 26(4):259–268
12. MERCURY Study Group (2006) Diagnostic accuracy
of preoperative magnetic resonance imaging in pre-
dicting curative resection of rectal cancer, prospective
observational study. BMJ 333(7572):779
13. Beets-Tan RG, Lettinga T, Beets GL (2005) Pre-
operative imaging of rectal cancer and its impact on
surgical performance and treatment outcome. Eur J
Surg Oncol 31(6):681–688
14. Burton S, Brown G, Daniels IR et al (2006) MRI
directed multidisciplinary team preoperative treat-
ment strategy: the way to eliminate positive circum-
ferential margins? Br J Cancer 94(3):351–357
15. Vliegen RF, Beets GL, Lammering G et al (2008)
Mesorectal fascia invasion after neoadjuvant chemo-
therapy and radiation therapy for locally advanced
rectal cancer: accuracy of MR imaging for prediction.
Radiology 246(2):454–462
16. Kulkarni T, Gollins S, Maw A et al (2008) Magnetic
resonance imaging in rectal cancer downstaged
using neoadjuvant chemoradiation: accuracy of pre-
diction of tumour stage and circumferential resec-
tion margin status. Colorectal Dis 10(5):479–489,
Epub 2008 Mar 3
 How Can We Identify Nodal
Involvement? 9
Regina G.H. Beets-Tan

Contents 9.1 Introduction

9.1 Introduction ................................................... 73
With the shift from postoperative to preoperative
9.2 How Accurate Is Imaging
for Identifying Nodal Metastases? ............... 73
(chemo)radiotherapy (CRT) for rectal cancer
patients, tumor risk profile assessment, previ-
9.3 Has Modern Imaging Improved Its
ously based on histology of the resection speci-
Performance for Detection of Nodal
Metastases? .................................................... 74 men, is done with preoperative imaging. Imaging
provides information on the T-stage, N-stage, and
9.4 Are There New Developments
in Imaging Technology involvement of the mesorectal fascia. Nodal dis-
That May Improve Nodal Staging? ............. 74 ease is one of the most important risk factors both
for local and distant recurrence and is generally
9.5 Can Restaging MRI After
Preoperative Chemoradiotherapy considered an indication for neoadjuvant therapy.
Identify Patients with Sterilized This chapter will discuss whether we can accu-
Nodes (ypN0)? ............................................... 75 rately identify nodal involvement in patients with
References ................................................................. 75 rectal cancer using imaging methods.

9.2 How Accurate Is Imaging

for Identifying Nodal
Metastases?

For a long time, nodal staging was performed

with endorectal ultrasonography (EUS) and com-
puted tomography (CT). Nodal staging was
mainly based on nodal size measurements.
A node that was larger than 8 mm on imaging
was often considered as malignant. For a part this
is correct because in rectal cancer, lymph nodes
with a diameter of 9 mm or larger are invariably
malignant. For the majority of the cases, this is
R.G.H. Beets-Tan incorrect because around 60% of the metastatic
Department of Radiology,
rectal cancer nodes are smaller than 6 mm [1].
Maastricht University Medical Centre,
5800, Maastricht 6202 AZ, The Netherlands The pooled sensitivity and specificity of EUS
e-mail: r.beets.tan@mumc.nl in a meta-analysis based on 35 studies was around

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 73

DOI 10.1007/978-3-642-25005-7_9, © Springer-Verlag Berlin Heidelberg 2012
74
75% [2]. A comparative meta-analysis of CT,
EUS, and MRI showed that the receiver operating
characteristic (ROC) curves for all three modali-
ties were only moderate [3]. The sensitivity of
EUS, CT, and first-generation MRI for primary
nodal staging in rectal cancer varies between 55%
and 70% and specificity between 75% and 80%.
9.3 Has Modern Imaging Improved
Its Performance for Detection
of Nodal Metastases?
In the comparative meta-analysis, EUS performed
slightly better than CT or MRI, most likely
because of the use of criteria for nodal metastases
other than size alone: round shape, border irregu-
larity, and heterogeneous texture.
Recently, modern MRI technology was intro-
duced generating very high-resolution images.
Similar morphological criteria as with EUS (shape,
border irregularity, and heterogeneous signal) can
now also be evaluated with MRI and show improved
accuracy over size alone (Fig. 9.1) [4, 5].
Fig. 9.1 Axial T2-weighted MR image of a rectal cancer
patient. Two nodes are seen in the mesorectum, large and
small. Both nodes show morphological features strongly
indicative for malignant nodes (round, irregular border,
and heterogenous texture)
R.G.H. Beets-Tan
These morphological features are well visu-
alized in nodes larger than 6 mm, but a reliable
delineation of the nodal feature can be difficult
if not impossible in the smaller nodes. The prac-
tical difficulties in nodal staging with the stan-
dard imaging methods are illustrated by a
multicenter report in which T3N0 tumors, staged
with ERUS or MRI, were found to be node posi-
tive at histology in 22%, despite preoperative
chemoradiation [6].
9.4 Are There New Developments
in Imaging Technology That
May Improve Nodal Staging?
MR techniques and sequences are continuously
improving, and with modern and more powerful
machines, new sequences, and lymph node–
specific MR contrast agents, the accuracy is likely
to improve. An example of a MR contrast agent
proven highly accurate for nodal staging both in
urological and rectal cancer is ultrasmall super-
paramagnetic particles of iron oxide (USPIO)
[7]. Unfortunately, USPIO is not approved by the
Food and Drug Administration (FDA) and there-
fore not marketed.
A new functional MRI technique, promising
in oncology imaging, is diffusion-weighted MR
imaging. A restricted diffusion of the protons in a
tissue is associated with a tumoral tissue. This
restricted diffusion can be translated into a high
signal on MRI. It can also be quantified as a
coefficient, the apparent diffusion coefficient
(ADC). Visual perception of the MR signal of
nodes cannot discriminate between benign and
malignant nodes, because both show a high sig-
nal. The ADC of malignant nodes is generally
slightly lower than that of benign nodes, but with
an AUC of 0.66, it is very difficult to find the
right cutoff value for malignant nodes [8].
Thus, at the time of writing, despite the huge
variety of new imaging technology, the problem
of nodal staging in patients with rectal cancer
remains.
9 How Can We Identify Nodal Involvement?
9.5 Can Restaging MRI
After Preoperative
Chemoradiotherapy Identify
Patients with Sterilized Nodes
(ypN0)?
For patients treated with neoadjuvant CRT, there
is now a trend toward minimally invasive, organ-
saving treatment, when the tumor and nodes have
responded well to CRT. Organ-saving treatment
is only an option when the true node-negative
patients can be accurately selected.
A restaging MRI, performed 6–8 weeks after
completion of chemoradiotherapy, has proven
valuable for evaluation of tumor response and
nodal response.
In contrast to primary staging, a restaging
MRI shows a high NPV of around 95% for the
detection of nodal disease. In other words, the
ypN0 patients can be identified with post-CRT
MRI [7, 9]. Due to CRT, the number of small
nodes decreases and so does the number of inter-
pretation errors. After CRT, the prevalence of
node-positive patients is lower. These may
explain why in a restaging setting size criteria
seem to work.
Conclusion and Recommendations
So far, clinicians have been reluctant to make
decisions based on the nodal staging by
imaging because of its insufficient accuracy.
A reliable preoperative staging of nodes
could however benefit patients with rectal
cancer.
The most practical strategy to work with in
daily practice is the following, while always
keeping in mind the limitations of imaging:
If on rectal cancer MRI, no nodes are visi-
ble, the patient is considered N0.
Patients with nodes ³8 mm that show two
or more of the morphological features (round,
irregular border, and heterogenous texture) are
considered N+.
For patients who have nodes £7 mm, the
nodal status is less certain and one should
75
take into account the prevalence of nodal
metastases according to the T-stage. If the
patient’s MRI only shows small nodes, yet
these nodes show obvious features strongly
indicative for malignancy (round, irregular
border, and heterogenous texture), these
patients can be considered N+. In all other
circumstances, the nodal status on imaging
remains uncertain.
References
1. Wang C, Zhou Z, Wang Z et al (2005) Patterns of neo-
plastic foci and lymph node micrometastasis within the
mesorectum. Langenbecks Arch Surg 390(4):312–318
2. Puli SR, Reddy JB, Bechtold ML et al (2009) Accuracy
of endoscopic ultrasound to diagnose nodal invasion by
rectal cancers: a meta-analysis and systematic review.
Ann Surg Oncol 16(5):1255–1265
3. Lahaye MJ, Engelen SM, Nelemans PJ et al (2005)
Imaging for predicting the risk factors – the circumfer-
ential resection margin and nodal disease – of local
recurrence in rectal cancer: a meta-analysis. Semin
Ultrasound CT MR 26(4):259–268
4. Brown G, Richards CJ, Bourne MW et al (2003)
Morphologic predictors of lymph node status in rectal
cancer with use of high-spatial-resolution MR imaging
with histopathologic comparison. Radiology 227(2):
371–377
5. Kim JH, Beets GL, Kim MJ et al (2004) High-resolution
MR imaging for nodal staging in rectal cancer: are
there any criteria in addition to the size? Eur J Radiol
52(1):78–83
6. Guillem JG, Diaz-Gonzalez JA, Minsky BD et al
(2008) cT3N0 rectal cancer: potential overtreatment
with preoperative chemoradiotherapy is warranted. J
Clin Oncol 26(3):368–373
7. Lahaye MJ, Beets GL, Engelen SM et al (2009)
Locally advanced rectal cancer: MR imaging for
restaging after neoadjuvant radiation therapy with con-
comitant chemotherapy. Part II. What are the criteria
to predict involved lymph nodes? Radiology 252(1):
81–91
8. Lambregts DM, Maas M, Riedl RG et al (2011) Value
of ADC measurements for nodal staging after chemo-
radiation in locally advanced rectal cancer-a per lesion
validation study. Eur Radiol 21(2):265–273
9. Barbaro B, Fiorucci C, Tebala C et al (2009) Locally
advanced rectal cancer: MR imaging in prediction of
response after preoperative chemotherapy and radia-
tion therapy. Radiology 250(3):730–739
 How Can We Identify Pathologic
Complete Responders After 10
Radiochemotherapy?

Brunella Barbaro and Lucia Leccisotti

Contents 10.1 Introduction

10.1 Introduction ................................................ 77
Complete tumor regression (pCR) may develop
10.2 Magnetic Resonance Imaging (MRI) ....... 79
after neoadjuvant chemoradiation therapy (CRT)
10.2.1 Morphologic Assessment of MRI ............. 79 for rectal cancer, and it is essential to select accu-
10.2.2 Diffusion-Weighted Magnetic Resonance
rately true complete responders in the manage-
Imaging (DWI)............................................. 79
ment of these patients [1]. Some authors proposed
10.3 Perfusion Computed Tomography that definition of a complete clinical response
(pCT) and Dynamic Contrast-Enhanced
MR Imaging (DCE-MRI) .......................... 87 (CR) should be based on very strict clinical and
endoscopic criteria. The finding of any residual
10.4 Positron Emission Tomography-
superficial ulceration, irregularity, or nodule
Computed Tomography (PET-CT) ........... 88
10.4.1 Pretreatment FDG PET-CT .......................... 89 should be considered residual tumor, and con-
10.4.2 Early Response Evaluation by versely, complete clinical responders should har-
FDG PET-CT ............................................... 89 bor no more than whitening of the mucosa,
10.4.3 Presurgical FDG PET-CT ............................ 89
telangiectasia with mucosal integrity. Definition
References ................................................................. 92 of a CR should be performed using digital exami-
nation, endoscopy, and biopsy, but these methods
are not infallible.
Response evaluation with diagnostic imaging
has evolved over the past 25 years, and methods
for assessing response following oncologic thera-
pies continue to evolve. In 2000, the Response
Evaluation Criteria in Solid Tumors (RECIST)
guidelines were introduced by the EORTC, the
B. Barbaro (*) US National Cancer Institute, and others. These
Department of Bioimaging and Radiological Sciences
investigators published four categories of
Catholic University, School of Medicine
Via della Mendola, 82, 00135 Rome, responses (complete response [CR], partial
Italy response [PR], stable disease [SD], and progres-
e-mail: bbarbaro@rm.unicatt.it sive disease PD). A CR is defined as the disap-
L. Leccisotti pearance of all target lesions, =/>30% decrease of
Department of Bioimaging and Radiological Sciences, the maximum diameter as PR. PD is defined as a
Catholic University, School of Medicine,
20% increase in of the maximum diameter of the
Largo A. Gemelli, 1, 00168 Rome,
Italy target lesions or the appearance of any new
e-mail: lucialeccisotti@yahoo.it lesions, and SD is defined as changes that do not

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 77

DOI 10.1007/978-3-642-25005-7_10, © Springer-Verlag Berlin Heidelberg 2012
78
a b
c d
Fig. 10.1 Rectal cancer in a pCR 59-year-old woman.
(a, b) HR oblique T2-weighted images of tumor before
(a) and at the end (b) of treatment show the tumor contour
by manual tracing with a cursor. (c) Pre- and (d) posttreat-
ment 3D reconstructions define 90% tumor volume reduc-
meet the previous three criteria. Volumetric analysis
provides reliable and more reproducible data than
conventional measurements which may be
affected by the anatomy of the viscera, including
the rectum which is a hollow viscus with irregular
morphology, and the intrinsic irregularity of tumor
shape (Fig. 10.1). Tumor volume measurement is
widely used for antitumor therapy response.
Recently, Lambrecht et al. [2] demonstrated in 21
patients with locally advanced rectal cancer that
ROC analysis showed an AUC of 86% at an opti-
mal cutoff value of 77% volume reduction after
B. Barbaro and L. Leccisotti
tion after CRT. The lesion volumes were displayed
automatically in three-dimensional format and were cal-
culated by summing each of the cross-sectional volumes
(multiplying cross-sectional area by section thickness) for
the entire lesion. Courtesy of [5]
CRT, yielding a sensitivity of 83% and specificity
of 86% for prediction of pCR. Kang et al. [3]
reported that more than 75% of the tumor volume
reduction ratios after CRT were significantly
associated with a high pCR rate in 84 patients
with rectal cancer. To date, the correlation between
rectal tumor histopathologic downstaging after
CRT and tumor volume reduction remains contro-
versial, especially concerning the hypothesis that
percentage volume reduction may indicate pCR.
The metric for positive response is based only on
anatomical and morphological changes which are
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy?
temporally downstream manifestations of under-
lying pathophysiological changes which may
occur earlier. In early 2009, RECIST was updated,
as RECIST 1.1, and a major development was the
incorporation of fluorodeoxyglucose positron
emission tomography (FDG-PET) in the guide-
lines, albeit in the limited role of assessing pro-
gressive disease. This is exciting in the sense that
this is the first time the working group has incor-
porated a nonanatomical imaging modality in the
assessment of tumor response, a trend that will
almost certainly continue in the future.
More advanced and specific imaging methods
are needed to characterize the underlying
pathophysiological changes induced by specific
targeting agents. Such methods may be consider-
ably more likely to offer earlier—and more
specific—information on response to treatment
when compared to changes in longest tumor
dimensions. This may be especially true in the
case of neoadjuvant treatment of rectal cancer.
pCR is highly predictive of survival in rectal can-
cer and offers an earlier endpoint for preliminary
validation of image-based response criteria.
10.2 Magnetic Resonance Imaging
(MRI)
10.2.1 Morphologic Assessment of MRI
MR imaging is considered the most accurate tool
for primary staging of the tumor extent; however, it
is not accurate in rectal cancer restaging after CRT,
especially when there is a fibrotic thickening of the
rectal wall, in distinguishing between ypT0, ypT1,
ypT2, or ypT3 tumors [4]. The untreated tumor on
T2-weighted images has intermediate signal inten-
sity between the high signal intensity of the fat tis-
sue and the low signal intensity of the muscular
layer and invades mesorectal fat with nodular pat-
tern growth. After CRT, complete disappearance of
the tumor is classified as CR (Fig. 10.2). Most
tumors develop fibrosis, leading to reduction of T2
signal and decrease in tumor size. A decrease in
signal intensity when compared with the pretreat-
ment examination represents response with fibrosis,
that is, replacement of neoplasm by fibrosis. The
79
fibrous tissue present after treatment causes thick-
ening of the rectal wall in most cases; thus, MR
imaging cannot readily differentiate yT0 or yT1
stage tumors from yT2 tumors because it is not
possible to visualize individual rectal wall layers,
and thus, thickened hypointense rectal wall is
classified as yT0–2 lesions at morphologic restag-
ing (Fig. 10.3). Some treated tumors develop a
“colloid” response with mucin production that
results in a very high signal intensity on a
T2-weighted image, which is potentially confus-
ing. When MR imaging is used in posttreatment
restaging, an increase in tumor signal intensity
when compared to pretreatment MR findings is
generally considered indicative of a mucinous
response. This is not to be confused with the highly
hyperintense areas seen in pretreatment MR images
which instead correspond to pretreatment muci-
nous tumors [5]. Irradiated tumors may show a
mucin component larger than 50% of the whole
tumor, reaching 80–90%; thus, it is possible to rec-
ognize in MR images posttreatment mucin differ-
entiation as lake of high increase in the signal
intensity (Fig. 10.4). However, MR restaging is
unable to differentiate mucinous response or
fibroinflammatory tissue from residual tumor as
persistent intermediate signal intensity. In conclu-
sion on standard MRI, a normalized rectal wall
without any detectable wall thickening is consid-
ered a definite criterion for a CR (Fig. 10.2). A solid
residual mass with intermediate signal intensity on
T2-weighted MRI is considered a definite criterion
for residual tumor. Hypointense signal intensity
that changes indicated fibrosis remains undeter-
mined; thus, purely anatomic MR imaging is
insufficient to reliably assess the true complete
responders, and there is considerable enthusiasm
for employing functional methods for selection of
these patients with high positive predictive values
and consequently to avoid put them at risk for
undertreatment.
10.2.2 Diffusion-Weighted Magnetic
Resonance Imaging (DWI)
DW-MR imaging may be an appropriate tool to
monitor the effects of treatment in vivo. Advantages
80
a b
d e
Fig. 10.2 Rectal cancer in a pCR 47-year-old man. (a)
HR oblique T2-weighted image of tumor before CRT
shows a tumor on the right lateral rectal wall protruding
into the rectal lumen as moderate hyperintense mass,
invading the rectal wall. It is difficult to determine whether
the perirectal fat (arrow) is infiltrated or spared; thus, MR
pretreatment stage was borderline tumor as stage T2 or
initial stage T3. The tumor appears as area high in signal
Fig. 10.3 A 58-year-old man with pCR low rectal can-
cer. (a) Axial DW MRIs, with a b value of 1,000 s/mm2
showed the tumor as areas of high signal intensity; (b)
the tumor as low signal intensity areas (opposite to DW
images) was drawn manually in the ADC maps based on
the corresponding (c) axial T2-weighted MRIs before,
during, and after treatment. In the DW-MRIs, the refer-
ence signal was the prostate (P), before and during treat-
ment (black arrows in a); we found no residual
hyperintense area in the corresponding tumor at the end
of treatment as possible CR (white * in a). In the corre-
sponding areas on the ADC maps, the ADC value
increased in the tumor from 1 × 10−3 to 1.3 × 10−3 mm2/s
(30%) during treatment, which indicated a possible early
response. At the end of treatment, the ADC value of the
whole tumor was 1.2 × 10−3 mm2/s. (d) Coronal
T2-weighted MRIs before and after treatment. Before
treatment, the tumor was detected as an intermediate
intensity signal that extended into the surrounding
B. Barbaro and L. Leccisotti
c
f
intensity at DW image (arrow in b) with b factor 1,000
(arrow in d) and as avid tracer FDG uptake in pretreat-
ment PET-CT (c). The tumor disappears in posttreatment
oblique (arrow in e) HR T2-weighted (arrow in c) MR
image (d) and in axial DW image (e). No FDG uptake in
the posttreatment PET-CT (f). Note concordance in mor-
phologic MR image (d), DW image (e), and FDG-PET
CT image (f) in this pCR
mesorectal fat, through the pelvic floor, indicating potential
involvement of the left levator ani muscle (white arrow).
After treatment, before surgery, the tumor showed
shrinkage and the rectal wall was hypointense and thick-
ened. The isointense to muscle intensity persisted on the
left site (white arrow). The patient underwent transanal
endoscopic microsurgery. In the bottom left corner, pho-
tomicrograph (original magnification, ×20; H&E stain)
after surgery shows marked fibrosis (black arrows) in the
rectal wall. No viable cells were detected in the rectal
wall. Final evaluation was ypT0, TRG 1/5. In this patient,
the fibrous tissue represents the site of previous tumor
and this fibrosis caused thickening of rectal wall; thus,
morphologic MR imaging cannot really differentiate T0
to T2 stage because visualization of individual rectal
wall layers is not possible, but areas of fibrosis typically
have a low cellular density, which results in low signal
intensity on high b value (b1000); thus, visual diffusion
images could hypothesize CR in this patient
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy? 81

d
82 B. Barbaro and L. Leccisotti

a b

c d

Fig. 10.4 62-year-old man with locally advanced lower
rectal cancer. (a, b) Pretreatment coronal (a) and HR
oblique (b) T2-weighted MR images show hyperintense
mass on the lateral low rectal wall with infiltration of the
levator ani muscle corresponding to T4 stage (white arrow
in a). (c, d) The pretreatment ADC map (c) corresponding
to HR oblique T2-weighted MR image (b) shows a calcu-
lated ADC tumor of 1 × 10−³ mm2/s which appears preva-
lent green in color map (d). (e, f) Coronal (e) and HR
oblique (f) T2-weighted MR images obtained 6 weeks
after the end of CRT show the residual tumor in the rectal
wall containing heterogeneous high signal intensity in
keeping with mucin production as possible response
(black arrows in e and f). T0–T2 stage at morphologic
presurgical MR imaging. (g, h) Posttreatment ADC map
(g) shows region of interest (ROI) which is drawn manu-
ally using the corresponding oblique HR T2-weighted
image (f) to identify the residual tumor regions. ADC
value increases to 1.7 × 10−3 mm2/s reaching
1.9 × 10−3 mm2/s in the area of mucin degeneration seen
as red area in color ADC map (white * in h), as the endolu-
minal sonography gel (black *). (i) Photomicrograph
(original magnification, × 20; [H-E] stain) shows no tumor
in the rectal wall but only inactive mucin lakes (black
arrows) in persistent areas of high signal intensity: ypT0
TRG 1/5. Note the heterogeneous response in this patient
with a substantial posttreatment ADC value increase
related to mucinous response. Courtesy of [5]
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy?
f
e
g h
Fig. 10.4 (continued)
of this technique are that it is completely noninva-
sive, does not require exposure to ionizing radia-
tion or injection of contrast materials, and does not
cause patient discomfort. Another advantage of
DW-MR imaging is that it can be easily added to
an MR examination protocol because it requires
83
only a minimal extension of examination time.
However, the limited spatial resolution and the
relatively poor signal-to-noise ratio on high-b-value
DW-MR imaging should be considered a limita-
tion, and echo-planar imaging sequences, more-
over, have a propensity to yield distorted images.
84
DW imaging derives its image contrast from dif-
ferences in the motion of water molecules between
tissues.
10.2.2.1 Qualitative Assessment of DWI
In tissues with normal cellularity, water protons
can diffuse relatively freely, which results in a
loss of signal on DWI. Conversely, in tissues with
increased cellularity (tumor), the diffusion of
water is restricted, resulting in remaining high
signal on DWI. Visual assessment of the relative
tissue signal attenuation at DWI is being applied
for tumor detection, tumor characterization, and
the evaluation of treatment response in patients
with cancer. In many reports, DWI has shown
promise for identification of malignant tumors,
and recent studies on rectal cancer have indicated
that DWI also may be useful. High-b-value
DW-MR imaging has shown sufficient diagnostic
ability for detecting colorectal cancer as reflected
in its high sensitivity and specificity (however,
tissues such as the brain, spinal cord, salivary
glands, testes, prostate, endometrium, bowel
mucosa, and lymphatic tissues can also be
visualized).
10.2.2.2 Quantitative Assessment of DWI
In vivo, intracellular and extracellular compart-
ments will have their own unique water diffusion
constants, which are measured in mm2/s. DWI is
typically performed using at least two b values
(e.g., b = 0 s/mm2 and other b values from 0 to
1,000 s/mm2). By performing DWI using differ-
ent b values, quantitative analysis is possible.
This analysis is usually performed at a push of a
button on the scanner or workstation that results
in the calculation of the apparent diffusion
coefficient (ADC).
By drawing regions of interests on these maps,
the ADCs of different tissues can be derived.
Areas of restricted diffusion in highly cellular
areas show low ADC values compared with less
cellular areas that return higher ADC values. At
this point, it is important to mention that although
areas of restricted diffusion will appear to be higher
in signal intensity on the DW images, these areas
will appear as low signal intensity areas (opposite
to DW images) on the ADC map (Fig. 10.3).
B. Barbaro and L. Leccisotti
With increasing tumor cellularity and archi-
tectural distortion, any increase in the tortuosity
of the extracellular space will additionally con-
tribute to decreased ADC values. It would, there-
fore, be expected that ADC values would correlate
with tumor cellularity and grade. Inverse correla-
tions between MRI-determined ADC values and
cellularity and tumor grade have been noted in
xenograft and human tumors. The measured
ADC is, therefore, inversely related to the cellu-
larity of tumors.
10.2.2.3 Pretreatment ADC Value
One of the most intriguing findings associated
with the use of DWI in cancer patients has been
that ADC measurements appear to be able to pre-
dict the response of tumor to chemotherapy and
radiation treatment. Many of the clinical studies
evaluating DWI for assessing treatment response
have been performed in patients with rectal can-
cer that produced provocative results. Dzik-Jurasz
et al. [6] were among the first to find a strong
negative correlation between the mean pretreat-
ment tumor ADC and the percentage shrinkage of
a rectal tumor after CRT. Recently, Sun et al. [7]
reported a similar observation, and Lambrecht
et al. [8] showed that, in 22 patients, the initial
ADC was significantly lower in patients with
pCR compared to those without pCR after CRT.
This negative association is consistent with the
known relationship between necrosis which
causes increases in ADC values and poor response
to treatment in cancer. Some authors [9], on the
other hand, found that the pretreatment mean
ADCs in patients with rectal cancer did not pre-
dict treatment response. The effects of high-grade
tumors on ADC values are potentially problem-
atic when trying to assign predictive significance
to pretherapy diffusion MRI values. It is conceiv-
able that low-grade tumors with little necrosis
could have similar mean high ADC values to
necrotic high-grade tumors; conversely, low pre-
therapy ADC value could be an indicator of tumor
aggressiveness related to the high cellularity in
high-grade tumors, particularly for tumors that
are known to do not readily undergo necrosis.
Nevertheless, caution should be used when
assigning prognostic significance to a mean tumor
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy?
pretherapy ADC value. Patterson et al. [10] scored
strength of evidence using a five point of scale
(1–5: weak–moderate–substantial–firm–definite)
based on authors’ perceptions of the literature
used for their review and scored as moderate (2/5)
the value of pretherapy ADC maps as possible
indicator of outcome of therapy and concluded
that, although acknowledging the potential role of
pre-CRT ADC as a quantitative biomarker to dis-
criminate the T-downstaged group from the non-
downstaged group in neoadjuvant CRT for locally
advanced rectal cancer, the role of pre-CRT ADC
seems to be very limited, particularly when
focused on the prediction of pCR.
10.2.2.4 Early Response Evaluation
The sensitivity of DW-MRI to changes in tissue
microstructure and organization has led to
increasing interest in the potential of ADC mea-
surements as a biomarker for early evaluation of
response to treatment, and these changes pre-
ceded significant reductions in tumor volume.
This response occurs within days of initiating
therapy and appears to be a consequence of cel-
lular damage leading to necrosis and, thus, a uni-
versal response to therapy. Viable tumor cells
restrict the mobility of water, whereas necrotic
tumor cells allow increased diffusion of water
molecules as a result of treatment-induced tumor
regression such as necrosis, decreased cellular-
ity, and compromised cell membrane integrity.
In a number of clinical and preclinical studies,
increases in tumor ADC values were noted early
during the course of therapy, allowing early pre-
diction of treatment response. Although there
have been few clinical studies of the effects of
treatment on tumor ADC in rectal cancer pub-
lished to date, the results of the existing studies
are promising. Some authors showed that, at the
end of the second week of CRT, significant
increases in tumor ADCs occurred in the down-
staged group. More recently, Lambrecht et al.
[2] showed an optimal cutoff point of 50% for
the percentage of ADC change during therapy
for prediction of pCR with a sensitivity,
specificity, PPV, and NPV of 100%. Patterson
et al. [10] scored (1–5) strength of evidence scale
as moderate-firm (2–4/5) the increase in ADC
85
values as prediction of clinical outcome for some
tumors during treatment. Nevertheless, the body
of evidence suggests that percentage increase of
ADC value measurement is a potentially useful
tool for personalized treatment management and
should be more widely investigated in large clin-
ical studies in the future (Figs. 10.3 and 10.5).
10.2.2.5 Presurgical Diffusion-Weighted
Magnetic Resonance Imaging
(DWI)
In 2009, the first study by Kim et al. [11] in 40
patients investigated the value of visual DWI for
predicting a pCR after CRT. Results for two inde-
pendent readers indicated that the addition of
DWI to standard rectal MRI significantly
improved the diagnostic performance for selec-
tion of pCR from an AUC of 0.68 and 0.66,
respectively for standard MRI to an AUC of 0.88
and 0.82 for standard MRI + DWI. Results of a
larger, multicenter study [12] confirm these previ-
ous findings and showed that the diagnostic per-
formance for predicting a pCR after CRT
improved for standard MRI + DWI as compared
to standard MRI only and resulted in a substantial
reduction in the number of equivocal scores and
an improved interobserver agreement. In this
multicenter study with the addition of DWI, sen-
sitivity for identification of a pCR improved by
16–52% for the three readers, and it resulted in
less overestimation of residual tumor. This is
mainly because on the restaging MRI without
DWI, many interpretation difficulties were
observed when the primary tumor bed had become
fibrotic as a result of the radiation treatment. In
these cases, it is difficult to differentiate small
areas of residual tumor from mere fibrosis and
readers tend to overestimate the presence of tumor
(Fig. 10.3). Apparently, this is where the func-
tional information from DWI proves beneficial.
Areas of fibrosis typically have a low cellular
density, which results in low signal intensity on
high-b-value (b1000) visual diffusion images.
Conversely, residual tumor areas have a relatively
high cellular density and show high signal on
DWI, which stands out within the low signal of
the surrounding tissue/fibrosis. This is the reason
why small areas of residual tumor are better
86
Fig. 10.5 70-year-old-woman with T3 middle rectal can-
cer. Axial DW MRIs (a), with a b value of 1,000 s/mm2
before, during, and after treatment compared to FDG-
PET-CT images (b) before, during, and after treatment,
show the tumor as areas of high signal intensity in pre-
treatment DW image and as avid tracer FDG uptake in
pretreatment PET-CT. At Axial DW MR image, a tumor
signal intensity reduction, yellow arrows in (a), which
corresponds to 30% ADC increase and at FDG-PET-CT
image qualitative and semiquantitative metabolic response
in the second week, are well evident (50% decrease in
depicted on DWI. Nevertheless, interpretation
errors were still observed with DWI resulting in a
suboptimal sensitivity of 52–64%. When the sig-
nal of the normal rectal wall is not fully sup-
pressed on DWI, high signal at the location of the
initial tumor area may erroneously be interpreted
as residual tumor, resulting in overstaging errors.
In addition, some imaging artifacts may occur on
DWI, particularly around air-tissue interfaces. In
this multicenter study, specificity for MRI and
B. Barbaro and L. Leccisotti
SUVmax). At the end of treatment, the comparison between
DW image (a) and FDG PET-CT image (b) reveals nei-
ther area of restricted diffusion nor uptake of FDG as pos-
sible CR. (c) Pretreatment and presurgical HR oblique
T2-weighted MR images show tumor shrinkage after
CRT, yellow arrows in (c) (in the bottom left corner, the
tumor was drawn manually in the ADC maps). The stage
was ypT2 at histology, TRG 2/5. In this patient, both
DW-MRIs and FDG-PET-CT images cannot reliably dis-
criminate residual viable tumor cells from fibrosis
microscopically
DWI is >90%, indicating that the residual tumors
are accurately detected and the risk for under-
treatment will be <10%. Although DWI allows
detection of even small (2–5 mm) tumor volumes,
the challenge will remain the detection of micro-
scopically small clusters of residual tumor cells,
which are difficult to detect—even at histology—
and are currently beyond the detection level of any
available imaging modality, including DWI
(Fig. 10.5).
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy?
In some studies, the diffusion images were not
only analyzed visually, but also quantitatively by
measuring the ADC of the tumors.
Patterson et al. [10] describes the behavior of
tumor after successful therapy and reported that
removal of dead and/or dying cells is followed by
tissue compaction, fibrosis, and regeneration of
native tissues. These processes can result in
decreases in ADC from the elevated levels caused
by decreased cellularity (Fig. 10.3). In addition, the
presence of residual active disease or repopulation
by resistant cells can also decrease ADC values;
thus, these authors concluded that interpretation of
changing ADC values must, therefore, be made
with caution. Preliminary results of many clinical
studies evaluating quantitative DWI for ADC val-
ues at the end of treatment in relatively small num-
bers of patients with rectal cancer reported that a
reduction in ADC values at the end of CRT which
they ascribed to tumor sloughing (i.e., apoptotic
cell removal) and tissue compaction (i.e., fibrosis)
and reductions in blood flow. Conversely, some
authors more recently reported that the post-CRT
ADCs in the pCR were significantly higher than
those in the non-pCR. Clinical application of the
cutoff ADC value of 1.30 × 10−3 mm2/s in the study
of Kim et al. [9] showed a perfect negative-predictive
value (NPV) useful for proper selection of the non-
CR group but low positive-predictive value (PPV)
of 52%. In these authors’ opinion, the main reason
for this poor PPV is the considerable overlap of
ADC values between pCR and near-pCR and
concluded that, although ADC is a promising
potential quantitative biomarker, it suffers from the
problem that it cannot reliably discriminate residual
viable tumor cells from fibrosis microscopically
(Fig. 10.5).
Careful consideration should be given to the
role of ADC measurements in the determination
of CR in patients with mucinous tumors because
patients in this subset supposedly have higher
ADC values than do patients with ordinary ade-
nocarcinomas. Furthermore, it is still a challenge
to predict disease activity in patients with muci-
nous tumors on conventional MR images, as it is
difficult to differentiate residual tumors from
inactive mucin pools also in mucinous response
in non-mucinous pretreatment tumor.
87
The use of whole-tumor summary statistics
(mean) has the merit of simplicity but may have
the potential of overlooking tumor heterogeneity;
histogram or voxel-wise analyses are supposed to
be alternatives for evaluating tumor heterogeneity.
10.3 Perfusion Computed
Tomography (pCT) and
Dynamic Contrast-Enhanced
MR Imaging (DCE-MRI)
Perfusion computed tomography (pCT) and
dynamic contrast-enhanced magnetic resonance
imaging (DCE-MRI) are clinical imaging tech-
niques that are increasingly applied to noninva-
sively assess the microvascular status of tumor
tissue. In clinical cancer research, regression of
tumor microvasculature is considered an impor-
tant early surrogate marker for treatment response,
before reductions in tumor volume become appar-
ent. To date, both pCT and DCE-MRI are increas-
ingly used for the prediction and evaluation of
treatment response, as indicators of tumor angio-
genesis, and for primary tumor staging. Both
pCT and DCE-MRI are imaging modalities that
rely on the dynamic assessment of tracer uptake
kinetics, subsequently quantified by means of
pharmacokinetic models. These models describe,
in terms of pharmacokinetic parameters, the
wash-in and wash-out of contrast agent from the
microvasculature into the surrounding tissues. A
commonly applied pharmacokinetic two-com-
partment model is the extended Kety model,
which consists of the (transendothelial) volume
transfer constant Ktrans, the fractional volume of
the extravascular–extracellular space (EES), ve,
and the fractional blood plasma volume, vp.
Clinically, Ktrans is the most valuable pharmacoki-
netic parameter, which describes the transfer rate
of the contrast agent from the plasma space to the
EES and represents a combination of microvas-
cular blood flow, vessel wall permeability, and
vessel density (i.e., permeability surface area
product). The usefulness of DCE-MR and pCT in
characterizing rectal tumors and their response to
treatment has been demonstrated in several clini-
cal and preclinical studies to evaluate tumor
88
neoangiogenesis noninvasively in prediction
tumor response. Rectal tumors with higher per-
meability at presentation appear to respond better
to CRT than those of lower permeability.
Recently, Kierkels et al. [13] compared pre-
treatment scans with pCT vs. DCE-MRI in rectal
tumors and concluded that DCE-MRI is recom-
mended over pCT because of the better signal-
to-noise characteristics, stronger contrast uptake,
more complete evaluation of the microcirculatory
environment of the tumor, larger tumor coverage,
and the absence of ionizing radiation.
As Patterson et al. [10] supposed, fibrosis is
associated with reduced enhancement on DCE-
MRI, whereas residual active disease causes
marked enhancement on DCE-MRI; thus, as
these authors hypothesize, the combined use of
anatomic, DWI, and DCE-MR imaging should
provide more comprehensive and accurate assess-
ment of rectal cancer response to therapy, but to
our knowledge, no data are in the literature con-
cerning DCE-MRI or pCT in evaluating pCR
after CRT in patients with rectal cancer.
10.4 Positron Emission
Tomography-Computed
Tomography (PET-CT)
Integrated PET-CT is a hybrid noninvasive imag-
ing modality which has recently become an inte-
gral part of multidisciplinary cancer care. For
most oncological indications, PET-CT is per-
formed using 2-[18F]-fluoro-2-deoxy-d-glucose
(FDG), a glucose analogue that provides func-
tional information on tumor metabolism by dem-
onstrating augmented glycolysis in tumoral cells
compared to normal cells. However, FDG uptake
is not tumor specific as benign processes such as
infection and inflammation show increased glu-
cose utilization. Patient preparation includes a
6-h fast with an optimal blood glucose
level £ 180 mg/dl. Usually, a patient is injected
with 259–370 MBq of FDG, and after a
60 ± 10-min uptake period, a “low-dose” CT fol-
lowed by PET acquisition (2–3 min per bed posi-
tion) is obtained from the skull base to upper
thigh. PET data can be analyzed qualitatively and
B. Barbaro and L. Leccisotti
semiquantitatively by measuring the standardized
uptake value (SUV). The SUV is defined as the
ratio of the activity within the tissue (KBq/ml)
and the decay-corrected total activity injected
(MBq) divided by the body weight (kg). The SUV
is usually expressed as its maximum (SUVmax).
SUVmax value is the most consistent and less
dependent on region of interest dimension.
However, the measurement of the SUVmean most
likely better reflects the behavior of the entire
tumor mass which contains viable cells mixed
with necrosis or fibrosis. FDG PET-CT has sev-
eral recognized applications in rectal cancer
including preoperative evaluation of apparently
limited metastatic disease, disease recurrence
detection, clarification of equivocal lesions at ini-
tial staging, and investigation of unexplained ris-
ing tumor markers. Recently, the applications of
PET-CT in rectal cancer are emerging in therapy
response assessment. A tumor that has significant
reduction in size may still contain viable tumor
cells, and, conversely, a residual mass may repre-
sent posttherapy changes such as edema, fibrosis,
or necrosis with no viable tumoral cells. Since
metabolic changes precede morphological changes,
functional imaging using PET should be more
sensitive and specific for therapy response assess-
ment. A favorable response is often associated to
SUV reduction, in terms of absolute SUV differ-
ence (DSUV: SUV1 − SUV2) or response index
[RI: (SUV1 − SUV2)/SUV1]. A further meta-
bolic response parameter is the total lesion glyco-
lysis (TLG) which incorporates the differences in
tumor activity between baseline and posttherapy
scans but also takes into account changes in tumor
size [(SUV2*PETvol2)/(SUV1*PETvol1)*100].
Regardless of metabolic response evaluation, the
standardization of the scanning parameters, the
time points at which responses are measured
(during CRT vs. presurgical evaluation), the inter-
pretative criteria (visual vs. semiquantitative
analysis, tumor aggressiveness [SUVmax or
SUVmean] vs. tumor burden [metabolic volume]),
and the reference criteria (tumor regression grade
[TRG] which is based on the ratio of fibrosis to
residual cancer vs. post-treatment pathological T
stage [ypT]) are essential to minimize interob-
server variability.
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy?
10.4.1 Pretreatment FDG PET-CT
FDG PET-CT in initial staging of rectal cancer is
reserved for high-risk patients (locally advanced
disease, equivocal findings on morphological
imaging, and high CEA levels). It is well known
that 95–100% of known primary rectal cancers
are visible on FDG PET-CT. False-negative
results may be encountered with mucinous tumors
and very small primary tumor. The limited spatial
resolution of this technique (4–6 mm) does not
allow to define the relationship of the primary
lesion to the mesorectal fascia or to accurately
evaluate local nodal disease (sensitivity 30–35%;
specificity ~85%). Pretreatment SUVmax of the
primary tumor does not seem to differentiate pCR
or near-pCR (TRG1–2) from pathological non-
responders (TRG3–5). However, pretreatment
FDG PET-CT is essential as baseline scan to
assess metabolic changes of the primary tumor
during and after neoadjuvant treatment.
10.4.2 Early Response Evaluation
by FDG PET-CT
In locally advanced rectal cancer, there is mount-
ing evidence of the value of FDG PET-CT in the
early prediction of the pathological response after
neoadjuvant treatment. SUV reduction as early as
12 days after preoperative CRT has been shown
to predict TRG in several published studies.
Cascini et al. [14] correlated the changes in tumor
SUVmax 12 days after starting preoperative CRT
and 6–8 weeks after the end of preoperative CRT
with the pathological results in 33 patients. The
early median decrease of tumor SUV significantly
differed between TRG1–2 (−62%; range: −44%
to −100%) and TRG3–5 (−22%; range: −2% to
−48%) (p < 0.0001). Responders were correctly
identified by decreases in the SUVmean (with a
decrease of ³52% the accuracy was 100%) and
SUVmax (with a decrease ³42% the accuracy was
94%). Janssen MH et al. [15] studied 30 patients
with locally advanced rectal cancer with sequen-
tial FDG PET-CT imaging at four time points:
prior to therapy, at days 8 and 15 during CRT, and
shortly before surgery. Tumor metabolic treat-
89
ment response was correlated with the pathologi-
cal response by the evaluation of the TRG and
ypT stage of the resected specimens. Based on
TRG evaluation, 13 patients were classified as
pathological responders (TRG1–2), whereas 17
patients were classified as pathological nonre-
sponders (TRG3–5). The RI calculated after the
first 2 weeks of CRT provided the best predictor
of pathological treatment response, reaching
AUCs of 0.87 and 0.84 for the TRG and the ypT
stage, respectively. A cutoff value of 43% for the
reduction of SUVmax resulted in a sensitivity of
77% and a specificity of 93%. Recently, the same
authors validated their preliminary results on a
larger patient population (n = 51), confirming the
potential of PET-based response prediction early
during CRT treatment [16]. Applying a cutoff
value of 48%, SUVmax reduction to differentiate
pathological responders (TRG1–2) from nonre-
sponders (TRG3–5) resulted in a specificity and
sensitivity of, respectively, 93% and 83%, with
only one of the pathological nonresponders being
false-positively predicted as pathological respond-
ing. However, data deriving from tailored therapy
based on metabolic response during neoadjuvant
CRT using alternative dosing, fractionation, or
agents are still lacking.
10.4.3 Presurgical FDG PET-CT
Presurgical PET-CT images usually show a
significant lower FDG uptake in the primary
tumor of patients with pathological confirmed
response compared to nonresponders. A mild and
diffuse FDG uptake, similar to background activ-
ity, is typical of patients with pCR or near-com-
plete pathological response (TRG1–2) (Figs. 10.2
and 10.5). Most of published studies correlated
the metabolic tumor response to TRG score and
more recently to ypT stage. The reported optimal
cutoff values of the mean reduction in SUV for
identifying a response to preoperative CRT are
heterogeneous, ranging from 40% to 70%, and
mainly rely on post-hoc analysis. Moreover, the
predictive values of FDG PET-CT response
(NPV) range between 85% and 95%, while pre-
dictive values of FDG PET-CT nonresponse
90
(PPV) range from 75% to 85%. Capirci et al. [17]
studied 45 patients with locally advanced rectal
cancer at baseline and at 5–6 weeks after the
completion of neoadjuvant CRT. The baseline
SUVmax (median 16.7) was not predictive of path-
ological response. The RI showed a good correla-
tion with the TRG. A cutoff value of 66.2%
decrease in SUVmax, identified by ROC analysis,
allowed differentiation of responders (8 TRG1 + 15
TRG2) from nonresponders (9 TRG3 + 13 TRG4–
5) with 80% overall accuracy. Melton et al. [18]
showed that FDG PET-CT parameters are best for
assessing tumor downstaging and percentage of
residual tumor after neoadjuvant treatment of rec-
tal cancer. pCR or microscopic disease (n = 7,
33%) was associated with DSUV (AUC = 0.79,
p = 0.01), while tumor downstaging (n = 14, 67%)
was associated with greater DPET volume
(AUC = 0.82, p < 0.001) and DSUV (AUC = 0.82,
p < 0.001). Recently, van Stiphout et al. [19]
developed predictive models based on clinical
and FDG PET-CT data for pCR based on a pooled
multicenter database of 953 patients with locally
advanced rectal cancer. The authors showed that
tumor dimension in combination with RI and
posttreatment SUVmax are the most predictive
variable sets for pCR resulting in very good over-
all performance AUCs of 0.86. It should be keep
in mind that false-negative presurgical PET
images may be related to a significant tumor
downsizing after a long course of CRT which can
result in an underestimation of the FDG uptake
within the tumor due to partial volume effect.
Fig. 10.6 Rectal cancer in a pCR 47-year-old man. (a)
HR oblique T2-weighted image of tumor before treatment
shows a T3 tumor on the anterior rectal wall protruding
into the rectal lumen as moderate hyperintense mass
(arrow). After treatment, before surgery, the tumor showed
shrinkage and appears as hypointense area on the anterior
site (arrow) (in the bottom left corner, the residual tumor
was drawn manually in the corresponding presurgical
ADC map). The rectal wall is thickened and alternative
rectal wall layers are well evident (yellow * indicates sub-
mucosa which is thickened and hyperintense to muscle
intensity). Axial DW-MRIs before treatment and before
surgery (b). The tumor appears as area high in signal
intensity in pretreatment DW image (arrow) with b factor
1,000 and disappears in posttreatment axial DW image
B. Barbaro and L. Leccisotti
Moreover, the “stunning” of tumor cells second-
ary to a therapy-induced reversible decrease in
glucose metabolism could mimic a response.
Therefore, FDG PET-CT is not accurate in dif-
ferentiating TRG1 from TRG2, in completely
assessing pCR or predicting tumor clearance from
the mesorectal fascia following neoadjuvant CRT
treatment. The sensitivity for assessing response
in regional nodes is also disappointing. Therefore,
a negative presurgical FDG PET-CT scan cannot
be considered as surrogate for pCR, because it is
not possible to exclude residual microscopic dis-
ease (Fig. 10.5). On the other hand, false-positive
presurgical PET images are usually related to the
inflammation induced by radiotherapy. Activated
macrophages, neutrophils, fibroblasts, and granu-
lation tissue induced by radiotherapy are known
to avidly consume FDG accounting for a consid-
erable accumulation of FDG in noncancerous
parts of the tumor (Fig. 10.6). Dynamic and dual
time point FDG PET-CT imaging as well as dif-
ferent PET tracers (i.e., 18F-FLT) might be able to
distinguish malignant from inflammatory tissue.
The emerging need to accurately identify nonin-
vasively the pCR after preoperative CRT requires
a reliable test characterized by very PPV to avoid
undertreatment of patients who still have viable
tumor cells. Although the sensitivity for pCR
with FDG PET-CT is quite high with the provided
cutoff values, the specificity is actually too low
for clinical use. To date, for neither DSUVmax-
mean nor RI, a threshold level rendering a PPV >
90% has yet been determined.
(arrow) as possible CR. Note that in the alternative rectal
wall layers in posttreatment DW image, the mucosa is
homogeneously hyperintense, black *, and the submucosa
is dark, white *, related to edema. ADC value increases to
1.6 × 10−3 mm2/s in the presurgical image. FDG-PET CT
scans before and after treatment (c). Focal FDG uptake
persists in presurgical FDG-PET-CT image (47% decrease
in SUVmax at presurgical exam). Histology reveals abun-
dant fibroinflammation tissue without residual viable
cells. The stage was ypT0, TRG 1/5. Inflammation caused
errors in FDG PET-CT imaging and is a common source
of inaccuracy in tumor restaging. In this patient, the asso-
ciation between DW imaging and FDG PET-CT was use-
ful for predicting response to avoid misinterpretation of
high residual FDG uptake as residual tumor
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy? 91

c
92
Conclusion
In this time of changing treatments, it clearly
appears that a common standard for large het-
erogeneous patient groups have to be substi-
tuted by more individualized therapies. The
radiologist’s role in the preoperative multidis-
ciplinary team’s decision-making process has
become critical because the information pro-
vided by detailed imaging of the primary
tumor guides the team to help achieve better
outcomes for patients with rectal cancer. The
use of functional imaging offers an early indi-
cation of tumor response in rectal cancer
which may ultimately allow the development
of individualized regimens. The ability to dis-
tinguish residual neoplastic tissue from scar-
ring after CRT, when restaging the patient
before surgery, is the major challenge, but the
detection of small clusters of residual tumor
cells remains a problem. In general, we can
state that the integration of functional and
molecular imaging modalities into the treat-
ment paradigm, together with the numerous
potential molecular markers, will provide a
bulk of information on each individual patient.
A good cooperation between clinics and sta-
tistics will be necessary to mine these data and
provide a predictive model enabling the pre-
diction of the response for each individual
patient allowing to optimize and individualize
treatment.
References
1. Maas M, Nelemans PJ, Valentini V et al (2010)
Pathologic complete response after chemoradiation
for rectal cancer is associated with improved long-
term outcome: a pooled analysis of 3105 patients.
Lancet Oncol 11(9):835–844
2. Lambrecht M, Vandecaveye V, De Keyzer F et al
(2012) Value of diffusion-weighted magnetic reso-
nance imaging for prediction and early assessment of
response to neoadjuvant radiochemotherapy in rectal
cancer: preliminary results. Int J Radiat Oncol Biol
Phys 82(2):863–870
3. Kang JH, Kim YC, Kim H et al (2010) Tumor volume
changes assessed by three-dimensional magnetic
resonance volumetry in rectal cancer patients after
B. Barbaro and L. Leccisotti
preoperative chemoradiation: the impact of the vol-
ume reduction ratio on the prediction of pathologic
complete response. Int J Radiat Oncol Biol Phys
76(4):1018–1025
4. Barbaro B, Fiorucci C, Tebala C et al (2009) Locally
advanced rectal cancer: MR imaging in prediction of
response after preoperative chemotherapy and radia-
tion therapy. Radiology 250(3):730–739
5. Barbaro B, Vitale R, Leccisotti L et al (2010) Restaging
locally advanced rectal cancer with MR imaging after
chemoradiation therapy. Radiographics 30(3):716–719
6. Dzik-Jurasz A, Domenig C, George M et al (2002)
Diffusion MRI for prediction of response of rectal
cancer to chemoradiation. Lancet 360(9329):307–308
7. Sun YS, Zhang XP, Tang L et al (2010) Locally
advanced rectal carcinoma treated with preoperative
chemotherapy and radiation therapy: preliminary
analysis of diffusion-weighted MR imaging for early
detection of tumor histopathologic downstaging.
Radiology 254(1):170–178
8. Lambrecht M (2010) The use of FDG-PET/CT and
diffusion-weighted magnetic resonance imaging for
response prediction before, during and after preopera-
tive chemoradiotherapy for rectal cancer. Acta Oncol
49:956–963
9. Kim SH, Lee JY, Lee JM, Han JK, Choi BI (2011)
Apparent diffusion coefficient for evaluating tumour
response to neoadjuvant chemoradiation therapy for
locally advanced rectal cancer. Eur Radiol 21(5):987–
995. doi:10.1007/s00330-010-1989-y
10. Patterson DM, Padhani AR, Collins DJ (2008)
Technology insight: water diffusion MRI-a potential
new biomarker of response to cancer therapy. Nat Clin
Pract Oncol 5(4):220–233
11. Kim SH, Lee JM, Hong SH et al (2009) Locally
advanced rectal cancer: added value of diffusion-
weighted MR imaging in the evaluation of tumor
response to neoadjuvant chemo- and radiation ther-
apy. Radiology 253(1):116–125
12. Lambregts DM, Vandecaveye V, Barbaro B et al
(2011) Diffusion-weighted MRI for selection of com-
plete responders after chemoradiation for locally
advanced rectal cancer: a multicenter study. Ann Surg
Oncol 18(8):2224–2231
13. Kierkels RG, Backes WH, Janssen MH et al (2010)
Comparison between perfusion computed tomogra-
phy and dynamic contrast-enhanced magnetic reso-
nance imaging in rectal cancer. Int J Radiat Oncol
Biol Phys 77(2):400–408
14. Cascini GL, Avallone A, Delrio P et al (2006) 18F-
FDG PET is an early predictor of pathologic tumor
response to preoperative radiochemotherapy in locally
advanced rectal cancer. J Nucl Med 47:1241–1248
15. Janssen MH, Ollers MC, Riedl RG et al (2010)
Accurate prediction of pathological rectal tumor
response after two weeks of preoperative radiochemo-
therapy using (18)F-fluorodeoxyglucose-positron
emission tomography-computed tomography imag-
ing. Int J Radiat Oncol Biol Phys 77(2):392–399
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy?
16. Janssen MH, Ollers MC, van Stiphout RG et al (2012)
PET-based treatment response evaluation in rectal
cancer: prediction and validation. Int J Radiat Oncol
Biol Phys 82(2):871–876
17. Capirci C, Rampin L, Erba PA et al (2007) Sequential
FDG-PET/CT reliably predicts response of locally
advanced rectal cancer to neo-adjuvant chemo-radiation
therapy. Eur J Nucl Med Mol Imaging 34:1583–1593
18. Melton GB, Lavely WC, Jacene HA et al (2007) Efficacy
of preoperative combined 18-fluorodeoxyglucose
93
positron emission tomography and computed tomogra-
phy for assessing primary rectal cancer response to neo-
adjuvant therapy. J Gastrointest Surg 11:961–969
19. van Stiphout RG, Lammering G, Buijsen J et al (2011)
Development and external validation of a predictive
model for pathological complete response of rectal
cancer patients including sequential PET-CT imaging.
Radiother Oncol 98:126–133
 How Can We Identify Local Relapse?
11
Doenja M.J. Lambregts
and Regina G.H. Beets-Tan

Contents 11.3.6 What Are the Limitations in the Imaging

Detection of Local Relapse? ...................... 99
11.3.7 Are There Any New Techniques
11.1 Introduction/Clinical Background .......... 96 That May Help in the Evaluation
of Local Relapse? ....................................... 100
11.2 Detection of Local Relapse During Routine
Surveillance After Rectal Surgery .......... 96 References ............................................................... 102
11.2.1 Why Follow-up and Is It Necessary? ......... 96
11.2.2 Which Tools Should Be Used
for Surveillance and at
What Frequency?........................................ 96
11.2.3 What Is the Role of CEA During
Routine Surveillance?................................. 97
11.2.4 What Is the Role of Clinical Abbreviations
Examination (Endoscopy)
During Routine Surveillance? .................... 97
11.2.5 What Is the Role of Imaging
ASCO American Society of Clinical
During Routine Surveillance? .................... 97 Oncology
CEA Carcinoembryonic Antigen
11.3 Detection of Local Relapse in Case
of an Increased Risk for Recurrence ...... 97 CT Computed Tomography
11.3.1 Which Patients Constitute DCE Dynamic Contrast Enhanced
the ‘Increased Risk’ Group? ....................... 97 DWI Diffusion-Weighted (magnetic
11.3.2 What Is the Role
resonance) Imaging
of Clinical Examination? ............................ 98
11.3.3 What Is the Role of CT? ............................. 98 ESMO European Society of Medical
11.3.4 What Is the Role of PET? ........................... 98 Oncology
11.3.5 What Is the Role of MRI? .......................... 98 FACS (trial) Follow-up After Colorectal
Surgery
GILDA (trial) Gruppo Italiano di Lavoro per
la Diagnosi Anticipata
MRI Magnetic Resonance Imaging
PET/FDG-PET Positron Emission Tomography
/18F-fluorodeoxygenase-Positron
D.M.J. Lambregts (*) • R.G.H. Beets-Tan Emission Tomography
Department of Radiology,
RCT Randomised Controlled Trial
Maastricht University Medical Centre,
P.O. Box 5800, 6202 AZ Maastricht, The Netherlands TME Total Mesorectal Excision
e-mail: d.lambregts@mumc.nl; r.beets.tan@mumc.nl TNM Tumour Node Metastasis

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 95

DOI 10.1007/978-3-642-25005-7_11, © Springer-Verlag Berlin Heidelberg 2012
96
11.1 Introduction/Clinical
Background
After surgical treatment for colorectal cancer,
approximately 35% of patients develop recur-
rent disease, the majority of which occurring
during the first 3 years after surgery. Twenty-
five to thirty percent of patients present with
metachronous metastases in the liver (20%) and/
or lungs (5–10%). These distant relapses are an
important determinant for patient outcome and
survival. Around 5–15% of patients develop a
local relapse during follow-up. These local
recurrences have little impact on survival, but
are associated with significant morbidity and
therefore significantly affect the quality of life.
If detected when they are still small, local recur-
rences can be treated with curative salvage sur-
gery, often combined with (neo)adjuvant chemo
and/or radiation treatment. The problem is that
at the time of detection, many recurrences are
already in an advanced stage and only a limited
number are curable.
11.2 Detection of Local Relapse
During Routine Surveillance
After Rectal Surgery
11.2.1 Why Follow-up and Is It
Necessary?
‘Routine’ clinical surveillance after treatment
serves several goals. The main aim is to detect
recurrent and/or metastatic disease, to identify
the patients who require salvage or other curative
treatment and thereby improve survival.
Secondary goals are to manage late post-treat-
ment complications, to document treatment out-
come and to meet patients’ psychological needs
and improve the patient-doctor relationship.
Whether routine clinical follow-up is beneficial
and cost-effective has been the subject of ongo-
ing debates and strong evidence supporting its
use is lacking. So far, mainly cohort and case–
control studies have been performed, together
with a limited number of randomised controlled
trials (RCT). The results of these RCTs have been
compared and combined in four systematic
D.M.J. Lambregts and R.G.H. Beets-Tan
reviews with meta-analyses [3, 5, 8, 10]. The
main outcomes of these meta-analyses were that
a more intensive follow-up leads to a 7% improve-
ment in survival and to the detection of more cur-
able recurrences.
11.2.2 Which Tools Should Be Used
for Surveillance and at What
Frequency?
The frequency of follow-up and routinely used
follow-up tools differs between the published
studies. As a result, there is no consensus as to
how frequently and with which modalities
patients should be followed. As distant metasta-
ses have the most significant impact on patient
outcome, the main focus of surveillance is the
detection of metastatic disease. Imaging should
therefore not only aim at detecting a local
relapse but also focus on detecting distant
relapse by a complete evaluation of the whole
body including the most likely sites for distant
metastases. So far, the largest body of evidence
exists for a beneficial role of routine carcinoem-
bryonic antigen (CEA) testing and some sort of
liver imaging, although it is not clear with which
imaging modalities (CT, ultrasound) and at what
frequency this should best be performed. Three
large European RCTs are still ongoing (the
GILDA trial in Italy, the FACS trial in the UK
and the COLOFOL trial performed in Denmark,
Sweden, Poland, Ireland and Uruguay) investi-
gating the surveillance of colorectal cancer
patients after curative surgery. Hopefully, the
results of these trials will provide more definite
evidence and result in more uniform and evi-
dence-based recommendations. While awaiting
the outcome of these trials, current guidelines
differ between Europe and the United States and
are mainly based on common clinical practice
and the (conflicting) evidence from earlier stud-
ies. As it is known that the majority of recur-
rences occur in the first 3 years after treatment,
it seems logical to at least perform regular
(6 monthly) follow-up during these first 3 years.
Especially in the high-risk patients (for instance
the locally advanced rectal cancers), this may be
extended over the first 5 years.
11 How Can We Identify Local Relapse?
11.2.3 What Is the Role of CEA During
Routine Surveillance?
Together with clinical symptoms, elevated CEA
levels have been reported to be the most frequent
first clinical indicator of relapse [1]. The colorec-
tal cancer surveillance guideline of the American
Society of Clinical Oncology (ASCO) recom-
mends 3-monthly CEA testing in patients with
stage II or III disease for at least 3 years after the
diagnosis [2]. Furthermore, it is advised to initi-
ate the CEA surveillance after adjuvant chemo-
therapy is finished, as CEA levels may be falsely
elevated in patients who are still receiving
fluorouracil-based treatment. A second issue to
take into account is the fact that CEA levels are
only elevated in approximately 60% of the
patients with colorectal cancer. Therefore, it may
be considered to only perform routine CEA test-
ing in those patients whose CEA levels were ini-
tially elevated at the time of their primary tumour
diagnosis.
11.2.4 What Is the Role of Clinical
Examination (Endoscopy)
During Routine Surveillance?
Both the ASCO guidelines, the guidelines of the
European Society of Medical Oncology (ESMO)
[4], as well as a recent European consensus paper
[11], recommend a colonoscopy every 3–5 years
after treatment, with the aim to exclude second-
ary tumours in the remaining colon and in rectal
cancer patients to detect a local recurrence. For
patients with an increased familial or inherited
risk, a more intensive colonoscopic surveillance
is required, depending on their risk category
(which is based on the number of first-, second-
and third-degree relatives with colorectal cancer
and/or genetic carriership for familial adenoma-
tous polyposis or hereditary non-polyposis col-
orectal cancer). The yield of colonoscopy in the
detection of locally recurrent tumour in normal
risk patients is, however, very low. Colonoscopy
seldom provides the first signs of recurrence and
sensitivity for detection of local relapse is less
than 50% [6]. Since the prevalence of a local
relapse in rectal cancer patients is much higher
97
than in patients with colon cancer, a more fre-
quent (3–6 monthly) endoscopic evaluation of
the rectum or rectosigmoid seems to be justified.
Especially in patients who have not received pre-
operative treatment or who have undergone a
local or subtotal excision instead of total mesorec-
tal excision (TME), more frequent endoscopic
evaluation is indicated.
11.2.5 What Is the Role of Imaging
During Routine Surveillance?
There is no solid evidence that routine imaging is
beneficial during the surveillance of patients after
colorectal cancer surgery. The ASCO guidelines
state that routine imaging is only justified in
patients with an increased risk for recurrence and
should mainly consist of annual CT of the chest
and abdomen. Especially regular monitoring of
the liver by imaging (CT or ultrasound) has been
shown to contribute to an improved survival.
Equal results were reported for CT and CEA for
the detection of curable recurrent disease. Pelvic
imaging may be considered in patients with rectal
cancer, in particular in patients who have not been
treated with radiotherapy. There is no role for rou-
tine surveillance using positron emission tomog-
raphy (PET), as the benefits do not outweigh the
high costs. Although MRI is known to be the pre-
ferred modality for the primary assessment of rec-
tal tumours, pelvic surveillance by MRI as part of
the routine follow-up scheme is not justified as it
is known that – compared to follow-up using only
CEA testing – only little additional curable and
resectable recurrences are detected with MRI and
the yield is less than one percent [9].
11.3 Detection of Local Relapse
in Case of an Increased Risk
for Recurrence
11.3.1 Which Patients Constitute
the ‘Increased Risk’ Group?
It has been suggested by different authors that a
more intensive follow-up should be preserved for
patients that have an increased risk to develop
98
recurrent disease. This includes patients with
prognostically unfavourable primary tumours
(high TNM stage, poor histologic grade, blood/
lymphatic vessel and perineural invasion, low
number of nodes investigated at pathology),
patients who have not undergone radiation treat-
ment, patients with elevated CEA levels or abnor-
mal liver function tests and patients with clinical
symptoms suspicious for recurrent disease.
Recently, a pooled analysis of the individual
patient data from five European trials was per-
formed with the aim to develop a predictive model
(based on clinical, treatment and pathologic
patient variables) to identify patient groups that
have an increased risk for local recurrence and/or
distant metastases and may benefit from more
close follow-up. Although the use of such ‘nomo-
grams’ will need to be validated using external
patient data, it may prove to be a useful support
tool to modulate the intensity of follow-up based
on a patient’s individual risk profile [12].
11.3.2 What Is the Role of Clinical
Examination?
In patients with an increased risk for recurrence
(i.e., rectal cancer patients who have not under-
gone radiation treatment and/or who have under-
gone local excision instead of total mesorectal
excision), routine endoscopic surveillance is
indicated. In addition, endoscopic examination
should be considered in patients in whom an
endoluminal recurrence is expected based on
clinical symptoms (e.g., faecal blood loss) or
digital rectal examination.
11.3.3 What Is the Role of CT?
In patients with an increased risk for a local
relapse (mainly patients with elevated CEA lev-
els and/or clinical symptoms), pelvic CT is the
modality of first choice and is generally com-
bined with a CT of the chest and abdomen to
cover the whole body and simultaneously check
for a distant relapse. CT is mainly useful to detect
a local relapse when there is a growing pelvic
D.M.J. Lambregts and R.G.H. Beets-Tan
mass on consecutive CT examinations (Fig. 11.1).
In many patients, however, pelvic CT remains
inconclusive and patients need to be referred for
additional imaging (PET and/or MRI). A draw-
back of CT is that its limited soft tissue contrast
does not allow for an assessment of tumour resec-
tability once a recurrent tumour is suspected.
11.3.4 What Is the Role of PET?
PET is generally applied as the second-line tech-
nique in patients with a (strong) clinical suspicion
of a local relapse in whom CT findings are equiv-
ocal (Fig. 11.2). A recent meta-analysis that com-
pared the use of PET, CT and combined PET-CT
for the detection of recurrent disease after col-
orectal cancer surgery found that PET and PET-CT
are superior to CT, especially in the specific sub-
group of patients who have a strong clinical suspi-
cion for recurrence (based on elevated CEA levels
or clinical symptoms). Hence, it may be defensi-
ble to immediately go for PET in these particular
high-risk patients [7], although this is not the case
in routine practice, because of the invasiveness of
the technique and its high costs. Like CT, PET is
of limited value to determine tumour resectability.
Moreover, false-positive PET findings are fre-
quently observed in areas of inflammation, in dis-
placed small bowel loops and in the proximity of
the urinary bladder. Conversely, false-negative
findings are known to occur in recurrent tumours
of the mucinous tumour type.
11.3.5 What Is the Role of MRI?
Several studies have shown that MRI is more accu-
rate than CT for the detection of a local relapse.
Nevertheless, the primary use of MRI for detec-
tion of recurrent disease has rarely been investi-
gated, and MRI is not widely available. Therefore,
MRI is not worldwide adopted in clinical practice.
This is also due to the fact that in patients with a
suspicion of locally recurrent disease, the simulta-
neous search for distant metastases requires a more
consolidated whole-body imaging technique such
as CT. MRI has so far been less suitable than CT
11 How Can We Identify Local Relapse?
a b
Fig. 11.1 Two consecutive pelvic CT examinations of a
patient treated with TME for a primary T3N2 rectal
tumour. CT examinations were performed 6 (a) and 14 (b)
months after rectal cancer surgery. (a) On the CT per-
formed after 6 months, there are no signs of a local relapse.
and PET because of the long acquisition times
required to cover the whole body and because of
its limited use for the evaluation of metastatic lung
disease. There are, however, several authors that
have advocated MRI as the technique of first
choice for the evaluation of local relapse. Due to
its excellent soft-tissue contrast, MRI is a valu-
able tool to assess the extent of a locally recurrent
tumour and to evaluate possible tumour growth
into adjacent organs and tissues. Hence, MRI has
proven most valuable in determining whether a
local relapse is still resectable (Fig. 11.3).
99
(b) On the CT performed after 14 months, a growing
pelvic mass (arrows) is identified, suspected for a recur-
rent tumour. (c) Corresponding PET-CT confirmed the
suspicious finding of a local relapse, which was confirmed
to be recurrent adenocarcinoma at biopsy
11.3.6 What Are the Limitations
in the Imaging Detection
of Local Relapse?
It has been shown that pelvic imaging mainly
fails in detecting anastomotic, intraluminal recur-
rences, which tend to be smaller in size. For the
assessment of this type of relapse, endoscopy is
better suitable. Furthermore, the techniques of
first choice (CT and to a lesser extent PET) are
of limited use for the assessment of local tumour
resectability, whereas MRI – which is more
100
a b
Fig. 11.2 CT (a), PET (b) and fused PET-CT (c) images
of a patient suspected of recurrent tumour. (a) On CT, a
mass (arrowheads) is visible, but it is not possible to dif-
ferentiate between postoperative scar tissue and a local
accurate for the latter purpose – is not helpful for
whole-body staging of recurrent disease. So far,
none of the available imaging techniques thus
qualifies as a complete one-stop-shop technique.
11.3.7 Are There Any New Techniques
That May Help in the Evaluation
of Local Relapse?
Numerous studies are being undertaken investi-
gating the clinical value of prognostic and predic-
tive markers, including molecular markers (e.g.
tumour suppressor genes and growth factors),
D.M.J. Lambregts and R.G.H. Beets-Tan
relapse. (b/c) On the corresponding PET examination (b)
and the fused PET-CT images (c), a clear area of increased
FDG uptake is identified, which was confirmed to be a
local relapse at biopsy
cell proteins and carbohydrates, and other factors
such as microvessel density, DNA content and
cell proliferation indices. In the future, such
factors may help to determine prognosis and aid
in establishing a risk-adapted surveillance strat-
egy. However, since multivariate analyses and
prospective validation studies are not yet avail-
able, the use of these markers is currently not
recommended. New imaging techniques, com-
bining functional and morphological imaging
information, are also being investigated. The first
pilot results on techniques such as dynamic con-
trast-enhanced MRI (DCE-MRI), diffusion-
weighted MRI (DWI) and image fusion techniques
11 How Can We Identify Local Relapse?
a b
Fig. 11.3 CT (a), PET (b) and MRI (c) examinations of a
patient with a local relapse after rectal cancer surgery. (a)
On CT, a mass is visible, although it is difficult to dis-
criminate between postoperative scar tissue and tumour.
(b) On PET, a clear uptake of FDG highly suspicious of
recurrent tumour can be discerned. It is, however, not
combining PET/MRI and DWI/MRI have shown
encouraging results, and further large-scale
patient studies are required to establish their
potential clinical value for the evaluation of
recurrent disease.
Conclusion
To date, there is no strong evidence yet
on what should be considered the most opti-
mal surveillance strategy after colorectal can-
cer surgery. While awaiting the evidence of
101
feasible to determine the tumour ingrowth into adjacent
organs or structures. (c) On MRI, it can be appreciated
that the tumour grows into the sacrum (arrowheads), the
iliac vessels on the right side (white arrow) and into the
bladder (black arrow). This example illustrates that MRI
is the preferred technique to evaluate tumour resectability
ongoing large trials investigating this issue,
current guidelines are based on common clini-
cal practice and the evidence provided by pre-
vious meta-analyses, which used different
follow-up schedules. These state that routine
follow-up in patients with rectal cancer should
at least include regular clinical examination,
CEA testing and some sort of liver imaging. In
patients with an increased risk for local recur-
rence (based on prognostic factors, elevated
CEA levels or clinical symptoms), imaging is
102
justified and CT is the technique of first choice.
In case of equivocal CT findings, PET is more
beneficial in identifying a local relapse. The
main role of MRI is to establish the resectabil-
ity of a local tumour recurrence once it has
been diagnosed.
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 Part IV
Q&As on Radiotherapy
 When Should Preoperative
Short-Course Radiotherapy 12
or Long-Course Chemoradiotherapy
Be Performed?

David Sebag-Montefiore and Robert Glynne-Jones

Contents 12.1 Introduction

12.1 Introduction ................................................ 105
Traditionally, there has been a high local recurrence
12.2 Rationale for the Different Approaches ... 106
rate after radical surgery in rectal cancer, and
12.3 Evidence Supporting the Efficacy of 10–40% of patients require a permanent stoma.
Short-Course Radiotherapy ...................... 106 Both short-course preoperative radiotherapy
12.3.1 Clinical Trials............................................... 106
12.3.2 Population-Based Data ................................ 108 (SCPRT) and long-course preoperative chemoradia-
12.3.3 Meta-analysis ............................................... 108 tion (CRT) are advocated to reduce this risk of local
12.4 Evidence Supporting Long-Course
recurrence and enable a curative resection. The role
Preoperative Chemoradiotherapy ............ 109 of preoperative radiotherapy to facilitate sphincter
12.4.1 Clinical Trials............................................... 109 sparing surgery remains highly contentious.
12.4.2 Meta-analysis ............................................... 109 There is considerable debate regarding the
12.5 Direct Comparison choice of preoperative radiotherapy regimen that
of the Two Approaches .............................. 111 should be used in patients with resectable rectal
12.6 Acute and Late Toxicity cancer, i.e., where staging MRI suggests that a
of SCPRT and CRT ................................... 111 standard conventional total mesorectal excision
12.7 Summary of the Current Data .................. 113 (TME) is considered to offer a curative option.
There is a strong supporting evidence base for
12.8 Preoperative Staging .................................. 113
both short-course radiotherapy (SCRT) and con-
12.9 Selection of Patients for Preoperative current chemoradiotherapy (CRT), and it is note-
Radiotherapy (SCPRT or CRT) ............... 113
worthy that the strongest support for either approach
References ................................................................. 116 is from the countries in which the key phase III tri-
als were performed. For example, short-course
radiotherapy is used more frequently in Scandinavia,
D. Sebag-Montefiore (*)
Department of Clinical Oncology, the Netherlands and the United Kingdom. Long-
University of Leeds, St James’s Institute of Oncology, course chemoradiotherapy is more frequently used
St James’s University Hospital, in southern European countries and the United
Beckett St, LS9 7TF Leeds, UK
States. Radiation oncologists usually favour one or
e-mail: d.sebagmontefiore@leeds.ac.uk
other of these approaches. This debate focuses
R. Glynne-Jonesfi more on a blanket approach and previous experi-
Department of Clinical Oncology, ence with these different schedules, with one or
Mount Vernon Centre for Cancer Treatment,
other of the above aims being predominant, rather
Rickmansworth Rd,
Northwood, Middlesex HA6 2RN, UK than choosing treatment based on the individual
e-mail: rob.glynnejones@nhs.net circumstances/stage.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 105

DOI 10.1007/978-3-642-25005-7_12, © Springer-Verlag Berlin Heidelberg 2012
106
In contrast, where the MRI suggests the cir-
cumferential resection margin (CRM) or, more
accurately, the mesorectal fascia (MRF) is poten-
tially involved, and a standard conventional total
mesorectal excision (TME) will not offer a cura-
tive option, there is almost universal agreement
that the patient requires preoperative chemora-
diotherapy with an interval to allow for downsiz-
ing/downstaging.
This chapter assesses the role of radiation
therapy in rectal cancer, with emphasis on patient
selection for preoperative chemoradiotherapy
(CRT) and short-course preoperative radiother-
apy (SCPRT) and the outcomes obtained from
each of these strategies.
12.2 Rationale for the Different
Approaches
The rationale for SCPRT is based on the short
overall treatment time (OTT), which allows sur-
gery to take place promptly (ideally within
7 days) before the radiation reaction is expressed.
The radiotherapy dose (5 × 5 Gy) is high in bio-
logical terms and avoids the potential for accel-
erated repopulation which may occur in the latter
part of long-course chemoradiation. Other
advantages include a very short period of deliv-
ery, high compliance and low cost. Adjuvant
chemotherapy with systemically active sched-
ules (e.g., FOLFOX) can be started with mini-
mal delay if deemed necessary, within a few
weeks of diagnosis. The disadvantage is that
there is insufficient time for substantial downsiz-
ing/downstaging to occur, although this may in
fact be an advantage because it allows accurate
pathological staging in terms of the nodal status.
However, SCPRT may compensate only partially
for a positive CRM.
The rationale for long-course chemoradiation
is to achieve additive effects both locally and
systemically with a concurrent fluoropyrimidine,
thereby inducing downstaging/downsizing
reducing metastases and in a small group of
patients achieving tumour sterilisation. Its role
in facilitating sphincter sparing procedures is
contentious.
D. Sebag-Montefiore and R. Glynne-Jones
12.3 Evidence Supporting the
Efficacy of Short-Course
Radiotherapy
Short-course radiotherapy was developed in
Sweden at a time when surgery was the sole treat-
ment modality for rectal cancer and there was no
evidence to support the use of adjuvant preopera-
tive radiotherapy. In order to test the role of pre-
operative radiotherapy, a minimal delay to surgical
resection was essential, and Swedish investigators
elected to evaluate the use of a high dose per frac-
tion, hypofractionated 1-week regimen.
12.3.1 Clinical Trials
Following initial development, a sequence of ran-
domised phase III trials were performed compar-
ing SCPRT followed by surgery with surgery
alone. Although earlier studies used 5 Gy per
fraction with total doses of 15–20 Gy, subsequent
trials evaluated 25 Gy in 5F. Between 1980 and
1993, over 2,000 patients were evaluated in the
Stockholm and Swedish Rectal Cancer trials. The
Stockholm I trial used parallel opposed fields
treating a large volume. This approach was asso-
ciated with increased operative mortality and
substantial late toxicity.
The Swedish rectal cancer trial [1] (Table 12.1)
was performed between 1987 and 1990 and ran-
domised 1,168 patients to receive either SCPRT
followed by surgery or surgery alone. The use of a
3- or 4-field radiotherapy technique and a reduc-
tion in the superior limit of the target volume to the
mid-L4 vertebral body prevented any increase in
operative mortality. Local recurrence was reduced
from 27% to 11% (p < 0.001), and 5-year survival
increased from 48% to 58% with surgery alone
and SPCRT and surgery, respectively (p = 0.004).
A recent report confirms that the benefits shown
are sustained after 13 years of follow-up.
The above trials reported local recurrence
rates of >20% with surgery alone and reflect sur-
gical practice at the time the trials were con-
ducted. However, surgical techniques improved
with the adoption of total mesorectal excision
(TME) described by Heald, resulting in reported
 12

Table 12.1 Key trials of short-course radiotherapy and surgery versus surgery alone/selective post-operative (chemo)radiotherapy
Duration PAT 1° end
Trial of trial NOS Randomisation NOS TME point LR METS OS DFS
Swedish 1987–1997 1,168 25 Gy/5# + surgery 553 11% 23% 58%
Rectal No OS 5 years 5 years 5 years Not stated
Cancer Surgery alone 557 27% 24% 48%
Trial
(1997)
Updated 9% 34% 38%
(2005) 13 years 13 years 13 years Not stated
26% 34% 30%
Dutch Trial 1996–1999 1,861 25 Gy/5# + surgery 897 2% 14.8% 82%
CKVO Yes LR 2 years 2 years 2 years Not stated
95–04 Surgery + highly 908 8% 16.8% 81.8%
(2001) selective RT
Updated 5% 25% 48%
(2011) 10 years 10 years 10 years Not stated
When Should Preoperative Short-Course Radiotherapy or Long-Course

11% 28% 49%

CRO7 1997–2005 1,350 25 Gy/5# + surgery 674 5% 19% 80% 78%
(2008) Yes LR 3 years 3 years 3 years 3 years
Surgery + highly 676 11% 21% 79% 72%
selective CRT
TME total mesorectal excision, LR local recurrence, DFS disease-free survival, OS overall survival
107
108
local recurrence rates of 10% or less. A key ques-
tion at this time was whether SCPRT compen-
sated for poor surgical technique, and further
trials were then designed to test the role of SCPRT
combined with TME.
The Dutch TME trial [2] and the Medical
Research Council CR07 trial [3] (Table 12.1)
compared a policy of routine SPCRT and imme-
diate surgery against initial surgery with a policy
of highly selective post-operative (chemo)radio-
therapy restricted to patients with involvement of
the circumferential resection margin (the Dutch
trial used radiotherapy alone and CR07 concur-
rent 5FU chemoradiation). Adjuvant chemother-
apy was not used in the Dutch trial, whereas
patients with stage III disease received 5FU che-
motherapy in the CR07 trial.
The two trials recruited a combined total of
3,150 patients and have reported very similar
results which are summarised in Table 12.1. The
rate of local recurrence was approximately halved
from 11% with TME to 4–5% with the addition of
SCPRT to TME. There is no evidence of any
impact on overall survival for the whole trial pop-
ulation. In the CR07 trial, pathologists assessed
the plane of surgery achieved in the surgical resec-
tion specimen (mesorectal, intra-mesorectal and
muscularis propria planes). A higher rate of LR
was seen in the muscularis propria plane, and a
reduction in LR was seen with SCPRT for all three
planes. This latter finding confirms that adjuvant
preoperative radiotherapy is of additional benefit
even when the surgical technique is optimised.
The Dutch group have recently reported 10-year
outcome data. Subset analysis of the CRM-ve
subset demonstrated a benefit for SCPRT for all
rectal subsites. The initial CR07 trial report also
described this finding. A further subset analysis
showed a statistically improved overall survival
for patients with stage III CRM-ve disease with
the addition of SCPRT. Long-term follow-up from
the CR07 data is awaited regarding this finding.
12.3.2 Population-Based Data
Den Dulk et al. used cancer registry records to
identify 3,179 patients with rectal cancer treated
D. Sebag-Montefiore and R. Glynne-Jones
between 1990 and 2002 that were then divided
into three time intervals: prior to, during and after
the Dutch TME trial. The 5-year overall survival
was 56%, 62% and 65% for the three groups,
respectively. Multivariate analysis demonstrated
preoperative radiotherapy had a statistically
significant impact on survival (p < 0.001).
A recent publication from Sweden [4] has
evaluated 6,878 patients receiving treatment for
rectal cancer between 1995 and 2001 when 41%
of patients received SCPRT. Local recurrence at
5 years was 6% with SPCRT + surgery and 12%
with surgery alone. The authors elected to com-
pare the overall survival of the two groups
restricted to patients under the age of 75 and
undergoing anterior resection or APER. The
Hazard Ratio for overall survival was 0.70 (0.69–
0.72) in favour of SCPRT. However, the
justification for this subset analysis of 3,466
patients is limited to the authors stating that the
excluded patients have ‘higher comorbidity, their
expected survivals are lower and they are less fre-
quently referred for irradiation.’
12.3.3 Meta-analysis
A number of meta-analyses have been performed
of the phase III clinical trials that tested the addi-
tion of preoperative radiotherapy to surgery
alone. The Colorectal Cancer Collaborative
Group [5] identified 14 preoperative trials that
recruited a total of 6,350 patients, with seven tri-
als using a short-course of radiotherapy with
5 Gy fractions. A significant reduction was dem-
onstrated in both local recurrence (p < 0.00001)
and overall recurrence (p < 0.00001). A 2.9%
absolute difference in overall survival was seen
in favour of adjuvant radiotherapy (p = 0.06).
A significant increase in non-cancer-related
deaths was also seen for patients who received
preoperative radiotherapy. The reasons for this
latter finding remain unclear 10 years after this
finding was reported. Other meta-analyses
broadly concur with these findings.
There is a strong evidence base supporting
the benefit of SCPRT with an approximate
halving in local recurrence both before and
12 When Should Preoperative Short-Course Radiotherapy or Long-Course
after the introduction of TME. Its impact on
overall survival is less clear, but the current
evidence suggests that if any survival advan-
tage is achieved, it is very small and does not
exceed 2–3%. Other meta-analyses have reported
similar conclusions.
12.4 Evidence Supporting
Long-Course Preoperative
Chemoradiotherapy
12.4.1 Clinical Trials
This approach was initially developed as post-
operative adjuvant therapy. In North America, an
NIH consensus statement in 1990 recommend
the use of adjuvant post-operative chemotherapy
and concurrent chemoradiotherapy using 5FU for
all patients with T3/4 or node-positive resected
rectal cancer.
In Europe, two phase III trials were performed
between 1993 and 2003 that compared long-
course preoperative radiotherapy (45 Gy in 25
fractions) with concurrent 5FU leucovorin added
to the same radiotherapy schedule (Table 12.2).
The FFCD 9203 trial [6] recruited 762 patients
and recommended post-operative 5FU/LV for all
patients, whereas the EORTC 22921 [7] recruited
1,011 patients phase III trials and used a factorial
design that also compared post-operative CRT
versus no chemotherapy.
Both trials demonstrated that the addition of
concurrent 5FU/LV was associated with an
acceptable increase in acute toxicity and path-
ological downstaging. Both trials reported very
similar findings with a significant reduction in
the rate of local recurrence from 15% to
8–10%, but with no difference in disease-free
or overall survival. The results are summarised
in Table 12.1.
The German rectal cancer group [8]
(Table 12.3) then directly compared preoperative
versus post-operative 5FU CRT. A total of 823
patients were randomised between 1995 and
2002. The rate of local recurrence was reduced
from 12% with post-operative CRT compared
with 6% with preoperative CRT. Acute and late
109
toxicity was also significantly less with the pre-
operative approach.
The results of these three trials led to a major
shift from selective post-operative CRT-based
to imaging-based selection of patients for pre-
operative CRT. This strategy has been further
supported by the results of the NSABP R03 trial
(Table 12.3) The NSABP R03 used a similar
design to the German trial but only recruited
267 of its planned patient target number
(n = 900), so results should be interpreted with
caution. Five-year loco-regional recurrence was
10.7% in each treatment arm (p = 0.693).
A significant improvement of 5-year DFS (65%
vs. 53% p = 0.011) and a non-significant
improvement in 5-year OS (75% vs. 66%
p = 0.065) were also observed for the preopera-
tive arm.
Whilst the trials discussed above selected
patients with resectable disease, a Scandinavian
trial of 207 patients with non-resectable rectal
cancer conducted between 1996 and 2003 ran-
domised patients to receive CRT with 50 Gy plus
5FU/LV versus long-course radiotherapy alone
(50 Gy). In this more advanced high-risk group, a
statistically significant reduction in local failure,
time to treatment failure and cancer-specific sur-
vival was observed in patients who received pre-
operative CRT.
We are not aware of any population-based
analyses of the use of preoperative CRT. This
approach is however widely used. Concurrent
chemotherapy may consist of 5FU either as a
continuous infusion, in combination with leuco-
vorin or using an oral fluoropyrimidine such as
capecitabine.
12.4.2 Meta-analysis
A Cochrane overview identified four trials and
concluded that preoperative CRT enhances path-
ological response and improves local control but
does not benefit disease-free or overall survival.
A recent pooled analysis of 2,795 patients from
five European trials showed that preoperative
CRT impacted on distant metastases and overall
survival [9].
 110

Table 12.2 Key trials of preoperative radiotherapy versus preoperative chemoradiotherapy

Duration of
Trial trial PAT NOS Randomisation NOS TME 1° end point Local recurrence METS Overall survival Disease-free survival
EORTC 1993–2003 1,011 45 Gy vs. 505 No OS 17% vs. 9% 5 years 32% 65% vs. 5 years 54% vs. 5 years
22921 FUFA + 45GY 506 No overall 66% 56%
(2006)
FFCD 9203 1993–2003 762 45 Gy vs. 367 No OS 17% vs. 8% 5 years No data 68% vs. 5 years No data 375
(2006) FUFA + 45GY 375 No 67%

Table 12.3 Key trials of preoperative chemoradiotherapy versus post-operative chemoradiotherapy

Duration of 1° end Disease-free
Trial trial PATNOS Randomisation NOS TME point Local recurrence METS Overall survival survival
NSABP 1993–1999 267 Preoperative 123 No OS 11% vs. 5 years Not stated 74% vs. 5 years 64% vs. 5 years
RO3 (2010) 45 Gy + FUFA 131 11% 66% 53%
vs. Post-
operative
Gy + FUFA
CAA/ARO/ 1995–2002 823 Preoperative 421 Yes OS 6% vs. 13% 5 years 36% vs. 76% vs. 5 years 68% vs. 5 years
AIO-94 50.4 Gy +5FU 402 38% 74% 65%
(2004) vs. Post-
operative
55.8 Gy +5FU
D. Sebag-Montefiore and R. Glynne-Jones
12 When Should Preoperative Short-Course Radiotherapy or Long-Course
12.5 Direct Comparison of the Two
Approaches
Two phase III trials have reported a direct com-
parison of SCPRT with preoperative CRT
(Table 12.4). The Polish trial [10] randomised
312 patients with resectable rectal cancer between
1999 and 2002. The trial tested the hypothesis
that the use of preoperative CRT with a 4–6-week
delay to surgery would increase the rate of sphinc-
ter preserving resection compared with SPCRT
and immediate surgery. No difference in the pri-
mary end point of the sphincter preservation rate
was seen. The 5-year rate of local recurrence was
9% and 14% (p = 0.17) for SCPRT and CRT,
respectively, with no significant difference in
disease-free and overall survival.
The Trans Tasman Group (TROG) trial also
randomised 326 patients with resectable rectal
cancer between 2001 and 2006 to receive either
SPCRT or preoperative CRT to compare the rate
of local recurrence. The initial report at ASCO in
2010 reported no statistical difference in the pri-
mary end point of local recurrence or secondary
end pointes of failure-free or overall survival.
The two trials discussed above are underpow-
ered, either individually or combined, to detect a
clinically relevant but small difference in LR (i.e.
5%) and therefore do not provide sufficient evi-
dence to definitively compare efficacy.
12.6 Acute and Late Toxicity
of SCPRT and CRT
As SCPRT and CRT appear broadly comparable in
terms of efficacy despite the dangers of cross trial
comparison, a comparison of acute and late toxic-
ity is of considerable importance. Data from the
Polish trial demonstrated 18% acute toxicity with
CRT compared with 3% with SCPRT, respectively
(p < 0.001). The provisional report from the TROG
trial shows a similar pattern. In contrast, SCPRT is
associated with a subacute neuropathy in <1–2%
of patients which is usually reversible. This side
effect has not been reported after CRT. Late toxic-
ity appears also equivalent in the two trials, although
the details and documentation are limited.
111
The main concern for many clinicians is the
use of 5 Gy fractions with the SCPRT regimen
and the risk of substantial late toxicity. This view
is supported by reports from the Stockholm I and
II trial that reported a significant increase in
venous thromboembolism, pelvic and femoral
neck fractures, small bowel obstruction and post-
operative fistulae. It is possible that the 2-field
technique and the large field sizes used may
explain some of these findings.
However, the Dutch and CR07 trials have
reported an increase in faecal incontinence, uri-
nary and sexual dysfunction and second malig-
nancy when SCPRT is combined with TME.
The data from the MCR CR07 trial demonstrate
that a substantial component of late toxicity is
attributable to surgery with a smaller but
significant additional impact due to the addition
of SPCRT [11].
These findings support the concerns regard-
ing late radiation toxicity with the use of 5 Gy
fraction size. However, it is important to recog-
nise that the key trials of SCPRT have all
reported detailed analyses of late toxicity. This
contrasts with very few publications that report
the incidence of late complications after preop-
erative CRT.
A recent publication by Tiv et al. [12] describes
quality of life outcomes in the EORTC 22921
trial after a median of 4.6 years. Low quality of
life scores for sexual functioning were reported
and were more severe in men than women. The
addition of chemotherapy to radiotherapy was
associated with increased diarrhoea and lower
global quality of life. There is no data that com-
pares the late toxicity of surgery versus preopera-
tive CRT.
The Polish and the TROG trials are of con-
siderable importance when comparing the late
toxicity of SCPRT against preoperative CRT
due to the randomised comparison of the two
treatment approaches. The Polish trial [10]
reported no significant difference for severe late
toxicity with rates of 10% and 7% for SPCRT
and CRT, respectively (p = 0.17). A recent pre-
sentation from the TROG trial did not detect any
significant quality of life differences between
the treatment arms.
 112

Table 12.4 Key trials of preoperative short-course radiotherapy versus chemoradiotherapy

Duration PAT 1° end
Trial of trial NOS Randomisation NOS TME point Local recurrence METS Overall survival Disease-free survival PCR
Polish 1999–2004 316 25 Gy/5# 155 Yes SPS 11% vs. 4 years No data 67% vs. 4 years 58% vs. 4 years 1%
Trial SCPRT vs. 157 16% 66% 56% 16%
(2006) FUFA
+50.4 Gy
Trans 2001–2006 326 25 Gy/5# No data Yes Local 7% vs. 4% 3 years No data 74% vs. 5 years No data No data
Tasman SCPRT vs. recurrence 70%
Radiation 50.4 Gy + PVI
Oncology 5FU
Group
TROG
01–04
(ASCO
2010)
SPS sphincter preserving surgery
D. Sebag-Montefiore and R. Glynne-Jones
12 When Should Preoperative Short-Course Radiotherapy or Long-Course
12.7 Summary of the Current Data
There is strong evidence that supports the use of
both SPCRT and preoperative CRT. Regarding
efficacy, both approaches approximately halve
the rate of local recurrence with no convincing
evidence of an impact in disease-free or overall
survival within the individual clinical trials. This
finding probably reflects the observation that the
majority of patients within these trials had early
stage disease.
Local recurrence reflects both tumour stage
and surgical technique, but the development of
metastases appears relatively independent of sur-
gery as the clinical trials demonstrate that 25–40%
of patients with resectable disease develop metas-
tases despite increasingly low rates of local recur-
rence. Hence, the consistent improvement in
local control resulting from SCPRT and CRT in
rectal cancer in the total mesorectal excision era
has not translated into a benefit in overall
survival.
Both approaches increase the rate of late tox-
icity when added to TME, and although there are
more publications describing late toxicity after
SCPRT, it is likely that CRT results in similar lev-
els of toxicity. This conclusion is supported by
the data from the Polish trial. It is therefore essen-
tial that we consider both the risks as well as the
benefits when considering the use of either
SCPRT or CRT.
12.8 Preoperative Staging
High-quality imaging investigations are of crit-
ical importance to determine whether there is
any evidence of metastatic disease and the local
disease extent within the pelvis. In early stage
disease, transrectal ultrasound has an important
role, although in the majority of patients, high-
resolution pelvic MRI is considered the investi-
gation of choice. The prospective multicentre
MERCURY trial established that the measured
extramural spread of primary tumour seen on
pelvic imaging was equivalent to the same mea-
surement in the resection specimen. The mac-
roscopic extramural spread can be measured as
113
well as the distance from the most lateral extent
of gross tumour to the mesorectal fascia, leva-
tor or anal sphincter depending on the level
within the rectum. All imaging modalities have
limitations in their accuracy of predicting
lymph node involvement. However, enlarged
nodes with an irregular border and mixed signal
characteristics are more likely to be involved
by tumour.
In routine clinical practice, the radiologist can
identify the imaging T stage and the presence or
absence of any involved nodes using the above
criteria, macroscopic extramural vascular inva-
sion, and patients where the lateral resection mar-
gin is at risk (<1 mm) or involved by tumour.
12.9 Selection of Patients for
Preoperative Radiotherapy
(SCPRT or CRT)
The local disease extent demonstrated on pelvic
staging investigations results in a spectrum of
disease ranging from the smallest tumour consid-
ered on imaging to be T2 or less without any
adverse radiological features through to very
large and bulky T3/4 tumours.
Many centres will seek to identify patients
with early stage disease where preoperative
radiotherapy can be avoided at the early end of
the disease spectrum. The Dutch and CR07 trials
both demonstrate a 3% rate of local recurrence
for patients with T1–2 N0 disease. It is impor-
tant to exclude the presence of any adverse risk
factors (including EMVI and unequivocal lymph
node involvement) to safely omit SPCRT or CRT
in patients with a primary tumour staged as T2
or less.
At the other end of the spectrum, preoperative
CRT is the treatment of choice when the primary
tumour is staged radiologically as T4b (involve-
ment of another organ) or when macroscopic
tumour involved or threatens (<1 mm) the
mesorectal fascia levator or sphincter complex.
Current evidence supports the use of concur-
rent 5FU/LV, continuous infusion 5FU or an oral
fluoropyrimidine. There is limited comparative
data regarding the choice of fluoropyrimidine,
114 D. Sebag-Montefiore and R. Glynne-Jones

Table 12.5 Risk of local recurrence according to local disease extent

High A threatened (<1 mm) or breached resection margin or low tumours encroaching
onto the intersphincteric plane or with levator involvement
Moderate Any cT3b or greater in which the potential surgical margin is not threatened or any
suspicious lymph node not threatening the surgical resection margin or the presence
of extramural vascular invasion
Low T1 or cT2 or cT3a and no lymph node involvement

although an initial report at ASCO 2011 from the
NSABP R04 trial suggests similar toxicity for
concurrent capecitabine compared with continu-
ous infusion 5FU. The addition of biological or
chemotherapy agents should only be evaluated in
the context of clinical trials and is discussed in
Chapters 19 and 18 respectively.
When preoperative CRT is given, an interval
of 4–12 weeks is used to allow tumour regression
prior to resection with little research evidence to
indicate the best time interval to use.
Some patients are considered unsuitable for
preoperative CRT, on the basis of biological age,
performance status or major cardiovascular co-
morbidity. In this situation, an alternative option
is to use SCPRT with a delay of 6–12 weeks prior
to surgery. The supporting evidence for this
approach is limited. Individual centre experience
has been reported from Upsalla in Sweden and
Leeds in the United Kingdom. This is further
supported (albeit in resectable cancers) by an
interim analysis of the Stockholm IV trial which
compares SCPRT with immediate surgery,
SCPRT with delay and 50 Gy in 25 fractions with
delay to surgery.
The remaining patients, where the primary
tumour is staged as T3 but does not involve or
threaten the margins, represent over 50% of
patients with rectal cancer, and it is this group
where the role of SPCRT or CRT is frequently
debated. The routine use of either SPCRT or CRT
represents substantial overtreatment, and in the
opinion of the authors, a selective approach is
essential, attempting to balance the benefits in the
reduction of local recurrence against the late tox-
icity associated with SCPRT or CRT.
This underlines the need to identify predictive
factors to assist the decision-making process. Little
progress has been made in the identification of
molecular biomarkers to either assist the selection
of patients at higher risk of local recurrence or pre-
dict which patients would benefit most. We there-
fore rely on known histopathological prognostic
factors that can also be identified on pelvic MRI
prior to surgical resection. This included the mea-
sured depth of extramural spread of primary T3
disease, the presence of macroscopic vascular
invasion and involvement of lymph nodes using
the criteria described above.
There is clear evidence that supports the
choice of either SCPRT or preoperative CRT for
this group. The current evidence that has com-
pared these two approaches is limited but sug-
gests that the two approaches are broadly similar
in their ability to lower the risk of local recur-
rence and so both approaches are acceptable. The
authors believe that both SCPRT and CRT are
acceptable options.
The National Institute of Health and Clinical
Excellence has recently released the pre-publica-
tion of the 2011 colorectal guidelines for the
United Kingdom (http://guidance.nice.org.uk/
CG/Wave16/2). This document describes the
identification of three differing levels of risk for
local recurrence and is shown in Table 12.5.
Patients are considered low risk when the pelvic
MRI demonstrated T3a disease or less without
adverse features. The authors support the view
that this patient group should avoid radiotherapy
altogether and have surgery alone.
Moderate risk is defined as any patient with
imaging stage T3b or greater tumour (>5 mm
beyond the muscularis propria) or EMVI or
lymph node involvement without any threat to
the margin. The authors support the view that this
patient group should be considered for either
SPCRT or preoperative CRT. Both approaches
have supporting evidence, and it is not possible to
distinguish any clear efficacy or late toxicity dif-
ferences based on the available data.
12 When Should Preoperative Short-Course Radiotherapy or Long-Course 115

Fig. 12.1 Management of Management of local disease - patients with rectal cancer
local disease (From 2011
NICE guidance)
Patient with
rectal cancer

MRI to assess local recurrence

determined by anticipated resection
margin, tumour and lymph node staging,
unless contraindicated

Patient information and support

Risk of local recurrence

High risk (locally

Low risk Moderate risk
advanced)1

Consider Consider
Chemoradio−
therapy2

SCPRT

Interval before surgery to allow

shrinkage and response
Proceed immediately to

Surgery

See algorithm on “Post−operative care”

Patients are considered high risk if tumour
breaches or threatens (<1 mm) the mesorectal fas-
cia, levator or intersphincteric plane (Fig. 12.1).
Conclusions
Preoperative radiotherapy has a strong sup-
porting evidence base demonstrating that the
rate of local recurrence can be approximately
halved when combined with TME. In contrast
to unresectable/borderline resectable cancers,
there is no evidence for increased efficacy of
CRT over SCPRT in moderate-risk resectable
cancers. The two strategies appear equally
effective, and the main rationale for choosing
between them in this setting relies on high-
quality MRI-based staging to identify the
extent of local disease and the presence of key
prognostic factors, which increase the risk of
local recurrence and entail a high risk of meta-
static disease. In contrast to 5FU-based CRT
with an interval to allow downsizing, SCPRT
allows definitive surgery to take place without
delay and allows the use of systemically active
chemotherapy (FOLFOX) within weeks.
In view of the well-documented long-term
side effects associated with radiation, it is
important to identify patients at low risk of
local recurrence who can avoid radiotherapy
altogether. Imaging can clearly identify patients
whose margins are at risk and require preoper-
ative CRT.
The main challenge is the majority of patients
with T3 disease where the balance between risk
and benefit must be carefully considered and
where both SPCRT and preoperative CRT are
acceptable treatments. Further research is needed
116
in translational molecular biology, pharmacog-
enomics and biological imaging to identify
patients either at excess risk of radiation-related
toxicity or whose cancers are more likely to
benefit from preoperative radiation and/or
fluoropyrimidine chemotherapy.
References
1. Swedish Rectal Cancer Trial (1997) Improved sur-
vival with preoperative radiotherapy in resectable rec-
tal cancer. Swedish Rectal Cancer Trial. N Engl J Med
336(14):980–987
2. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H,
Steup WH, Wiggers T et al (2001) Preoperative radio-
therapy combined with total mesorectal excision for
resectable rectal cancer. N Engl J Med 345(9):638–646
3. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J,
Grieve R, Khanna S et al (2009) Preoperative radio-
therapy versus selective postoperative chemoradiother-
apy in patients with rectal cancer (MRC CR07 and
NCIC-CTG C016): a multicentre, randomised trial.
Lancet 373(9666):811–820
4. Tiefenthal M, Nilsson PJ, Johansson R, Glimelius B,
Pahlman L (2011) The effects of short-course preop-
erative irradiation on local recurrence rate and sur-
vival in rectal cancer: a population-based nationwide
study. Dis Colon Rectum 54(6):672–680
5. Colorectal Cancer Collaborative Group (2001)
Adjuvant radiotherapy for rectal cancer: a systematic
overview of 8,507 patients from 22 randomised trials.
Lancet 358(9290):1291–1304
D. Sebag-Montefiore and R. Glynne-Jones
6. Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet
O, Closon-Dejardin MT et al (2006) Preoperative
radiotherapy with or without concurrent fluorouracil
and leucovorin in T3–4 rectal cancers: results of
FFCD 9203. J Clin Oncol 24(28):4620–4625
7. Bosset JF, Collette L, Calais G, Mineur L, Maingon P,
Radosevic-Jelic L et al (2006) Chemotherapy with
preoperative radiotherapy in rectal cancer. N Engl J
Med 355(11):1114–1123
8. Sauer R, Becker H, Hohenberger W, Rodel C,
Wittekind C, Fietkau R et al (2004) Preoperative ver-
sus postoperative chemoradiotherapy for rectal can-
cer. N Engl J Med 351(17):1731–1740
9. Valentini V, van Stiphout RG, Lammering G,
Gambacorta MA, Barba MC, Bebenek M et al (2011)
Nomograms for predicting local recurrence, distant
metastases, and overall survival for patients with locally
advanced rectal cancer on the basis of European ran-
domized clinical trials. J Clin Oncol 29(23):3163–3172
10. Bujko K, Nowacki MP, Nasierowska-Guttmejer A,
Michalski W, Bebenek M, Kryj M (2006) Long-term
results of a randomized trial comparing preoperative
short-course radiotherapy with preoperative conven-
tionally fractionated chemoradiation for rectal cancer.
Br J Surg 93(10):1215–1223
11. Stephens RJ, Thompson LC, Quirke P, Steele R,
Grieve R, Couture J et al (2010) Impact of short-
course preoperative radiotherapy for rectal cancer on
patients’ quality of life: data from the medical research
council CR07/National Cancer Institute of Canada
Clinical Trials Group C016 randomized clinical trial.
J Clin Oncol 28(27):4233–4239
12. Tiv M, Puyraveau M, Mineur L, Calais G, Maingon P,
Bardet E et al (2010) Long-term quality of life in
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(chemo)-radiotherapy within a randomized trial.
Cancer Radiother 14(6–7):530–534
 Should We Tailor the Delineation
of Pelvic Structures According 13
to Tumor Presentation?

Maria Antonietta Gambacorta and Vincenzo Valentini

Contents For decades, radiotherapy has played a funda-

13.1 Contouring Guidelines .............................. 118 mental role in promoting local control in rectal
cancer. Local control was further increased with
13.2 Local Recurrences...................................... 118
the addition of total mesorectal excision (TME)
13.3 Guidelines Proposal ................................... 121 to radiotherapy as demonstrated in randomized
13.4 CTV Definition ........................................... 125 trials [1–4].
Despite the current use of 3D techniques to
References ................................................................. 126
plan the radiotherapy treatment, the field
definition to encompass the PTV is still often
driven by the pelvic bone anatomy visible on
simulation films, DRRs, or a combination of con-
ventional technique and CT contouring–based
planning [2–6]. The main reason for this could
result from the differences in training and in
interpretation of CTV contouring between radia-
tion oncologists, which leads to large systematic
error, up to a standard deviation of 1 cm, as dem-
onstrated in some reports [7, 8].
This could be also one of the reasons why,
although the “horseshoe” shape of the PTV rep-
resents an ideal target to be treated with IMRT
resulting in a clear advantage in sparing the small
bowel and bladder, the use of this new technique
is far to be adopted into daily practice [9].
Moreover, IMRT could provide a differentiation
of dose prescription and distribution into the pel-
vic volume; for that reasons, CTV should include
subsites at different risks of local recurrence
according to tumor presentation and location.
Following the introduction of 3D radiotherapy
M.A. Gambacorta (*) • V. Valentini techniques, guidelines for CT contouring of pel-
Department of Radiotherapy,
vic nodes at risk in rectal cancer were published
Università Cattolica Sacro Cuore, Rome, Italy
e-mail: magambacorta@rm.unicatt.it; and resulted in decreased interobserver variabil-
vvalentini@rm.unicatt.it ity in CTV delineation [10–12]. However, patients

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 117

DOI 10.1007/978-3-642-25005-7_13, © Springer-Verlag Berlin Heidelberg 2012
118
with rectal cancer continue to be treated with
standard pelvic radiotherapy fields irrespective to
tumor presentation at diagnosis.
13.1 Contouring Guidelines
After the introduction of conformal radiotherapy,
recommendations for contouring were published;
the most followed are essentially two: one from
Europe and the other from the USA [10, 11].
In the European guidelines, provided by Roels
and coworkers, five different pelvic subsites were
identified according to the analysis of the inci-
dence and site of pelvic relapses in rectal cancer:
• Mesorectal subsite (MS) encompassing the
entire mesorectum and the mesorectal fascia
• Posterior pelvic subsite (PPS) corresponding
to the presacral space
• Inferior pelvic subsite (IPS) corresponding to
the ischio-rectal fossae
• Lateral pelvic subsite (LPS) encompassing to
the extramesorectal nodes corresponding to
the obturator an internal iliac nodes
• Anterior pelvic subsite (APS) corresponding
to all pelvic organs that are located ventrally
from the MS
Anatomical boundaries for CT delineation
were defined for each subsite.
The US guidelines, proposed by RTOG, devel-
oped three elective CTVs for the contouring of rec-
tal and anal cancers, based on a consensus process:
• CTV A defined as the presacral, perirectal, and
internal iliac nodes
• CTV B defined as the external iliac nodes
• CTV C defined as the inguinal nodes
Anatomical boundaries for CT delineation
were defined for each CTV.
13.2 Local Recurrences
Data reporting the patterns of local recurrence in
rectal cancer, in the TME era, are scarce and con-
tradictory, leading to confusion regarding the
definition of radiotherapy treatment volumes.
Anyway, the following separated areas at risk
could be identified.
M.A. Gambacorta and V. Valentini
The presacral space represents the area where
the majority of local relapses of all rectal cancer
are concentrated. All studies analyzing rate and
site of local recurrences in rectal cancer described
the majority of them located in the posterior pel-
vis. Although decreased after the introduction of
TME, the presacral space remains the first area of
local recurrence in rectal cancer; long-term
results from Dutch-TME trial show the presacral
space as the first area of local recurrence in both
randomization groups: RT + TME 2% versus
TME 3.6% [13]. The mechanism of occurrence
of presacral recurrence is puzzling: the presacral
space is the easiest plane of dissection during
surgery, is always included in the radiotherapy
field, is often boosted when long-course radio-
therapy is delivered, and develops despite pre-
sacral IORT is delivered. A recent anatomical
analysis did not find lymphatic tissues in the pre-
sacral space. Different mechanisms for local
relapse were supposed other than lymph node
involvement: tumor cell spillage from positive
margins, although presacral recurrence is com-
mon even in patients with negative margins, and
seedings from tumor cells in the lateral spaces
during surgical manipulation [14].
The mesorectum with its fascia must always
be included in the CTV delineation.
The mesorectum is the adipose tissue, bound-
ing the mesorectal fascia, which posteriorly and
laterally surrounds the extraperitoneal rectum. It
contains the neural and lymphovascular structures
and is the first site of lymph node involvement in
rectal cancer. Surgical series analyzing mesorec-
tal lymph node involvement showed at least one
positive lymph node in this area in 46% of patients
[10]. After the introduction of TME, the inci-
dence of recurrence in this site is very low.
However, the analysis of radiological exams of
patients with local recurrence after TME showed a
50% of presence of perirectal fat below the anasto-
mosis, suggesting a not complete mesorectal exci-
sion although TME surgery was declared by the
surgeon; moreover, the majority of patients having
a local relapse at the anastomosis had residual
mesorectal fat, suggesting a possible increased
rate of anastomotic recurrence due to the residual
mesorectal fat left behind after surgery [15].
13 Should We Tailor the Delineation of Pelvic Structures According to Tumor Presentation?
This supposition is also supported by the long-
term results of the Dutch-TME trial in which the
rate of recurrence was higher in patients with pos-
itive nodes in the TME arm, when the distal mar-
gin was 2 cm or lower; in the RT arm, the rate of
local recurrence was low except when the distal
margin was less than 5 mm. Data from pathologi-
cal specimens showed a presence of positive
lymph nodes or tumor deposits in the perirectal fat
distal to the tumor between 6.4% and 20.2% and
usually located within 2–3 cm from the cancer. A
higher probability of distal tumor deposits when
positive mesorectal nodes are present may explain
the higher incidence of local relapses in the TME
arm of the Dutch trial [13]. For the reasons men-
tioned above, the mesorectum should always be
included in the CTV of patients with rectal cancer
treated with preoperative radiotherapy.
The involvement of CRM has been demon-
strated to be a highly independent predictor of
both local control and survival; its positivity is
well predicted by preoperative MR. The impor-
tance of inclusion of the entire mesorectal fascia
in the CTV, even when negative, is based on a
subset of patients from a Japanese surgical study
reported by Moriya et al. [16]. In this trial,
patients with pathologic positive nodes who
underwent lateral lymph node dissection com-
bined with resection of the autonomic nervous
system, located along the parietal mesorectal fas-
cia, on the affected site had a significant better
DFS compared to patients with positive lateral
nodes who underwent lateral dissection with
preservation of the autonomic nervous system
(53% vs. 27%). These data suggest the presence
of microscopic residual tumor remaining on
the parietal fascia following surgery. Recently,
Nagtegaal reported increased local recurrence
rates, distant metastases, and a 50% decrease in
survival in patients with close or positive circum-
ferential radial margins (CRM) after TME as
well as the presence of tumor cells in the radial
margin far from the macroscopic tumor invasion
[17]. These data are further supported by the
autopsy data from pelvic dissection in the ten
fetuses which confirmed the presence of lym-
phatic tissue around the medial part of the infe-
rior hypogastric plexus, anatomically located
119
laterally to the parietal fascia of the mesorectum
which is usually not removed with the TME sur-
gical procedure [14]. This supports the impor-
tance of the inclusion of the entire mesorectal
fascia (visceral and parietal) in the treatment vol-
umes. Further supporting this is the fact that the
higher tumor regression achievable with preop-
erative long-course chemoradiation compared
with short-course radiotherapy could be due to
the sterilization of the mesorectal fascia, allow-
ing a TME with clear CRM [18].
More controversial is the decision to include
the lymph nodes located in the lateral spaces.
A revision of the sites of local recurrence after
the introduction of TME recommends reducing
the volume of treatment due to the higher rate of
recurrence in the posterior pelvis and the anasto-
mosis (overall 68% and as high as 89% when
excluding cT4 at diagnosis which was significantly
associated with anterior recurrence) [19]. These
data are consistent with a recently published
study which demonstrated that radiological evi-
dence of recurrence in the lateral lymph nodes is
well below 5% [15]. However, these results could
be influenced by classification of the site of local
relapse on the radiologic images used in that
study. This finding, together with the observation
that the majority of local recurrences, even after
preoperative radiotherapy, are presacral or anas-
tomotic, supports the idea to limit the radiother-
apy field to the central areas at higher risk of
recurrence, at least in selected cases with both
negative mesorectal lymph nodes and CRM [20].
Conversely, the patterns of local recurrence in the
update from the Dutch-TME trial revealed the
presacral space as the first site of relapse in
both arms, a lower anastomotic recurrence in
the radiotherapy arm, and lateral recurrences
accounted for about 20% of all local recurrences
[13]. These data are consistent with those reported
in surgical series, in which patients with low-
lying tumors have approximately 10–25% [21–
25] positive lateral lymph nodes at diagnosis.
Furthermore, as high as 40% of patients with
involved extramesorectal nodes developed local
recurrence. The rate of local recurrence was
related to the number (³4) and the site (obturator
area) of positive lateral nodes [21].
120 M.A. Gambacorta and V. Valentini

Bilateral lymph node dissection, although not a

routinely practiced in the Western world, has a
lower risk of local relapse compared to a unilat-
eral dissection (14% vs. 33%) [26]. This finding,
together with the fact that in a unilateral lymph
node dissection the site of local relapse is not
always located in the undissected lateral side
wall, suggests that the presence of lateral nodes
influences the appearance of local recurrence
despite that there is no anatomical correlation
between the local relapse and the lateral lymph b
nodes. In addition, it is possible that the removal
of lateral lymph nodes also removes microscopic
tumor cells which are in transit in the lateral
lymph nodes route, which could otherwise
infiltrate the surgical wound [26]. A recent exam-
ination of ten serially sectioned human fetal pel-
vises provides the anatomic support to this
hypothesis, demonstrating a connection between
the mesorectal and extramesorectal lymph nodes
located below the peritoneal reflection through
the middle rectal vessels and the autonomic ner-
vous system [14].
Fig. 13.1 Autoptic pelvic dissection: (a) anatomy; (b)
These results may be useful with the definition
lateral lymph nodes grouping
of radiotherapy fields. In fact, some studies com-
paring lateral lymph node dissection (LLND) and
preoperative radiotherapy showed overlapping spread of pelvic malignancies. Each lateral pelvic
local recurrence and survival in both groups. The space can be divided into three volumes to group
surgically treated patients had inferior genitouri- the nodes identified by Mangan, according to
nary and sexual function, suggesting a beneficial their proximity to the vessels or the nerves: the
effect of radiotherapy in the sterilization of can- internal iliac space including nodal groups 6–9,
cer cells in the lateral lymph nodes and justifying obturator space including group 5, and the iliac
the irradiation of extramesorectal nodes [27, 28]. space including groups 2–4 [30] (Fig.13.1).
Yu et al. examined the pattern of local recur- Anatomically, the internal iliac nodes collect the
rence and the correlation of the site with the lymphatic drainage of the rectum, whereas the
radiotherapy fields and showed that 45% of obturator nodes and the external iliac nodes drain
relapses were either marginal or out of the field, the lymphatic flow of the anterior pelvic organs.
mostly located (about 60%) beyond the anterior Data from surgical series indicate that rectal can-
and superior border of the field in a site corre- cer located below the peritoneal reflection may
sponding to superior-anterior mesorectum area also drain in the obturator nodes (9%) [31].
and anterior obturator nodes area [29]. The rate of involvement of external iliac nodes
Lateral lymph nodes include different node in rectal cancer is below 5%, and they should be
stations. The nomenclature of the lymph node included in tumors with a massive infiltration of
groups draining the pelvic organs was derived the anterior pelvic organ which drains primarily
from gynecological classification proposed by in the external iliac chain [10]. Moreover, as for
Mangan et al. This system indicates nine major seminoma in which has been seen that the pres-
groups of nodes that provide lymph drainage of ence of positive lymph nodes may cause a rever-
the pelvic organs and may be involved in the sion of the lymphatic flow, the inclusion of
13 Should We Tailor the Delineation of Pelvic Structures According to Tumor Presentation?
Fig. 13.2 MR of a rectal cancer with a massive infiltration
of the left internal iliac node
external iliac nodes should be considered when
massive obturator nodes are present at diagnosis
(Fig. 13.2).
Concern remains about the preoperative
identification of nodal disease. Magnetic reso-
nance (MR) which uses morphological criteria
such as border contour and signal intensity
appears to be superior in the evaluation of lymph
nodes compared to CT which uses only a size cri-
teria. However, MR is not conclusive in the pre-
operative identification of nodal disease when the
node size is below 8 mm [32]. For that reason, it
is difficult to preoperatively identify patients who
can benefit from radiotherapy fields extended to
the lateral spaces. Preliminary reports of MRI
diffusion-weighted imaging (DWI) in combina-
tion with T(2)-weighted imaging (T(2)WI) for
the detection of rectal cancer as compared with
T(2)WI alone provide better identification of rec-
tal cancer and local nodes [33]. Ongoing research
will clarify the role of this imaging modality.
Data from surgical series suggest that the low
location of the tumor (<4 cm from the anal mar-
gin), undifferentiated grade 3 tumors, positive
mesenteric and mesorectal nodes, and tumor
stage (T3–T4) all significantly correlate with the
lateral lymph node positivity [24]. These factors
should be used in the radiotherapy decision mak-
ing to define areas at risk to be included in the
pelvic volume.
121
The inferior pelvic subsite, as described by
Roels, consists of the anal triangle of the
perineum containing the sphincter complex with
the surrounding perianal and perirectal space.
The analysis of the literature showed a rate of
recurrence in this site of 4%, being 8% for tumors
located <6 cm from the anal verge and 11% when
an APR was performed. The authors recommend
its inclusion in the target volume in case of low-
seated tumors (<6 cm from the anal verge) and
when an APR is required [10]. However, there is
no consensus in the literature about this issue
[34]. RTOG guidelines for anal-rectal malignan-
cies recommend to involve this site only when a
tumor infiltration in the ischio-rectal fossa is
present, adding 1–2 cm margin up to bone; in all
other cases, RTOG guidelines recommend to
limit the CTV to few millimeters beyond the
levator muscles [11]. Guidelines for rectal can-
cer surgery suggest 1 cm distal margin to be
adequate for low-seated tumors. The intramural
subclinical spread in the bowel rarely occurs
beyond 1–1.5 cm below the macroscopic caudal
edge and, when it happens, is usually associated
with advanced tumor, with aggressive histology,
features all predicting a poor prognosis. Surgery
with longer distal margin seems not to improve
outcomes. Moreover, levators constitute a barrier
against the cancer spread, no nodes are present in
the ischio-rectal fossa, and recurrences in this
site were reported only after abdomino-perineal
resection. From the above considerations, in
tumors without infiltration of the sphincter com-
plex, the inferior CTV should be limited to
1.5 cm from the caudal edge of the macroscopic
tumor [35].
13.3 Guidelines Proposal
Based on the above information, we propose to
identify seven different areas at risk to be con-
toured in rectal cancer: mesorectum (M), pre-
sacral space (PS), internal iliac nodes (IIN),
obturator nodes (ON), external iliac nodes (EIN),
sphincter complex (SC) inferior pelvic subsite
(IPS) corresponding to the ischio-rectal fossae
(Table 13.1) (Figs. 13.3 and 13.4) [36].
 122

Table 13.1 Guidelines for pelvic lymph node contouring in rectal cancer
Cranial Caudal Anterior Posterior Medial Lateral
Mesorectum Bifurcation of the Insertion of the levator Superior: Anterior limit Superior: Mesorectal Superior: Mesorectal
inferior mesenteric ani muscle into the rectal of superior rectal vessels fascia in front of sacral fascia/internal and
artery (IMA) in sigmoid wall/disappearing of or a virtual line between concavity external Iliac lymph
and superior rectal artery mesorectal fat tissue the anterior aspect of node area
around the rectum internal iliac vessels of
both sides
Inferior: Bladder, Inferior: Levator ani Inferior: Levator ani
prostate/seminal vesicle muscle muscle
in man, vaginal wall/
uterus in woman
Presacral space Sacral promontory Coccyx Superior: 1 cm in front Sacral concavity Lateral border of the
(posterior pelvic of the bone sacrum
subsite) Mid-inferior: Presacral
fascia/posterior
mesorectal fascia
Internal iliac nodes Bifurcation of common Ending of the mesorec- Superior: Behind the Lateral edge of the Mesorectal Superior: Psoas
(lymph node regions) iliac artery into internal tum /appearance of external iliac vessels sacro-iliac joint fascia, pelvic muscle and ileum
and external iliac arteries ischio-rectal fossae Mid-inferior: Behind Pyriform muscle organs Inferior: Internal
(bony reference L5–S1) obturator nerve obturator muscle
Obturator nodes (lymph Caudal border of The entrance of the Posterior aspect of the Posterior aspect of the Mesorectal Internal obturator
node regions) sacro-iliac joint obturator nerve/artery in external iliac vessels obturator nerve fascia, pelvic muscle and ileum
the obturator canal organs
External iliac nodes Bifurcation of common The start of the femoralSuperior-mid: 0.7 cm Posterior aspect of the Mesorectal Psoas muscle, iliac
(lymph node regions) iliac artery into internal vessels from the vessel external iliac vein fascia, pelvic muscle
and external iliac arteries Inferior: Abdominal wall organs
(bony reference L5–S1) muscles
Sphincter complex 1.5 cm around the internal and external anal sphincters
Inferior pelvic subsite Levator ani muscle Skin Obturator muscle A virtual line between Anal canal Obturator muscle and
(ischio-rectal fossae) the posterior profile of gluteus muscle
the gluteus muscle of
both sides
M.A. Gambacorta and V. Valentini
13 Should We Tailor the Delineation of Pelvic Structures According to Tumor Presentation? 123

MF

a b
MF

ONe GMM
PM

EIV
EIA
IM

c d
MF

GMM

IOM

e f

g h

Fig. 13.3 Anatomic atlas for rectal cancer contouring.
IPM: ileopsoas muscle (a–b); *: superior rectal artery (b);
MF: Mesorectal fascia (b–f); ONe: obturator nerve (c–d);
EIV: external iliac vein (b-e);, EIA: external iliac artery
(b–e); PM: pyriform muscle (c–d); U: uterus (e); IM: Iliac
muscle (c–d); B: bladder (f); IOM: internal obturator mus-
cle (f); GMM: gluteus major muscle (a–h) PS: yellow
(a–e); EIN: green (a–e); IIN: blue (a–f); M: brown (b–g);
ON: pink (c–f); IPS: dotted blue (g); SC: dotted yellow
(h) (Images by the courtesy of TIGER project)

Guidelines have the advantage to standardize the
target volume delineation; however, some uncer-
tainties still remain and are hard to be solved [8].
The mesorectum is easy to identify in the mid-
low pelvis where the pelvic organs (bladder,
uterus/vagina, prostate) are present; however, in
the superior pelvis, its anterior part has not an ana-
tomical boundary. We suggest to enclose all the
superior rectal vessels when visible, since several
times, lymph nodes can be visible in this area
124 M.A. Gambacorta and V. Valentini

GMM

IPM *
IPM

a b
MF
GMM
GMM PM
PM ONe

EIV U
U
IM EIA IM

c d
MF

GMM ONe
GMM

U IOM

B
GMM

e f

GMM GMM

g h

Fig. 13.4 CT Atlas for rectal cancer contouring. IPM:
ileopsoas muscle (a–b); * superior rectal artery (b); MF:
Mesorectal fascia (c–f); ONe: obturator nerve (c–f); EIV:
external iliac vein (c); EIA: external iliac artery (c); PM:
pyriform muscle (c–d); U: uterus (c–d); IM: Iliac muscle
(c–d); B: bladder (f) IOM: internal obturator muscle (f);
GMM: gluteus major muscle (b–h) PS: yellow (a–f); EIN:
green (a–e); IIN: blue (a–f); M: brown (b–g); ON: pink
(c–f); IPS: dotted blue (g); SC: dotted yellow (h)

(Figs. 13.3b and 13.4b), which corresponds usu-
ally with the anterior limit of the lateral nodes.
The presacral space is so tiny that it is often
not visible on CT scan or overlaps other areas at
risks. We suggest to enclose it in mesorectum.
The internal iliac nodes, in the mid-low pelvis,
have not a corresponding visible vessel on CT.
We suggest to contour the triangular lymphovas-
cular fat area located between the pelvic wall and
the mesorectum.
13 Should We Tailor the Delineation of Pelvic Structures According to Tumor Presentation? 125

Table 13.2 Target volume delineation according to tumor stage and location
Presacral Internal Obturator External Sphincter Ischio-rectal
space Mesorectum iliac nodes nodes iliac nodes complex fossae
cT3 high (above + + +
the peritoneal
reflection)
cT3 mid-low + + + + + (when anal + (when direct
(at the peritoneal canal tumor
reflection) invasion) infiltration)
Any cT with + + + + + (when anal + (when direct
massive positive canal tumor
internal iliac invasion) infiltration)
nodes
Any cT with + + + + + + (when anal + (when direct
massive positive canal tumor
obturator nodes invasion) infiltration)
cT4 with for + + + + + + (when anal + (when direct
anterior pelvic canal tumor
organ invasion) infiltration)

The obturator nerve used as posterior limit of
the obturator nodes could seem difficult to iden-
tify; however, although very tiny, it may be fol-
lowed, scrolling CT images, as a straight structure
located behind the external iliac vessels, through
the whole pelvis (Fig. 13.4c–f).
The external iliac nodes are the easiest to
identify, thanks to the external iliac arteries and
veins well visible on CT scan (Figs. 13.3c and
13.4c). We suggest to start from this structure for
the contouring of the lateral lymph nodes.
13.4 CTV Definition
The inclusion of lateral nodes in the pelvic target
volume for preoperative radiotherapy should be
personalized according to tumor stage, tumor
site, and lymph node location as follows
(Table 13.2): always include the primary tumor,
the entire mesorectum, presacral space, and inter-
nal iliac nodes in all T3 tumors. In addition, the
obturator nodes should be added for mid-low-
located T3 tumors (< at or below the peritoneal
reflection) or in high T3 with massive positive
IIN. In T4 tumors, with anterior organ invasion,
or in T3 tumors with massive obturator node
involvement, the addition of the external iliac
nodes is recommended [11, 34] (Fig. 13.5).
The lower edge of the CTV may be modulated
according to tumor extension and invasion: (1) in
rectal cancers located at >1.5 cm from the from
the anal-rectal ring, the lower border should be
limited at the end of the mesorectum; (2) in
tumors located £1.5 cm from the anal-rectal ring,
the lower border should extend to encompass
1 cm of the anal canal; (3) in tumors extending
through the anal canal, all the anal canal and the
sphincter complex should be included; although
in the literature the margin around the sphincter
complex is not indicated, we recommend
5–10 mm of fat around it; (4) when the rectal
fossa is directly infiltrated by the tumor, both the
ischio-rectal fossae should be enclosed.
Inguinal nodes are not the target in rectal can-
cer; however, when most of the anal canal or the
ischio-rectal fossa is infiltrated in both these cases
also, they should be part of the CTV.
The introduction of the IMRT for the treat-
ment of rectal cancer requires a proper and shared
definition of the volumes of interest on CT
images; moreover, a careful center-based evalua-
tion of the target motion results is fundamental
for the evaluation of the correct ITV to avoid tar-
get missing [37].
Conclusions
Although agreement exists on the areas at risk
for local recurrence to be included in the CTV,
however, this is not the case for the contouring
boundaries. In this chapter, guidelines for the
contouring of the pelvic subsites in rectal
126
a c
b d
Fig. 13.5 (a) CTV_T3 mid-low; (b) PTV_T3; (c) CTV_T4; (d) PTV_T4
cancer are proposed to increase the confor-
mity in volumes definition among different
3.
radiation oncologists, to decrease uncertain-
ties when more conformal technique of irra-
diation such as IMRT are used, to modulate 4.
volume definition according to tumor presen-
tation (stage and location), and to facilitate
training of radiation oncologists in training. 5.
6.
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 What Is the Role of IMRT and IGRT
in Rectal Cancer? 14
Jasper Nijkamp, Karin Haustermans,
and Corrie A.M. Marijnen

Contents 14.6 IGRT ........................................................... 138

14.1 Introduction ................................................ 129 14.7 Geometric Uncertainties............................ 138
14.1.1 The Good ..................................................... 130 14.7.1 Set-up Errors ................................................ 138
14.1.2 The Bad ........................................................ 130 14.7.2 Target Volume Shape Variation.................... 138
14.1.3 The Ugly ...................................................... 130 14.7.3 Planning Target Volume Margins
to Account for Geometric Uncertainties ...... 139
14.2 Evolution of Radiotherapy Treatment 14.7.4 Correcting Shape Variation .......................... 141
Technique in Rectal Cancer ...................... 130
14.8 Response Evaluation .................................. 142
14.3 Benefits of IMRT ........................................ 132
14.9 Possibility of Dose Escalation.................... 143
14.4 Prerequisites for IMRT ............................. 133
14.4.1 Target Volume Definition ............................. 133 References ................................................................ 145
14.4.2 Target Volume Delineation .......................... 133
14.5 Measures to Reduce Irradiated
Small Bowel Volume .................................. 134
14.5.1 Full Bladder Protocol ................................... 134
14.5.2 Patient Orientation and Belly Board Use ..... 136
14.5.3 Reduction of CTV........................................ 136
14.1 Introduction

Over the past decades, advances in multi-

modality treatment strategies have contributed
significantly to the improvement of outcome in
rectal cancer patients [1–6]. Decisions about the
J. Nijkamp therapeutic regimen are based on tumour charac-
Department of Radiation Oncology, The Netherlands teristics such as TNM stage and the involvement
Cancer Institute – Antoni van Leeuwenhoek Hospital,
of the mesorectal fascia (MRF), determined with
Amsterdam, The Netherlands
magnetic resonance imaging (MRI) and endo-
K. Haustermans
scopic ultrasonography (EUS) at time of diagno-
Department of Radiation Oncology,
Leuven Cancer Institute, sis and on post-operative pathological evaluation.
University Hospital Gasthuisberg, Based on these characteristics, rectal cancers can
Leuven, Belgium be divided into three groups with respect to their
e-mail: karin.haustermans@uz.kuleuven.ac.be
chances of developing either local and/or distant
C.A.M. Marijnen (*) recurrences: low, intermediate and high risk or
Department of Clinical Oncology,
the ‘good’, the ‘bad’ and the ‘ugly’ [7, 8]. In each
Leiden University Medical Center,
Leiden, The Netherlands group, different risks are at stake which chal-
e-mail: marijnen@lumc.nl lenges the determination of optimal treatment.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 129

DOI 10.1007/978-3-642-25005-7_14, © Springer-Verlag Berlin Heidelberg 2012
130
14.1.1 The Good
The ‘good’ rectal cancers are T1 or T2, node-
negative rectal cancers that show no bad prognos-
tic factors on their MRI image. After TME
surgery, local recurrence rates in these patients
are very low and cure rates are high [9, 10]. More
experimental treatment options such as transanal
endoscopic microsurgery (TEM) with or without
preoperative chemoradiotherapy (CRT) or
chemoradiotherapy followed by a wait-and-see
policy are becoming more popular [11–15]. The
major aim of these strategies is rectum preserva-
tion with the subsequent improved quality of life
[16]. The question is whether these approaches
are safe and feasible with local recurrence rates
varying between 5% and 28% for T1 patients and
11–45% for T2 patients in the context without
preoperative treatment [11, 12]. Treatment with
TEM surgery alone should only be considered in
those patients with the lowest risk of local recur-
rence. Since lymph nodes are not removed with
TEM surgery, a negative lymph node status is by
far the most important prognostic factor for the
local recurrence risk in patients treated with TEM
only. At present, a chance of lymph node involve-
ment of 6% is considered acceptable to proceed
with local excision only.
14.1.2 The Bad
In general, ‘bad’ or intermediate risk rectal cancer
patients are considered to have a large T3N0 tumour
or a T1–3N1 tumour and will be treated with pre-
operative (chemo)radiotherapy followed by TME
surgery. Agreement exists that in case of a threat-
ened or involved mesorectal fascia, preoperative
chemoradiotherapy is the treatment of choice.
Since the prognosis of rectal cancer is stage depen-
dent, one can question whether T1/2–N1 and T3N0
patients benefit from preoperative treatment [4].
However, patient selection is hindered by imper-
fections in staging [17]. In addition, for intermedi-
ate-risk patients, the choice between preoperative
chemoradiotherapy and short-course (SC) radio-
therapy is still subject of debate.
J. Nijkamp et al.
14.1.3 The Ugly
‘Ugly’ tumours have features such as a T4 stage,
extensive lymph node involvement and are cor-
related to a high risk of local recurrence and dis-
tant metastases. Improvement in treatment can be
achieved by early prediction of response, allow-
ing quick adaptation of treatment such as
intensification of chemotherapy, dose escalation
or the addition of targeted therapies.
The above-mentioned approaches call for
improvement of the current possibilities. First of
all, we need appropriate imaging to select the
patients, to allow for preoperative risk indication.
Second, we need strategies to select patients well
responding to preoperative treatment, either to
have them qualified for organ-saving strategies or
to adapt the chemotherapy in non-responding
patients. We may need a higher dose to the gross
tumour volume to improve the complete response
rates of patients selected for organ-saving proce-
dures. An integrated boost may be a way to
accomplish this.
14.2 Evolution of Radiotherapy
Treatment Technique in Rectal
Cancer
In ideal radiotherapy, 3D volumetric imaging
with high soft tissue contrast is used on which the
gross tumour volume (GTV) and clinical target
volume (CTV) can be delineated. Subsequently, a
safety margin should be added to the CTV, creat-
ing a planning target volume (PTV) [18], which
accounts for geometric uncertainties during treat-
ment. Finally, dose delivery should fully conform
the PTV, assuring coverage of macroscopic and
microscopic disease, avoiding dose to the organs
at risk as much as possible.
The planning and delivery technique of radio-
therapy has improved greatly over the past 30 years.
In the early years, the radiotherapy dose was deliv-
ered using two opposed fields. With this technique,
a large square area received 100% of the dose,
without any shaping of the dose according to the
14 What Is the Role of IMRT and IGRT in Rectal Cancer?
Fig. 14.1 Example of a three-field conformal plan (left)
and a seven-field IMRT plan (right) on the same patient in
transversal (top) and sagittal (bottom) view. The CTV is
PTV. An improvement in conforming the dose to
the PTV was made with the introduction of three-
and four-field box techniques, although the lack
of visualization of the actual target volume
resulted in field borders defined by bony anatomy
on fluoroscopic images. Each beam was rectangle
shaped, and the size was defined by the outer bor-
ders of the PTV. With the introduction of com-
puted tomography (CT), delineation of the CTV,
3D treatment planning and the multi-leaf colli-
mator, each beam could be adapted to the actual
shape of the PTV, resulting in conformal RT.
Nowadays, we have the ability to deliver the RT
dose using intensity-modulated radiotherapy
(IMRT), where typically seven beams from dif-
ferent angles are subdivided into segments, for
which the intensity is modulated. With IMRT, the
conformality and homogeneity of the dose to the
PTV are further improved [19, 20] (Fig. 14.1).
131
outlined in dark blue, the PTV in aqua and small bowel in
yellow
Besides having a limited number of beam angles
(step and shoot), the IMRT can also be delivered
in a continuous fashion during which the collima-
tor, rotation speed and intensity can be modulated
(intensity-modulated arc therapy (IMAT)) [21].
Each of the above-described improvements in
radiotherapy delivery resulted in more confor-
mality to the PTV and, subsequently, lower dose
to the surrounding healthy tissues. Several options
are available to further improve radiotherapy.
The required PTV margin is based on geometri-
cal uncertainties, which describe the differences
between how the radiation was planned and
the actual treatment situation [18]. With the
introduction of image-guided radiotherapy
(IGRT), geometrical uncertainties can be mea-
sured and corrected during treatment, allowing
for a reduction of the PTV margin. The acquired
IGRT images also enable visualization of the
132
target volume during treatment, for example,
with cone beam CT scans, enabling better under-
standing of the treatment situation. With the
introduction of more sophisticated response
monitoring, such as with PET and diffusion-
weighted MRI [22], during treatment, the possi-
bility of adapting treatment according to
radiotherapy response has become possible.
These techniques allow for tailoring of the treat-
ment for each patient, improving the efficacy.
In this chapter, we will address the implications
of IMRT and IGRT for rectal cancer treatment as
well as the possible pitfalls that one may encoun-
ter during introduction of those techniques.
14.3 Benefits of IMRT
As mentioned before, CTV for radiotherapy of
rectal cancer generally consists of the tumour and
involved lymph nodes (GTV), the mesorectum,
the internal iliac lymph node regions and the pre-
sacral lymph node region [23]. This definition of
the CTV results in a horseshoe-shaped target vol-
ume when visualized in the transversal plane
(Fig. 14.1). The challenge in radiotherapy is to
deliver the dose to the target volume while mini-
mizing the dose to the surrounding organs at risk,
such as the small bowel and the bladder.
In current clinical practice, 3D conformal
three- or four-field dose delivery techniques are
used most often. For each field, the shape of the
beam is adapted to the shape of the target volume
using a multi-leaf collimator, while using a uni-
form intensity for the field. With this type of treat-
ment, it is impossible to fully conform to the
horseshoe shape of the CTV, resulting in delivery
of dose to the organs at risk anterior of the CTV,
especially the small bowel (Fig. 14.1). With IMRT,
it is possible to deliver more concave dose distri-
butions, which also have a more uniform dose dis-
tribution. During IMRT, typically seven or nine
fields from different gantry angles are used with
each field subdivided into different segments with
each of their own intensity (Fig. 14.1).
Important parameters for prediction of acute
and late bowel toxicity, such as the volume of
small bowel receiving 15 Gy or more (V15) [24,
J. Nijkamp et al.
25] and the volume receiving more than 45
(V45) and 50 Gy (V50) [26, 27], are significantly
reduced using IMRT [6–9]. Recently, Samuelian
et al. [28] compared 92 consecutive patients of
which 61 were treated with conformal RT (CRT)
and 31 were treated with IMRT. In the IMRT
group, significantly less patients experienced
acute grade 2 or higher GI toxicity with 32% vs.
62% in the CRT group, with differences espe-
cially in diarrhoea (23% vs. 48%) and enteritis
(6% vs. 30%). Although these findings were not
based on randomized phase III evidence, they
do indicate that the theoretical dosimetric benefit
of IMRT does translate into a clinical benefit.
IMRT has also shown to be an excellent tech-
nique to deliver a boost to the GTV, simultane-
ously delivering the standard dose to the CTV [19,
29, 30] without compromising the organ at risk
dose. The boost dose can be used to increase
down-staging, improve the ability to have an R0
resection and increase the percentage of patho-
logic complete responders [31]. With 3D confor-
mal RT, it is almost impossible to deliver a
simultaneously integrated boost (SIB) without
increasing the dose to the organs at risk. More
often, the boost dose is delivered in a number of
fractions after the standard dose is delivered, unfa-
vourably increasing the overall treatment time.
The general advantage of IMRT is a more accu-
rate delivery of the dose to the target volume, espe-
cially when the shape of the target differs from a
sphere-like shape. Different tumour presentations
will generally not result in different shape complex-
ities, and as a consequence, advantages of IMRT
will be applicable to all tumour presentations. IMRT
should therefore ideally be implemented for all rec-
tal cancer RT treatments. However, IMRT cannot
be safely implemented without attention for a num-
ber of difficulties that need to be solved.
14.4 Prerequisites for IMRT
14.4.1 Target Volume Definition
As more conformality to the target volume is
reached with IMRT, knowledge and application
of geometrical uncertainties in the construction
14 What Is the Role of IMRT and IGRT in Rectal Cancer?
of a PTV is important to prevent underdosage of
the target volume.
The first step that needs to be taken for every
patient is defining the CTV. In general, the
tumour, involved lymph nodes, the mesorectum
and the perirectal, presacral and internal iliac
lymph node regions are advised to be included. In
rectal cancer RT, several guidelines are available
as how to interpret these CTV definitions [23, 32,
33]. Roels et al. [23] developed an atlas by first
selecting required subregions based on literature
about patterns of local recurrences and subse-
quently defining the anatomical borders of these
subregions of the CTV. The atlas of Myerson
et al. [32] was developed by an RTOG consensus
panel. The atlas of Nijkamp et al. [33] was based
on the guidelines of Roels et al. [23] and was pro-
vided digitally, such that users could approach
the atlas similar to approaching a CT scan at
delineation.
14.4.2 Target Volume Delineation
Delineation variation of the CTV in rectal can-
cer is known to be larger than set-up errors [33,
34]. Interpretation differences of the CTV
between radiation oncologists can result in
CTV differences up to centimetres, resulting in
large systematic errors (up to a standard devia-
tion (SD) of 1 cm) (Fig. 14.2). Delineation vari-
ation is not the same for all regions of the CTV.
Close to bony anatomy and muscles, variation
is in the order of 0.2–0.4 cm SD, while for the
upper anterior part, close to the bladder and
small bowel, variation up to 1 cm SD is mea-
sured [33, 34].
Measures to reduce delineation variation are
the use of guidelines and delineation atlases, the
use of central reviewing experts and addition of
other modality scans such as MR and PET to
increase the anatomic and functional information.
Guidelines and a delineation atlas can reduce
the delineation variation significantly down to
approximately 0.7 cm SD [33].
In the ongoing Belgium PROCARE radio-
therapy reviewing project, CTV delineations are
reviewed in a central expert institution to monitor
133
CTV and OAR delineation nationwide and estab-
lish a learning curve by giving feedback [35].
Multi-modality imaging has been proven to
reduce target volume delineation variation in
other tumour sites [36, 37]. For rectal cancer
target volume delineation, there is only one study
available evaluating the influence of FDG-PET/
CT imaging [38] (Fig. 14.3). The use of FDG-
PET resulted in reduced variation for delineation
of the GTV. However, tumour cells might also be
present outside this GTV and should therefore be
included in the CTV. So far, no reliable imaging
of microscopic tumour cells is available, and
from this perspective, the FDG-PET has no addi-
tional value.
The value of the MRI in visualizing the
tumour, mesorectal fat and mesorectal fascia is
undisputable. Despite this common knowl-
edge, delineation on MRI is not routinely done,
and studies demonstrating its superiority are
not available, except for delineation of the
GTV in low-seated tumours [39] (Fig. 14.4).
Challenges in CTV delineation on MR for
treatment planning are in the image fusion with
the planning CT. Problems may occur when
large anatomic differences exist between both
scans (Fig. 14.4).
14.4.2.1 Small Bowel Toxicity
One of the critical organs in treatment for rectal
cancer is the small bowel. Due to its mobility,
there is no easily defined maximum tolerated
dose. However, from literature it can be concluded
that the occurrence of toxicity is primarily depen-
dent on the amount of dose to the small bowel.
Baglan et al. [24] showed that a cut-off at
150 cc of small bowel receiving more than
15 Gy divided a group of 40 patients into 0%
and 50% chance of developing acute grade 3
diarrhoea. This was later confirmed in a larger
study by Robertson et al. [25], who showed that
a cut-off point of 120 cc and 15 Gy divided the
group into 9% vs. 38% risk of developing grade
3 diarrhoea.
For late toxicity, Gallagher et al. [26] found
already in 1986 a critical level of 45 Gy to 78 cc
and 50 Gy to 17 cc of the small bowel predictive
in post-operative RT. Letschert et al. [27] showed
134 J. Nijkamp et al.

Fig. 14.2 Example images of

a patient for which the CTV
was delineated by 11 radiation
oncologists, showing the
difference in delineation
variation between delineation
based on local hospital policy
(left) and delineation using a
consensus guideline and
digital delineation atlas
(right). The top image is the
most caudal common
delineated slice. The middle
image is a mid-rectum slice
just cranial of the bladder. The
bottom image is the sagittal
view. Each observer has a
corresponding colour on all
images

afterwards, at a dose range of 40–50 Gy, that a
small bowel volume increase by a factor of 2
demands for a total dose reduction of 17% for the
same complication rate.
Besides the earlier-described effect of using
IMRT instead of conformal RT, several additional
measures can be taken to further reduce the irra-
diated small bowel volume. In the section below,
an overview of all measures and their possible
advantages is given.
14.5 Measures to Reduce Irradiated
Small Bowel Volume
14.5.1 Full Bladder Protocol
Due to the definition of the CTV up to the bifurca-
tion of the common iliac artery into the internal and
external iliac artery, there is a high probability that
small bowel will be located anterior of the CTV. In
order to reduce the dose to the small bowel, it is
14 What Is the Role of IMRT and IGRT in Rectal Cancer?
a b
Fig. 14.3 Example images acquired using a PET-CT
scanner. In (a), a sagittal view of a total body FDG-PET
image is shown, with clear uptake in the brain, the bladder
necessary to push the small bowel out of the high-
dose region. Kim et al. [40] showed in a study
comparing the small bowel dose using conformal
radiotherapy on full and empty bladder scans of the
same individuals a significant reduction in bowel
exposure with increasing bladder volumes. In a
recent study by Nijkamp et al. [41], the relation
135
and also in the rectum. In (b), the same patient is shown in
a transversal view, with the CT image on the left and on
the right the PET overlaid on the CT image
between increasing bladder volume and decreasing
bowel dose was shown in the context of IMRT.
A disadvantage of full bladder instructions is
the large day-to-day variation of the bladder vol-
ume [42]. This can potentially lead to large sys-
tematic differences between planned and delivered
dose to the small bowel.
136
Fig. 14.4 Sagittal view of a male rectal cancer patient
both on CT (left) and MR (right) after bony anatomy reg-
istration. The MR image has clear superiority in soft tis-
14.5.2 Patient Orientation and Belly
Board Use
The position of the small bowel can also be
influenced by the orientation of the patient dur-
ing treatment. Supine set-up is generally associ-
ated with more stability during irradiation, easier
set-up and more patient comfort, while prone
treatment, especially on a belly board, is associ-
ated with reduced dose to the small bowel [40,
41, 43, 44].
In many radiotherapy institutes, patients are
treated in prone positioning on a flat table to
reduce small bowel toxicity. However, several
studies failed to show significant differences in
bowel exposure between prone and supine posi-
tioning on a flat table [41, 45].
Instead of using a flat table, patients can also be
positioned prone on a belly board, compressing the
lower abdomen and pushing small bowel away from
the high-dose region. With the belly board, the bowel
exposure is significantly reduced compared to prone
or supine positioning on a flat table [40, 41]. This
effect is present both when using conformal RT [40]
and when using IMRT [41]. The study of Kim et al.
[40] showed relatively more benefit from having a
full bladder than from the belly board, where the
J. Nijkamp et al.
sue contrast, especially useful in the caudal region at the
level of the prostate
combined measures resulted in the least bowel expo-
sure. When combining a full bladder and a belly
board, patients do however indicate discomfort due
to the pressure that is put on the full bladder. In the
study of Nijkamp et al. [41], the clinical relevance of
the significant reduction in bowel exposure using the
belly board was questioned. With IMRT and a full
bladder protocol, the bowel exposure was on average
already lower than the cut-off values, predicting
acute and late toxicity, independent of patient
orientation.
14.5.3 Reduction of CTV
Besides putting effort in changing the patient’s
anatomy or improving the conformality of the
treatment plan, it might also be possible to revise
the currently accepted definition of the clinical
target volume (CTV) in certain cases. The inter-
nationally recognized CTV definition [23] is
based on all available literature about patterns of
local recurrences to come to a general definition
of the CTV and is irrespective of known risk fac-
tors, such as T or N stage. In certain subgroups,
however, a smaller CTV might also be sufficient
[46–49]. Using a 3D-computed model of all
14 What Is the Role of IMRT and IGRT in Rectal Cancer?
Fig. 14.5 Representation of the locations of the local
recurrences in the Dutch TME study, with patients treated
with a TME only on the left and patients treated with
5 × 5 Gy followed by a TME on the right. Recurrence
Fig. 14.6 Selection of the local recurrences in the Dutch
TME study for patients with node-negative disease, a
negative CRM and the tumour <10 cm from the anal verge
(red dots). Patients in the left image were treated with
TME only; on the right, RT + TME was given. The top
recurrences in the Dutch TME study, Nijkamp
et al. [49] demonstrated that most cranial recur-
rences were located a few centimetres caudal of
the promontory, irrespective of whether the
137
locations are coloured for original tumour distance from
the anal verge, with 0–5 cm (aqua), 5–10 cm (yellow) and
>10 cm (red). The top plane indicates the cranial border
of the used RT treatment fields
plane indicates the cranial border of the used RT treat-
ment fields. The lower plane indicates the S2-S3 inter-
space, to which the cranial border of the CTV could be
lowered for these patients
patients received radiotherapy (Fig. 14.5). For
patients without primary nodal and MRF involve-
ment, the most cranial recurrences were all located
below the level of the S2–S3 interspace (Fig. 14.6).
138
Lowering the cranial CTV border in early rectal
cancers may therefore be a very effective way of
reducing the irradiated small bowel volume.
14.6 IGRT
Apart from the above-mentioned CTV and delinea-
tion uncertainties, geometrical uncertainties as
inter- and intra-fraction set-up errors and inter- and
intra-fraction target volume variation need to be
compensated for to ensure safe application of IMRT
in rectal cancer. All these factors together will
finally result in a CTV-PTV margin that ensures
sufficient coverage of the clinical target volume.
The introduction of the cone beam CT has made a
reliable estimate of these uncertainties possible.
14.7 Geometric Uncertainties
14.7.1 Set-up Errors
Set-up errors are measured at the treatment
machine using electronic portal imaging devices
(EPID) [50], cone beam CT (CBCT) [51, 52] or
tomotherapy CT [53]. Corrections for set-up errors
can be applied directly before treatment, by apply-
ing a table shift. These online corrections demand
for daily imaging and come with increased imag-
ing dose and treatment time. Online correction
protocols are often used for short-course RT of
5 × 5 Gy, since the amount of fractions is limited
and relatively high doses are given per fraction.
Corrections can also be applied in an offline set-
ting, using statistical models such as shrinking
action level or no action level protocols [54, 55].
The statistical models aim to separate the system-
atic errors, average difference between the plan-
ning CT situation and the treatment, from the
random errors that represent the day-to-day varia-
tion. Offline set-up correction protocols require a
limited amount of images, and image registration
can be performed at any time, not prolonging the
treatment time. With offline correction protocols,
set-up errors can be minimized to approximately
0.2–0.3 cm SD [50], while online set-up correc-
tion results in errors of £0.1 cm SD [51, 52]. For
J. Nijkamp et al.
conventional fractionated RT, the gain in set-up
accuracy should be balanced with the increase in
imaging dose and treatment time, but also with the
other uncertainties.
Set-up errors also occur during treatment frac-
tions. These intra-fraction set-up errors are gen-
erally not corrected but need to be quantified to
be taken into account in the PTV margin. The
magnitude of these errors is dependent on the ori-
entation of the patient and the immobilization
devices that are used for patient set-up. Prone
positioning on a flat table is associated with errors
up to 0.24 cm systematic and 0.22 cm random in
left-right direction [51], while supine positioning
is associated with errors £0.1 cm systematic and
random [52].
14.7.2 Target Volume Shape Variation
With the rectum located within the CTV, large
variation in the shape of the CTV occurs due to
changes in rectal filling. Like delineation varia-
tion, CTV shape variation is also heterogeneous
[51, 52, 56]; few data are available concerning the
shape variation of the CTV in rectal cancer
patients. Nuyttens et al. [56] described the move-
ment of the anterior border of the CTV, ranging
from 0.4 cm SD at the level of the anus to 1.0 cm
SD at 10 cm from the anus. In their study, advanced
rectal cancer patients, mostly post-operative, were
investigated using repeat CT scanning.
In early stage rectal cancer, Nijkamp et al. [51,
52] described the shape variation of the mesorectal
part of the CTV both for patients treated in prone
and supine position on a flat table. For the anterior
border of the CTV, shape variation was 0.2 cm sys-
tematic SD at the level of the anus up to 0.8 cm
systematic SD at the upper anterior border of the
mesorectum. No significant differences between
prone and supine were found.
In a recent repeat CT study, Nijkamp et al.
[57] investigated the shape variation of the entire
CTV, both for short- and long-course RT. For 33
patients receiving short-course radiotherapy
(5 × 5 Gy, SCRT), daily repeat CT scans were
acquired. For 30 chemoradiotherapy (CRT)
patients, daily repeat CT scans were acquired,
14 What Is the Role of IMRT and IGRT in Rectal Cancer?
Fig. 14.7 Male patient in a repeat CT study treated with
CRT. Sagittal view of a planning CT scan (top left) and nine
repeat CT scans. On each scan, the bladder (yellow), rectum
followed by weekly scans (Fig. 14.7). On a total
of 482 CT scans, the CTV, bladder and rectum
were delineated and the CTV shape variation was
determined. In this preoperative study, the het-
erogeneous shape variation as shown by Nuyttens
et al. [56] was confirmed (Fig. 14.8). In the
patients treated with CRT, a negative time trend
in rectal volume was present, which translated in
a group mean error of approximately 0.5 cm at
the upper anterior border of the mesorectum
(Fig. 14.8). The maximum systematic error was
slightly larger in the SCRT patients compared to
CRT. Based on these results, it is clear that the
CTV shape variation is one of the major geomet-
ric uncertainties in radiotherapy of rectal cancer.
The shape variation is also complex due to its
heterogeneous presentation in different areas of
the CTV.
139
(brown) and CTV (red) are delineated. On the last picture, all
CTVs of the repeat CT scans are projected on the planning
CT scan (with the planning CTV in white for visibility)
14.7.3 Planning Target Volume
Margins to Account for
Geometric Uncertainties
PTV margins are designed to take geometric
uncertainties into account and assure a certain
minimum dose to the CTV for a certain percent-
age of the patient population [18, 58]. Known
margin recipes for calculation of PTV margins
are defined for rigid translational geometric
uncertainties, such as patient set-up and CTV
position variation. However, as described above,
one of the major geometric uncertainties in
rectal cancer RT is shape variation of the CTV,
which cannot be incorporated in the currently
available PTV margin recipes [18, 58]. In the
design of a margin recipe for shape variation of
the CTV, the first step is to take the correlation
140 J. Nijkamp et al.

Fig. 14.8 Overview (cm)

of the group mean
0.5
(top), systematic
(middle) and random 0.4
(bottom) shape
variation of the CTV 0.3
in SCRT (left) and 0.2
CRT (right). The
group mean error is 0.1
determined in
0.0
absolute cm, the
systematic and −2.0
random errors
in cm SD −0.2
−0.3

−0.4
−0.5
(cm)

1.0
0.9

0.8

0.7
0.6

0.5

0.4

0.3
0.2
0.1

0.0
(cm)

1.0
0.9

0.8

0.7
0.6

0.5

0.4

0.3
0.2
0.1

0.0
14 What Is the Role of IMRT and IGRT in Rectal Cancer?
Fig. 14.9 Locally defined 5 × 5 Gy (n = 33)
rolling ball margins for the Rolling ball margins
5 × 5 Gy patients (left) and the
25 × 2 Gy patients (right)
between the different regions of the CTV into
account for the systematic error [59, 60]. In the
rigid setting, all movements are correlated,
which is taken into account in the van Herk mar-
gin recipe by multiplying the systematic error
with a factor a = 2.5 [18]. In the deformable set-
ting, it is unclear how, for example, the shape
variation around the sphincter is correlated to
shape variation of the anterior part of the
mesorectum. To overcome the step of determin-
ing the correlation between regions, Nijkamp
et al. [57] used the repeat CT data to estimate
factor a for shape variation. By varying a
between 2 and 4 in steps of 0.1, 21 different
PTVs were calculated using:
mPTV = α ´ å +0.7 ´ σ + GM
with the group mean, systematic and random
errors shown in Fig. 14.8. For each PTV, a dose
distribution was calculated, and the dose was
accumulated over the repeat CT data. With
a = 3.2, a minimum dose of 95% of the pre-
scribed dose could be assured for 90% of the
patients. The subsequent required margins are
shown in Fig. 14.9 for SCRT and CRT sepa-
rately. The provided margin recipe was devel-
oped and tested within one data set. To fully
validate the proposed margins, a confirmation
study is needed.
141
25 × 2 Gyv (n = 30)
Rolling ball margins
(cm)
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.5
1.3
1.1
0.9
0.7
0.5
0.3
0.1
It is important to note that these margins only
account for shape variation. Other uncertainties,
such as set-up and delineated errors, should also be
incorporated in the PTV margin. With online set-
up correction, only intra-fraction stability is impor-
tant for patient set-up errors. With intra-fraction
set-up errors being small compared to shape varia-
tion, influence on CTV coverage is small.
Incorporation of delineation uncertainties is much
more complex since generally the golden standard
CTV is not known. Observers who delineate always
too small or always too large will have a different
effect on cure and toxicity of a patient. Just adding
the derived standard deviations for delineation
variation to the shape and set-up variation in the
margin concept will probably not solve the prob-
lem. This would imply addition of several centime-
tres to PTV margin for delineation variation, while
clinical evidence on local control is generally good
and not suggesting underdosage. As suggested by
Weiss and Hess [61], it would be more beneficial to
focus on strict delineation guidelines, multi-modal-
ity information and multidisciplinary discussions
with radiologists to reduce delineation variation.
14.7.4 Correcting Shape Variation
Correcting for shape variation errors using IGRT
is not as easy as dealing with set-up errors. Due to
142
the changes in the shape of the CTV, a simple
adaptation of the table position is not sufficient.
Online shape variation correction would involve
on-site treatment planning or choosing the most
appropriate plan out of a library of plans for the
shape of that day. Although these strategies seem
promising, they have not been investigated in
clinical practice yet. Offline shape variation cor-
rection can be done by means of adaptive radio-
therapy (ART). By averaging the shape of the
CTV during the first fractions, a better estimate of
the ‘real’ CTV shape can be obtained. This ART
CTV can be used for replanning, in which smaller
PTV margins can be used because the shape vari-
ation error is reduced compared to using the plan-
ning CTV alone. ART has previously been
investigated for prostate cancer patients [62] but
never for rectal cancer. Like offline set-up correc-
tion, ART also focuses on minimizing the sys-
tematic part of the shape variation. Due to the
large systematic errors in shape variation, up to
1.0 cm SD at the upper anterior part of the CTV
(Fig. 14.8), ART seems to be promising for rectal
cancer RT. The downside of ART is that CTV
needs to be delineated on the scans made in the
beginning of the treatment as well as replanning
on the average CTV, which is labour intensive.
In summary, the dominant uncertainties that
need to be taken into account in the PTV margin
are shape and delineation variation of the CTV
and with smaller magnitude the set-up errors.
Current image-guided RT is very effective in
minimization of the set-up errors, but not for the
other uncertainties. Extensive research in offline
or online adaptive replanning or plan selection
needs to be performed to really utilize IGRT for
rectal cancer. In the meantime, proper training,
guidelines and delineation atlases need to be pro-
vided to minimize the delineation variation
between radiation oncologists.
14.8 Response Evaluation
With the current standard treatment of rectal can-
cer, about 10–30% of all patients achieve a com-
plete pathological response [63–66]. They have a
favourable long-term outcome with excellent
J. Nijkamp et al.
local control rates and disease-free survival
regardless of their initial clinical staging [67, 68].
Up to now, the gold standard to accurately
assess tumour response to preoperative CRT
remains pathological examination of the resec-
tion specimen. Standard imaging modalities
using morphologic and size-related criteria lack
sufficient accuracy for the differentiation of
responders from non-responders [69]. Functional
imaging modalities allow to assess treatment-
induced changes before volumetric changes
become apparent [70, 71].
In rectal cancer, two imaging techniques show
great promise for response prediction during and
after preoperative treatment, namely, 18fluoro-
deoxy glucose positron emission tomography-CT
(18F-FDG PET-CT, Fig. 14.3) and diffusion-
weighted MRI (DW-MRI). Changes in 18FDG
uptake, quantified by the standardized uptake
value (SUV), appear to be a valid predictive fac-
tor for treatment response. This has been investi-
gated in various studies [22, 64, 72–80]. All these
studies show that the metabolic response to CRT
in rectal cancer with 18FDG-PET-CT, both early
and pre-surgical, is correlated to the histo-
pathological response in rectal cancer, and this
is despite the differences in study set-up, scan
type, pathological and metabolic evaluation.
Based on both clinical tumour data and
sequential 18FDG-PET information, van Stiphout
et al. developed a predictive model for pathologi-
cal complete remission (pCR) based on a pooled
multicentre database of 953 patients [81].
Although further prospective validation is neces-
sary, this model could prove to be a valuable
decision support tool towards a more patient-
tailored approach.
However, 18FDG-PET has some inherent
shortcomings, such as spatial resolution and
difficulty in differentiation between tumour and
inflammation.
As a stand-alone modality in rectal cancer,
DW-MRI can be a powerful tool in response
assessment both before and during preoperative
treatment as it allows with a high specificity to
differentiate persistent tumour from therapy-
related inflammation or necrosis [82–87]. Patients
with a good response to treatment generally show
14 What Is the Role of IMRT and IGRT in Rectal Cancer?
a lower apparent diffusion coefficient (ADC)
prior to treatment, with a higher change in ADC
during and after CRT. The hypothesis is that a
low initial ADC value represents a more restric-
tive environment with less interstitial oedema,
necrosis and a higher cellularity. Necrosis is gen-
erally associated with an acidic environment and
a low oxygen concentration which influences the
response to radiotherapy and chemotherapy [88].
The combination of 18FDG-PET/CT and
DW-MRI increases the accuracy of the predic-
tion. The combination of the thresholds for the
initial ADC value and the change in SUVmax after
ten fractions of chemo-radiation increases the
sensitivity to 100% and the specificity to 94% for
prediction of a pathological complete remission
[22]. However, before these complex imaging
techniques and consequent analyses can be imple-
mented in daily practice, considerable effort
towards standardization of protocols and analysis
is necessary to ensure reproducibility of the results
and enable widespread implementation [89].
14.9 Possibility of Dose Escalation
Several studies have shown a dose-effect relation
in rectal cancer [90–93], implying that dose esca-
lation might be an interesting option. Dose escala-
tion generally consists of a boost dose given to the
GTV while maintaining a standardized dose to the
CTV, for which IMRT seems a suitable option.
With use of IMRT, it is possible to deliver a simul-
taneously integrated boost (SIB) to the GTV,
while giving the standard dose to the CTV [19, 29,
30]. The advantage of SIB over more local thera-
pies like contact therapy or brachytherapy is that
treatment time is not prolonged and treatment
burden is not increased, although dose to the
organs at risk might potentially be larger using
the SIB technique.
The concept of GTV as presently used is an
oversimplification of the reality as it does not
approach the complexity of the tumour biology.
A more elaborate delineation taking into account
the biological components of tumours should
allow a more tailored and refined dose prescrip-
tion and dose distribution, which might enhance
143
the response of the patient to radiotherapy [94]. If
dose escalation is considered, accurate knowl-
edge of the exact tumour volume is required to
maintain an acceptable small bowel and bladder
toxicity.
In rectal cancer, the data on the role of func-
tional imaging in dose painting are rather limited
[95]. Roels et al. investigated the different bio-
logical characteristics of rectal cancer by repeated
imaging with three different PET tracers (18F-
FDG, 18F-FLT and 18F-FMISO), aiming at refining
the definition of target volume and at testing the
possibility of radiation dose boosting. They found
that the mean 18F-FDG, 18F-FLT and 18F-FMISO-
PET tumour volumes showed a tendency to
shrink during preoperative CRT. At each time
point, the mean FDG-PET GTV was significantly
larger than the FMISO-PET GTV, but not
significantly larger than the mean FLT-PET GTV.
Mismatch analysis confirmed that FDG, FLT and
FMISO-PET reflect different biological charac-
teristics and can be used as a target for dose-esca-
lation RT in rectal cancer. In general, FDG and
FLT GTVs corresponded better than FDG and
FMISO GTVs, probably due to the non-specific
FMISO uptake in normoxic bowel wall and diffu-
sion of FMISO through the rectal wall. Moreover,
the spatial distribution of FMISO varied consid-
erably during RT, while FDG and FLT uptake
was less variable over time. These findings favour
the use of FDG and FLT as potential tracers for
TV definition in dose escalation and proof that
reimaging is important if these GTVs are used as
a target for dose escalation.
A second study by Roels et al. investigated
FDG-PET/CT and MRI before the start of treat-
ment, after ten fractions of radiation and before
surgery [96]. The FDG-PET GTV was automati-
cally delineated with two different segmentation
algorithms: a modified threshold-based method
and a gradient-based method. The mean FDG-
derived GTVs were significantly smaller when the
gradient-based method was used, and the FDG-
PET GTVs obtained in this way correlated best
with the GTV measured on the pathological speci-
men. Ciernik et al. found that the automated seg-
mentation of the FDG signal strongly correlated
with the CT-derived GTV and the volume as
144
assessed on pathology in 11 patients with rectal
cancer [97]. He stated that PET-based delineation
can be automated which makes it fast and less
prone to inter-observer variation and usable in
creating a working PTV (wPTV) based on the
PET GTV. There are however some limitations to
this study [98]. First, there was no pathological
correlation of the PET-based GTV. Second, the
limited accuracy of FDG-PET in detecting micro-
scopic lymph node invasion makes it unsuitable
for the automatic definition of a CTV or PTV [99].
Patel et al. also addressed the question concerning
PET and inter-observer variability. They com-
pared the nodal and primary tumour GTV contour
for a hypothetical boost volume on conventional
CT alone and on FDG- and FLT-PET/CT in six
rectal cancer patients [100]. Four radiation oncol-
ogists delineated primary and nodal GTV on all
scans. The boost TVs based on combined PET/CT
resulted in lower inter-observer variability com-
pared with CT alone, particularly for nodal dis-
ease. Again, this is only based on a limited number
of patients, and less variability does not necessar-
ily imply more correct delineation. Furthermore,
as stated above, visual delineation has the disad-
vantage that it is less independent and less objec-
tive than gradient-based methods. However, these
results suggest a potential value for the integration
of both 18F-FDG-PET and 18F-FLT-PET in the
preoperative treatment of rectal cancer [101].
Two other studies investigated the possibility of
automated segmentation of the FDG-PET-CT sig-
nal [95, 97, 102], which would facilitate the inte-
gration of this imaging technique in clinical
practice.
However, the use of dose escalation in the
standard treatment of rectal cancer can be ques-
tioned. The recent randomized trials with TME
surgery all show local recurrence rates far below
10% in the (chemo-)radiotherapy arm. It is
unlikely to expect a much further reduction in LR
rates with dose escalation, since aggressive
tumour biology is most probably responsible for
these recurrences. Therefore, dose escalation
should be reserved for selected patients.
In patients suitable for minimal invasive sur-
gery or a ‘wait-and-see’ approach, the most
important effect that needs to be achieved is
J. Nijkamp et al.
Fig. 14.10 Sagittal view of a locally advanced rectal can-
cer patient, with different positions of a pathologically
enlarged lymph node within repeat CT scans. The mea-
surement bar denotes 1 cm
tumour downstaging and downsizing with ulti-
mately a complete response. For these patients, a
boost on the gross tumour volume may have
additional value, although no data are available
on improved prognosis with complete responses
achieved by higher doses.
A word of warning concerns the reproducibil-
ity of the GTV on a daily basis. Although in post-
operative setting, Nuyttens et al. [56] reported
that clips placed at the anastomosis moved in
cranial-caudal direction in the order of 1–1.5 cm
from day to day. In another study, 2–3 gold mark-
ers were implanted in the tumour region preop-
eratively, and positional variation was measured
with a 3D deviation of 0.38 cm (1SD = 0.99) with
respect to the treatment fields [103]. Based on
these data, it is clear that a substantial GTV mar-
gin is needed to cover GTV motion. Similar to
the practice in prostate cancer, the use of
implanted fiducial markers may be attractive for
online image-guided RT.
To get an impression of lymph node move-
ment within the mesorectum, Nijkamp et al. [57]
delineated in a pilot study nine enlarged lymph
nodes in two locally advanced rectal cancer
patients (Fig. 14.10). Depending on the location
of the lymph node, day-to-day motion was in the
order of 0.2 cm close to the posterior wall of the
14 What Is the Role of IMRT and IGRT in Rectal Cancer?
mesorectum, while translations up to 1.5 cm were
found close to the rectum itself.
Second, it is important to realize that organ-
saving treatment, such as TEM or ‘wait-and-see’
policies, after preoperative (chemo-)radiotherapy
turns the rectum itself into an organ at risk.
Tolerance limits for the rectum are extensively
studied in prostate cancer patients, but dose dis-
tribution in these treatments are substantially
different compared to rectal cancer [104]. In
prostate cancer RT, only a small part of the rec-
tum is exposed to a high dose (>60 Gy), while in
rectal cancer patients, the whole rectum will be
part of the CTV, receiving a base dose of at least
45 Gy. Extensive dose escalation studies should
therefore be conducted to validate the tolerance
limits of adding a GTV boost on top.
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 What Are the Dose-Volume
Constraints to Reduce Late Toxicity? 15
Krzysztof Bujko

Contents 15.1 Introduction

15.1 Introduction .............................................. 149
Two recent randomized trials using modern
15.2 Cranial Border of the CTV ..................... 150
surgery (total mesorectal excision [TME]) have
15.3 Caudal Border of the CTV...................... 151 shown local recurrence risk reduction by approx-
References ............................................................... 153 imately 50% with preoperative radiation com-
pared to surgery alone [25, 28]. This benefit,
however, has not translated into improvement of
survivals. This lack of survival benefit and
significant late toxicity caused by radiation has
launched a debate on appropriate indications for
preoperative radiation. There are two main stand-
points regarding this issue. Advocates of using
preoperative radiation claim that all patients who
have clinically diagnosed T3 cancer require this
treatment [16], whereas others limit indications
for preoperative radiation for cT3 tumours with
deep infiltration into the mesorectum (>5 mm) [3].
Some authors do not recommend preoperative
radiation even for patients with ‘good prognosis’
nodal disease [27]. The latter authors point out
that with TME, the risk of local recurrence has
been diminished in specialized centres to less
than 10% and that postradiation toxicity is sub-
stantial which has a negative impact on the qual-
ity of life. This confers that only less than 5% of
irradiated patients (radiation reduces the pelvic
recurrence risk by half) benefit from this treat-
ment, and remaining 95% of patients are ‘unnec-
essarily’ exposed to the risk of radiation toxicity.
K. Bujko Thus, a risk/benefit ratio analysis may favour
Department of Radiotherapy,
omitting preoperative radiation. On the other
Maria Sklodowska-Curie Memorial Cancer Centre,
W.K. Roentgena 5, 02 781 Warsaw, Poland hand, advocates of the preoperative radiation
e-mail: bujko@coi.waw.pl approach point out that in the total population,

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 149

DOI 10.1007/978-3-642-25005-7_15, © Springer-Verlag Berlin Heidelberg 2012
150
the local recurrence rate after TME is higher
than observed in the specialized centres and
amounts 20% of pathologically staged T3 dis-
ease [6]. In addition, with radiotherapy technique
modifications, the risk of late toxicity might be
reduced. Taking both of the above arguments into
account, a risk/benefit ratio analysis may favour
the use of preoperative radiation for all cT3 can-
cers. Thus, a reduction of the risk of late postra-
diation toxicity is a key issue in the current debate
on the indications for preoperative radiotherapy.
In rectal cancer preoperative radiotherapy, two
guidelines showing anatomical borders of clini-
cal target volume (CTV) are available [15, 22].
The objective of the current article is to provide
readers with a proposal of modifying these guide-
lines in order to diminish the risk of postradiation
late side effects. It should be stressed that this
proposal is not accepted as a routine procedure
by all investigators and is still a matter of debate.
15.2 Cranial Border of the CTV
The recent update of the Dutch TME trial, which
compared preoperative radiation and TME with
TME alone, demonstrated no difference in over-
all survival [28]. However, when patients were
operated with negative circumferential margin,
higher cancer-specific survival and 10% gain in
overall survival at 10 years in stage III cancer
were reported in the preoperative radiation
group. Of note, slightly more non-cancer deaths,
mostly due to secondary malignancy, were
reported in the radiotherapy group. Similar
observations were recorded in Sweden. The data
from two trials demonstrated that, after a long
follow-up, 7% of patients had second cancers
[1]. More patients treated with radiotherapy and
surgery developed a second cancer as compared
to those treated with surgery alone; the relative
risk was 1.85 with 95% confidence interval
between 1.23 and 2.78. However, the favourable
effect of radiation still dominated, as 20.3% of
the irradiated patients got either local recurrence
or a secondary cancer, compared with 30.7% of
the patients treated with surgery alone (relative
risk, 0.55; 95% confidence interval 0.44–0.70).
The meta-analysis showed that the excess of
K. Bujko
non-cancer deaths after preoperative radiation
was also due to an increase in deaths attributed
to vascular and infective causes [5]. This meta-
analysis also showed that the favourable effect of
radiation still dominated, as at 5 years, there
were 3.3% more of non-cancer deaths and 8.3%
fewer rectal cancer deaths in the irradiated
patients compared to those treated with surgery
alone. The above results suggest that preopera-
tive radiation has a potential for improving over-
all survival which is counterbalanced by the
excess of non-cancer deaths.
Small bowel late toxicity has been reduced
after replacing postoperative radiation with pre-
operative radiation [8, 23]. This is because small
bowel fills up the dead space left behind in a pos-
terior pelvis after removal of mesorectum and
rectum. Thus, in order to provide large dose to
the tumour bed, irradiation of large volume of
small bowel cannot be avoided in the postopera-
tive setting. In contrast, in the preoperative set-
ting, when the mesorectum and rectum are still in
situ, the amount of irradiated small bowel is much
smaller. Despite this, in the Swedish randomized
trial, severe late small bowel side effect, namely,
small bowel obstruction, has occurred more often
after preoperative radiation and surgery than sur-
gery alone – 13.9% versus 5.5% at 14 years [2].
It might be reasonable to assume that a reduc-
tion of irradiated volume may result both in a
decreased risk of postradiation, second malig-
nancy and in the reduction of early and late small
bowel toxicity. Traditionally, the sacral promon-
tory has been the anatomical landmark for cranial
border of CTV [15, 22]. The appropriateness of
this rule has been questioned by two recent arti-
cles on location of in-pelvic recurrences after
TME. Syk et al. [26] identified a total of 155
patients with local recurrence from a population-
based cohort of 2,315 patients. The site of recur-
rence was observed in the lower half of the pelvis
in more than two-thirds of all patients. All recur-
rences were situated below S1–S2 interspace.
Nijkamp et al. [18] analysed the site of recurrence
in 94 patients treated within the frame of the
Dutch TME trial. Only 3% of recurrences were
situated above the S2–S3 interspace and addi-
tional 2% at the level of S2–S3 interspace.
However, if patients with negative circumferential
15 What Are the Dose-Volume Constraints to Reduce Late Toxicity?
resection margin were considered, only in 2% of
these patients, recurrence was observed above or
at S2–S3 interspace. The corresponding figure for
the patients with positive circumferential resec-
tion margin was 12%. Interestingly, in the patents
with positive circumferential resection margin,
the recurrence did not always appear at the same
level as the primary tumour. With a cranially
reduced CTV to the S2–S3 interspace, over 60%
of reduction of absolute small bowel exposure at
dose levels of 15–35 Gy could be achieved with
three-field conventional radiotherapy, increasing
to 80% when IMRT was used [18]. Both of the
above reports suggested that the cranial border of
CTV can be lowered to the S2–S3 interspace in
patients in whom pelvic MRI predicts negative
circumferential resection margin (Fig. 15.1). It
should be stressed that this guideline should be
used selectively. For patients with the primary-
tumour extension in the presacral region above
the S2–S3 interspace or with enlarged lymph
nodes abutting mesorectal fascia at this level,
CTV should be extended cranially. Nijkamp
et al. [18] recommended CTV reduction to the
S2–S3 interspace only in patients without
expected nodal or circumferential resection mar-
gin involvement.
Apart from lowering of caudal border of the
CTV, belly-board and distended urinary bladder
result in a reduction of small bowel radiation
exposure [11, 19] (Fig. 15.1).
15.3 Caudal Border of the CTV
Anorectal and sexual function impairments caused
by surgery and radiation are the most important
adverse side effects as they affect large proportion
of patients and are permanent as well as they inter-
fere with patients’ daily activity. These adverse
side effects have been reported in details on large
number of patients treated within the frame of the
Dutch TME trial and the MRC CR07 trial [14, 20,
24]. Faecal incontinence was reported in 62% of
patients having preoperative radiation compared to
38% of those treated with surgery alone, p < 0.001
in the Dutch TME trial [20] and 53.2% versus
37.3% in the MRC CR07 trial, p = 0.007, respec-
tively [24]. In the latter trial, the increase of incon-
151
tinence in the irradiated patients was observed
only at low level of severity; severe incontinence
rate was similar in both treatment-assigned groups.
In the Dutch TME trial, at 24 months post treat-
ment, 67% of male patients receiving preoperative
irradiation and who were previously sexually
active, were still active after treatment compared
to 76% of patients from the surgery alone group,
p = 0.06 [14]. For female patients, these figures
were 72% and 90%, respectively, p = 0.01. It should
be stressed that the main cause of faecal inconti-
nence and male sexual dysfunction is surgery,
rather than radiotherapy [24].
Excluding the anal canal, or part of it, from the
CTV is a strategy that prevents radiation-induced
faecal incontinence [12, 29]. Lange et al. [12]
reported incontinence in 93% of patients in whom
sphincter was included in the preoperative radia-
tion fields compared to 65% of patients in whom
sphincter was not irradiated, p = 0.059. In addi-
tion, one can assume that the exclusion of inferior
part of the vagina may prevent vaginal dryness
and pain during intercourse. It is also worth to
note that scattered cumulative radiation dose at
the testicles was reported between 0.7 and 8.4 Gy,
with a mean of 3.56 Gy [10]. Such doses may
result in a permanent infertility and in a risk of
hypogonadism in substantial proportion of pati-
ents [10, 30]. The increase of the distance between
lower field margin and testicles exponentially
decreased the amount of this dose [10]. Another
way of reducing sexual function impairment is
to avoid irradiation of the penile bulb. Several
studies reported that penile bulb dose-volume
parameters correlated with the risk of erectile dys-
function [21]. For example, erectile dysfunction
was observed in 0%, 80% or 100% of patients
with a D70 (i.e. minimum dose received by 70%
volume of the penile bulb) of 0–40, 40–70 and
>70 Gy, respectively [7]. In addition, excluding
the perineal skin and distal part of ischiorectal
fossa is a strategy that prevents wound healing
delay after abdomino-perineal resection and pain-
ful acute perineal skin reaction. Marijnen et al.
[13] reported that 31% of 174 patients irradiated
preoperatively with perineum included into the
fields had perineal wound complications in com-
parison with 18% of 40 patients in whom the
perineum was not irradiated.
152 K. Bujko

All of the above considerations suggest that

the sphincters’ complex, the caudal part of the
vagina, the penile bulb and the perineal skin
should be avoided in CTV delineation (Fig. 15.1),
provided these regions are not invaded by a distal
cancer extension.
When considering the anatomical boundaries
of the CTV, it is worth to refer to the rules and to
the rationales for the boundaries of surgical resec-
tion [4, 17]. This is because there is no reason to
assume that the anatomical boundaries of the CTV
should differ from the anatomical boundaries of
resection of the mesorectal tissue and the distal
bowel margin. Pathologic examinations of rectal
cancer postoperative specimen have demonstrated
that mesorectal cancer deposits are found up to
4 cm caudally from a lower pole of the primary

Fig. 15.1 Clinical target volume (CTV) contoured at the

middle sagittal plane. White thick arrow; lower border of
mesorectum (level of the puborectal muscle) and upper
border of the anal canal. Black thick arrow; S2–S3 inter-
face. White thin arrow; lower border of tumour. In all
patients, there was no upwards tumour extension or threat-
ened circumferential resection margin. Thus, the upper
border of CTV terminates at S2–S3 interface sparing
small bowel. (Panel a) Lower border of tumour was
located 8 cm from the anal verge and 5 cm from the ano-
rectal ring. The lower border of CTV terminates 4 cm cau-
dally from the lower border of tumour and does not
include the distal part of mesorectum. The entire anal
canal and the distal part of vagina are spared. The black
line perpendicular to the surface of the sacral bone and the
thin black arrow shows the possibility of further reduction
of the CTV in order to spare small bowel. (Panel b) Lower
border of tumour was located 2.5 cm from the anal verge
and invaded 0.5 cm of the upper part of the anal canal. The
patient was scheduled for abdomino-perineal resection.
The lower border of CTV terminates at 1.5 cm caudally
from the lower border of tumour to account for distal
intramural spread. The perineal skin is spared in order to
avoid the acute skin toxicity and the perineal wound heal-
ing delay. Sparing of the perineum increases the distance
between lower border of fields and the testicles, diminish-
ing scatter dose at the testicles. Distended urinary bladder
reduces the amount of small bowel within radiation beams.
Belly-board is used in this patient, although, admittedly,
its value is unproven when CTV terminates at S2–S3
interface and the urinary bladder is distended. (Panel c)
Lower border of tumour was located 5 cm from the anal
verge and 2 cm from the anorectal ring. The lower border
of CTV terminates at the anorectal ring and includes the
entire mesorectum. Note that even if a margin for the
planning target volume would be added, still the distal
part of anal canal and the distal part of vagina are spared
15 What Are the Dose-Volume Constraints to Reduce Late Toxicity?
gross cancer [9]. For this reason, it is recommended
that mesorectum with mesorectal visceral fascia
should be resected at least 4 cm caudally from the
tumour. This confers that for tumours in the upper
rectum, 4 cm of mesorectal clearance distal to the
tumour is sufficient, and for tumours located in the
lower rectum, total mesorectum is removed down
to the pelvic floor. Intramural subclinical spread
within a bowel wall may occur caudally from gross
primary cancer. This spread has been found rarely
beyond 1–1.5 cm from gross tumour. If distal
spread occurs beyond 1–1.5 cm, the prognosis is
poor due to a high risk of occult distant metastases.
For this reason, 1 cm of distal bowel surgical clear-
ance is regarded as sufficient in patients undergo-
ing anterior resection for low tumours [17]. It
should be pointed out that even in low-lying
tumours, if levators and external sphincter are not
invaded, anterior resection is still possible as the
ischiorectal fossa is not at risk of tumour recur-
rence. It seems that levators constitute an effective
barrier against downwards cancer spread. There
are no regional lymph nodes in the ischiorectal
fossa. In the literature, recurrences in the ischi-
orectal fossa or in the perineum were reported only
in the patients who have undergone abdomino-
perineal resection. It can be assumed that these
recurrences likely originate from contamination of
cancer cells during surgery because no such cases
were reported after anterior resection.
The above surgical rules can be applied in the
CTV construction. The examples are depicted in
the figure. It should be noted that the rules for
CTV lower border location presented in this
figure are different to those recommended by
other investigators [22].
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6. Eriksen MT, Wibe A, Haffner J et al (2007) Prognostic
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7. Fisch BM, Pickett B, Weinberg V et al (2001) Dose of
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8. Frykholm GJ, Glimelius B, Pahlman L (1993)
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9. Heald RJ, Husband EM, Ryall RD (1982) The
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10. Hermann RM, Henkel K, Christiansen H et al (2005)
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11. Kim TH, Kim DY, Cho YH et al (2005) Comparative
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12. Lange MM, den Dulk M, Bossema ER et al (2007)
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13. Marijnen CA, Kapiteijn E, van de Velde CJ (2002)
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 What Is the Contribution of
Intraoperative Radiotherapy 16
(IORT) in Tailoring Local Therapy
in Primary or Recurrent Rectal
Cancer?
Felipe A. Calvo

Contents 16.1 Introduction

16.1 Introduction ................................................ 155
The available evidences favor the use of neoad-
16.2 Locally Advanced Primary
Rectal Cancer ............................................. 155
juvant chemoradiation to maximize local con-
16.2.1 Pelvic Recurrence After Surgery Alone: trol in cT3–4 or N+ rectal cancer disease stages.
A Topographic Focus ................................... 155 Meta-analysis considering preoperative or
16.2.2 Presacral Recurrence: A Basic postoperative radiotherapy alone versus chemo-
Anatomical Study for Event
Explanation .................................................. 156
radiation strategies has shown significant
16.2.3 Topography of Pelvic Recurrence After improvement in local control by the use of
Combined Surgery and Radiotherapy .......... 156 preoperative chemoradiation. Surgery is the
16.3 Intraoperative Radiotherapy (IORT): decisive component of rectal cancer cures and
Topographic Results After a Limited local control achievement, but even in the con-
Intra-pelvic Radiation Boost ..................... 156 text of expert proven total mesorectal excision
16.3.1 Systematic Review Literature ...................... 156
(TME) performed, the local recurrence rate for
16.3.2 Randomized Trial......................................... 156
16.3.3 Single-Institution IORT Expert Data: surgery alone is in the range of 11–21% in
Topographic Failure Assessment ................. 157 unselected tumor stages [1]. In lymph node
16.3.4 Multi-institutional Pooled positive patients, local recurrence has been
Analysis Studies........................................... 157
reported superior in expert surgical groups:
16.4 Recurrent Rectal Cancer: Isolated 33% after unilateral lymph node dissection and
Pelvic Relapse ............................................. 158 14% for bilateral [2]. TME surgery and neoad-
16.4.1 Mayo Clinic 25 Years Experience ............... 158
16.4.2 Catharina Hospital and Leiden juvant chemoradiation are standards for daily
University Medical Center 1994–2008 practice.
Experience ................................................... 159
References ................................................................. 160
16.2 Locally Advanced Primary
Rectal Cancer

16.2.1 Pelvic Recurrence After Surgery

Alone: A Topographic Focus

F.A. Calvo The surgery alone scenario of quality practice and

Department of Oncology,
excellence describes [1] a local recurrence rate
Hospital General Universitario Gregorio Marañon,
Madrid, Spain related to T stage (12.2% T3, 21.4% T4),
e-mail: fcalvo.hgugm@salud.madrid.org N status (16% N+, 3.6% N−), and circumferential

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 155

DOI 10.1007/978-3-642-25005-7_16, © Springer-Verlag Berlin Heidelberg 2012
156
margin involvement (20% yes, 6.2% no). This
general pattern of local relapse can be further
analyzed in terms of topographic distribution
within the pelvic anatomy. After total mesorectal
excision (TME), the presacral subsite is the domi-
nant involved pelvic area with an incidence of
3.6% of all recurrences and 35% of the local
recurrences observed. Other sites of recurrences
identified are lateral (18%), anterior (18%), anas-
tomosis (24%), and perineum (5%).
16.2.2 Presacral Recurrence: A Basic
Anatomical Study for Event
Explanation
The potential origin of local recurrence after
rectal cancer treatment in the presacral space
has been elegantly studied by Kusters and
coworkers [3]. The examination of ten human
fetal pelvises allowed to analyze the development
of lymphatic structures of the human pelvis, in
particular the lateral lymph node distribution and
its relationship with the mesorectum. Three-
dimensional reconstruction of histological sections
showed that lateral lymph node tissues comprise
a major proportion of the pelvic tissue volume.
There were no lymph nodes located in the pre-
sacral area. Connections between the mesorectal
and extramesorectal lymph node system were
found in all fetal pelvises. The authors hypothesized
that mobilizing the rectum lymph fluid and tumor
cells flow into the lateral lymphatic system,
which is left behind after TME and ultimately
the fluid leaks and is collected in the presacral
seroma.
16.2.3 Topography of Pelvic
Recurrence After Combined
Surgery and Radiotherapy
The anatomical involvement of recurrences after
adjuvant (15%) or neoadjuvant (85%) radiother-
apy (5%) or chemoradiation (95%) describes an
estimated 5-year locoregional control of 91% [4].
In the MD Anderson experience (554 patients,
1989–2001 period), 36 patients had locoregional
F.A. Calvo
recurrences at 43 sites: 28 (65%) were in-field, 7
(16%) marginal, and 8 (19%) out-field radiother-
apy recurrences. The total rate of presacral
in-field recurrences was 41%, and the low pelvic
region was dominant for both pre- (60%) or post-
operative (43%) irradiation. Pathologic N1–2 sta-
tus was predictive of in-field locoregional
recurrence in multivariate analysis, while T4,
downstaging and pN status were significant in
univariant evaluation.
16.3 Intraoperative Radiotherapy
(IORT): Topographic Results
After a Limited Intra-pelvic
Radiation Boost
16.3.1 Systematic Review Literature
A 2011 systematic review identified 15 studies
selected out of 283 fully analyzed publications
and 30 candidates to quality criteria evaluation
papers that describe results of 5-year local con-
trol rates over 80% and survival close to 65% in
combined treatment containing an IORT compo-
nent in primary locally advanced rectal cancer.
For localized recurrences, 5-year overall survival
was 30%. The addition of IORT to conventional
treatment, in the author’s criteria, reduces the
incidence of local relapse within the radiation
area over 10%. The IORT in terms of toxicity
concludes that it is a safe technique [5].
16.3.2 Randomized Trial
A French multi-institutional randomized trial
performed with 142 patients, T3–4 or N+, M0
stages, has not demonstrated an improvement in
local control and disease-free survival in the
context of 40-Gy preoperative irradiation with
or without 18-Gy IORT pelvic boost [6]. The
5-year local control rates were 91.8% versus
92.8%, and postoperative complications inci-
dence were 29.6% (IORT) versus 19.1% (p = 0.15).
Topography of pelvic recurrences and technical
characteristics of IORT boosting were not
reported.
16 What Is the Contribution of Intraoperative Radiotherapy (IORT)
16.3.3 Single-Institution IORT Expert
Data: Topographic Failure
Assessment
Single-institution IORT expert experiences have
been reported with a meticulous analysis of ana-
tomical involvement of pelvic recurrences after
combined modality therapy including IORT.
At the University of Heidelberg, Roeder et al. [7]
observed 17 (7%) local failures in 243 patients
treated with a component of IOeRT (electron
IORT, 88 after neoadjuvant chemoradiation).
Local control was correlated positively with the
absence of nodal involvement and complete
resection. IOeRT boosted the presacral space
adjuvantly after surgical resection (10–15 Gy),
and 7 patients developed an in-field presacral
relapse (2.8%). Preoperative chemoradiation
(3/17) had less pelvic recurrences than postop-
erative (10/17). T4 stage had the highest risk of
relapse in retrovesical/retroprostatic site (3 out
of 5 recurrences), while node-positive specimens
had the highest risk for presacral recurrence
(4 out of 7).
Catharina Hospital and the University of
Leiden Medical Center have analyzed [8] the
patterns of local recurrence following IORT
containing combined modality therapy in the
context of a strategy not-a-fixed pelvic target for
IORT boosting in 290 patients treated from 1994
to 2006. After 5 years, 34 patients (13.2%)
developed local recurrences: 47% presacral (5%
of the total cohort), which was the most com-
mon site selecting only R0 patients (3.6%, 8/34
local recurrences). In 53% of procedures, the
IORT target was lateralized and in 16% was
ventral. In-field IORT recurrences were consid-
ered 17 out of 34: 11 had a lateral or ventral
positioning element. Presacral local recurrence
had a significant correlation (uni- and multivari-
ate analysis) with cancer involved circumferen-
tial margin or tumor distance more than 5 cm
from the anal verge. On the other hand, local
recurrence was not influenced (univariate) but
lymph node or margin positivity and no down-
staging, but in multivariate analysis, margin
positive (25 patients, IORT dose-escalated 12.5–
17.5 Gy) was significant.
157
A prognostic index to guide a tailored deci-
sion in locally advanced rectal cancer after multi-
modality treatment (neoadjuvant chemoradiation)
and IORT was proposed by Calvo and Diaz-
Gonzalez [9]. Based on gender and downstaging
response (mic versus mac categories), survival
varied from 100% (more favorable index) to 37%
(unfavorable). This institution has described, in
an update involving 241 patients and 15 years
period [10], a 3% presacral recurrence in the con-
text of a 12% presacral abnormalities findings
detected by follow-up imaging studies, in which
9% (21 out of 28 patients) had nonmalignant pre-
sacral masses (Fig. 16.1).
16.3.4 Multi-institutional Pooled
Analysis Studies
The European pooled analysis study of IORT
containing multimodality treatment included 605
patients treated in four institutions with preoper-
ative radiotherapy (64% chemoradiation), sur-
gery with IOeRT, and adjuvant chemotherapy
(42%) [1]. Local recurrence was seen in 61
patients (12% at 5 years). The risk factors associ-
ated with local recurrence were no downstaging,
nodal metastasis, margin involvement, and no
adjuvant chemotherapy. In patients who received
adjuvant chemotherapy, the local recurrence rate
was 5.5% versus 12% in patients who did not
(p = 0.026). Adjuvant chemotherapy improved
local recurrences rate from 21.6% to 12.3%
(p = 0.03) in patients with tumors in which no
downstaging had occurred after preoperative
treatment and in positive margin specimens,
23.8% versus 53.4% (p = 0.03). No information
was available in terms of topography of pelvic
recurrences.
The observation of the contribution of adju-
vant chemotherapy to local control promotion
was interpreted, speculating with the possibility
that high-dose local irradiation, in a single frac-
tion as it is delivered by IOeRT, may sensitize the
surgical and the IORT boosted target for subse-
quent adjuvant chemotherapy. This is a pioneer-
ing clinical and therapeutic observation of the
long-term proposed “seed and soil” biomedical
158 F.A. Calvo

Fig. 16.1 Three-dimensional virtual treatment planning of an IORT procedure with an electron beam positioned over
a limited area of the presacral space

paradigm. The large and mature nature of this 16.4 Recurrent Rectal Cancer:
cohort of patients allowed the authors to generate Isolated Pelvic Relapse
a prognostic model based on the calculation of an
individualized prognostic index formula. Overall 16.4.1 Mayo Clinic 25 Years Experience
survival of rectal cancer patients was able to be
grouped in four different prognostic categories Haddock and coworkers [11] have reported
using the following formula: results in 607 patients with recurrent colorectal
cancer that received an IOeRT (electrons) com-
Age over 70 years Yes:0.60;no:0 ponent of the treatment (70% rectal cancer, 46%
Male gender Yes:0.36;no:0 previous radiotherapy, 41% in-field relapses).
Any downstaging Yes:0;no:0.30 Survival at 5 and 10 years were 30% and 16%,
Lymph node positivity Yes:0.86;no:0 respectively. Local relapse at 5 years was observed
Margin positivity Yes:0.70;no:0
in 28% of patients. Survival was influenced by
Adjuvant Yes:0;no:0.64
chemotherapy
resection status, period of IORT (before or after
1997), and prior chemotherapy. Disease relapse
Survival ranged from 90% for category with in the central IORT boosted region at 10 years
prognostic index 0–0.5 or 20% for values over was 18% versus 12% regarding the fact of previ-
2.5 (Fig. 16.2). ous radiotherapy or not and 12% versus 16%
16 What Is the Contribution of Intraoperative Radiotherapy (IORT)
Fig. 16.2 ISIORT-European
pooled analysis prognostic
model for survival generated 1.0
in patients treated with a
component of IORT using the
index formula described [10]
0.8
Overall survival
0.6
0.4
Prognostic index
0.2
0.0
0.0
regarding margin involvement. Neuropathy was
observed in 94 patients and was more common
with IORT doses exceeding 12.5 Gy.
16.4.2 Catharina Hospital and Leiden
University Medical Center
1994–2008 Experience
Kusters, Rutten, and colleagues [12] described
that radicality of resection and survival is influenced
by subsite of locally recurrent rectal cancer after
multimodality treatment including a component of
IORT. In 170 patients (30% not receiving IORT),
22% had a presacral recurrence, 34% lateralized
disease, 22% anastomotic, 23% anterior, and 2.6%
perineal. Local re-recurrence occurred in 54
patients (46%) after 5 years: 52% in the presacral
subsite, 20% posterolaterally, 17% anterolaterally,
and 11% other sites. Anastomotic recurrences had
the highest cancer-specific survival (58%)
(significantly better than the combined group
34%). Presacral recurrences resulted in 19%
cancer-specific survival, significantly worse than
other recurrences in group (48%, p = 0.03). Radical
159
Survival functions
0−0.5
0.5−2
2−2.5
2.5>
10.0 20.0 30.0 40.0 50.0 60.0
Months after surgery
resection had a significantly worse prognosis in
posterolateral recurrent subsite. Authors suggest a
classification of subsite of pelvic recurrence as a
predictor for radical resection and consequently
promotion of improved survival.
Conclusions
1. IORT is a feasible, tolerable, and efficient
radiation-boosting technique that can be
explored in tailored treatment for rectal
cancer patients (Table 16.1).
2. Recommendations available to guide tai-
loring IORT in primary disease in terms of
local tumor control promotion are:
• The unfavorable nature of nodal and
margin positivity together with no
downstaging effects. IORT is an alter-
native for further dose-escalation and
target volume redesign to improve local
control under these conditions.
• The tendency of T4 stage to recur in
anterior pelvic structures, although
IORT has also been reported to promote
high local control rates in this disease
category [14].
160 F.A. Calvo

Table 16.1 IOeRT 5-year results in primary and recurrent rectal cancer: local control, in-field recurrence, and factors
associated with local relapse
In-field IORT Adverse factors for local
Author/year (reference) Pts Local control recurrence relapse
Dubois 2011a [6]; 72 91% na na
Primary
Roeder 2007 [7]; 243 93% 2.8% presacral Postoperative
Primary chemoradiation (10/17)
Node positive
(4/7 presacral)
Kusters 2009 [8]; 290 86% 5.9% Margin positive
Primary 64% (lateral/ventral)
Calvo 2011 [8, 10]; 241 92% 3% presacral Node positive
Primary
Kusters 2010 [13]; 605 88% na No downstaging
Primary Nodal metastasis
Margin involvement
No adjuvant
chemotherapy
Haddock 2011 [11]; 607 77% (3 year) 12% R1/R2 26% vs. RO 15%
Recurrent Previous RT 31% vs.
17%
Kusters 2009 [12]; 170 54% 14.9% R1/R2 54% vs. R0 9%
Recurrent (57% presacral)
na not available, pts patients
a
Randomized trial

• The excellent local results obtained in cancer (previous radiotherapy, micro-/

more favorable disease risk factors
which might reconsider the need for
radiation treatment intensification.
• The use of adjuvant chemotherapy
should be recommended after IORT
treatment.
3. Tailored IORT may be further defined by
establishing correlations between biologi-
cal equivalent dose (BED) calculations,
topographic patterns of recurrence, and
prognostic features for local effects. This
information is not available at present.
4. Recommendations available to guide tailor-
ing IORT in localized recurrent disease in
terms of local tumor control promotion are:
• The surgical effort should be stressed
due to the excellent in-field control rates
reported in completely resected tumor
bed areas.
• IORT reaches over 50% local control in
the context of adverse features for local
treatment, such as resistant/persistent
macroscopic residue, previous chemo-
therapy) and should be considered a
valuable treatment component to be
further optimized (improved target
definition, pharmacological radiation
modulation, etc.).
References
1. Kusters M, Marijnen CA, Van de Velde CJ et al (2010)
Patterns of local recurrence in rectal cancer; a study of
the Dutch TME trial. Eur J Surg Oncol 36:470–476
2. Kusters M, van de Velde CJ, Beets-Tan RG et al (2009)
Patterns of local recurrence in rectal cancer: a single-
center experience. Ann Surg Oncol 16:289–296
3. Kusters M, Wallner C, Lange MM et al (2010) Origin
of presacral local recurrence after rectal cancer treat-
ment. Br J Surg 97:1582–1587
4. Yu TK, Bhosale PR, Crane CH, Yyier RB et al (2008)
Patterns of locoregional recurrence after surgery and
radiotherapy or chemoradiation for rectal cancer. Int J
Radiat Oncol Biol Phys 71:1175–1180
5. Cantero-Muñoz P, Urién MA, Ruano-Ravina A (2011)
Efficacy and safety of intraoperative radiotherapy in
16 What Is the Contribution of Intraoperative Radiotherapy (IORT)
colorectal cancer: a systematic review. Cancer Lett
306:121–133
6. Dubois JB, Bussieres E, Richaud P et al (2011) Intra- 11.
operative radiotherapy of rectal cancer: results of the
French multi-institutional randomized study. Radiother
Oncol 98:298–303
7. Roeder F, Treiber M, Oertel S et al (2007) Patterns of 12.
failure and local control after intraoperative electron
boost radiotherapy to the presacral space in combina-
tion with total mesorectal excision in patients with
locally advanced rectal cancer. Int J Radiat Oncol Biol
Phys 67:1381 13.
8. Kusters M, Holman FA, Martijn H et al (2009) Patterns
of local recurrence in locally advanced rectal cancer
after intra-operative radiotherapy containing multimo-
dality treatment. Radiother Oncol 92:221–225
9. Díaz-Gonzalez JA, Calvo FA et al (2006) Prognostic 14.
factors for disease-free survival in patients with T3–4
or N + rectal cancer treated with preoperative chemo-
radiation therapy, surgery, and intraoperative irradia-
tion. Int J Radiat Oncol Biol Phys 64:1122–1128
10. Calvo F, Serrano J, Lozano MA et al (2011) Presacral
evolutive events after post-neoadjuvant intraoperative
161
presacral radiation boost for rectal cancer. Radiother
Oncol 99(suppl 1):S18
Haddock MG, Miller RC, Nelson H et al (2011)
Combined modality therapy including intraoperative
electron irradiation for locally recurrent colorectal
cancer. Int J Radiat Oncol Biol Phys 79:143–150
Kusters M, Dresen RC, Martin H et al (2009)
Radicality of resection and survival after multimodal-
ity treatment is influenced by subsite of locally
recurrent rectal cancer. Int J Radiat Oncol Biol Phys
75:1444–1449
Kusters M, Valentini V, Calvo FA et al (2010) Results
of European pooled analysis of IORT-containing mul-
timodality treatment for locally advanced rectal cancer:
adjuvant chemotherapy prevents local recurrence rather
than distant metastases. Ann Oncol 21:1279–1284
Valentini V, Coco C, Rizzo G et al (2009) Outcomes
of clinical T4M0 extra-peritoneal rectal cancer treated
with preoperative radiochemotherapy and surgery: a
prospective evaluation of a single institutional experi-
ence. Surgery 145:486–494
 What Is the Contribution
of Brachytherapy in Tailoring 17
Local Therapy?

Jean-Pierre Gérard, Te Vuong, Jean-Michel

Hannoun-Lévi, and Arthur Sun Myint

Contents 17.1 Definition

17.1 Definition..................................................... 163
Brachytherapy is a generic term to describe radi-
17.2 Techniques of Brachytherapy ................... 164
ation techniques using short (less than 6 cm)
17.2.1 Iridium 192 Brachytherapy .......................... 164
17.2.2 Contact X-Ray 50 kV (CXRT) .................... 165 focus skin distance (FSD). It is by opposition
17.2.3 Intraoperative Brachytherapy....................... 166 with “teletherapy,” usually performed with linear
17.3 Clinical Results........................................... 166 accelerators and a long FSD (80 cm or more)
17.3.1 Endoluminal HDR 192 Iridium ................... 166 often called external beam radiotherapy (EBRT).
17.3.2 Interstitial Iridium Implant........................... 167 The dose distribution in brachytherapy depends
17.3.3 Contact X-Ray 50 kV .................................. 167 for a major part on the inverse square law which
17.4 Contribution of Brachytherapy implies that with a short FSD (1–6 cm), the radia-
in Tailoring Treatment............................... 167 tion dose fall off is very rapid (percentage depth
17.5 Perspective .................................................. 168 dose close to 50% at 0.5 cm from the “surface
17.5.1 In Fit Operable Patient ................................. 168 dose”). This rapid fall off (and dose inhomogene-
17.5.2 Inoperable Elderly Patient ........................... 168
ity) is mainly independent of the beam energy
References ................................................................. 169 (50 kV, 0.3 MV, or 1.2 MV). Broadly speaking,
brachytherapy can be performed with two gen-
eral approaches: radionuclide brachytherapy usu-
ally with iridium 192 or with iodine 125
permanent implant (usually called curietherapy
in Europe) or X-ray brachytherapy (contact ther-
J.-P. Gérard (*) • J.-M.Hannoun-Lévi
apy). Such brachytherapy techniques can be used
Department of Oncology,
Antoine Lacassagne Cancer Center, in rectal cancer mainly for accessible tumors with
33 Avenue Valombrose, Nice Cedex 2 06189 France moderate volume (not exceeding 40 cc).
Université de Nice, UNSA, Tailoring Local Treatment for Rectal Cancer.
Nice Cedex 2, France Surgery is the main treatment of rectal cancer. In
e-mail: jean-pierre.gerard@nice.fnclcc.fr this context, brachytherapy can be used in two
Te Vuong situations to tailor the local treatment with the
Department of Radiation Oncology, main following objectives:
Jewish General Hospital, McGill University,
• In association with surgery
Montreal, Canada
– To increase local control for locally advance
A.S. Myint
tumors
Department of Radiation Oncology,
Clatterbridge Centre for Oncology, – To increase the chance of conservative
Wirral, UK treatment for distal tumors

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 163

DOI 10.1007/978-3-642-25005-7_17, © Springer-Verlag Berlin Heidelberg 2012
164
Fig. 17.1 Endoluminal HDR 192 iridium brachytherapy.
This figure is showing the rectal brachytherapy applicator,
the loading of five channels in front of the rectal tumor,
• Alone
– To cure early tumors (to palliate more
advanced lesions)
It is well admitted that brachytherapy (except
when used alone) has very little impact on
survival.
17.2 Techniques of Brachytherapy
These techniques have been used for many years.
Radium interstitial or endoluminal treatments
were initiated in 1906 and contact X-ray 50 kV
in 1936.
J.-P. Gérard et al.
20 mm
5 mm
the positioning of the applicator through the anus, and the
dose distribution in a sagittal plane
17.2.1 Iridium 192 Brachytherapy
17.2.1.1 Endoluminal
• The renaissance of this technique was pioneered
in the 1990s by Sun Myint in Clatterbridge [11]
and Vuong in Montreal [12]. It uses a high-dose-
rate (HDR) 192 source stepping in a dedicated
applicator. It is performed without general anes-
thesia. In this technique, the iridium sources are
at the periphery of the applicator (Fig. 17.1).
• Another applicator was designed in Vejle
(Denmark). It uses also HDR 192, but the source
is in the middle of the applicator to increase the
percentage depth dose. A lead protection can
shield the normal rectal mucosa [6].
17 What Is the Contribution of Brachytherapy in Tailoring Local Therapy?
Volume [cm^3]
60.0
50.0
40.0
30.0
20.0
10.0
0
Fig. 17.2 HDR 192 iridium implant for distal supra-anal
rectal cancer. This figure is showing the perineal template
fixed to the patient perineum and connected to the remote
iridium unit, the CT scan slices showing the needle
17.2.1.2 Interstitial
• The technique was initiated in Lyon with iridium
192 low-dose rate in the early 1970s to replace
radium needle implant [9]. It is performed under
general anesthesia. It uses perineal template and
4–6 needles implanted through the perineum. It
can be used for supra-anal rectal cancer up to
5 cm from the anal verge. The spacing between
needle is 1 cm. It is most of the time used in
association with contact X-ray and/or EBRT.
The dose delivered (Paris System) is between 15
and 30 Gy. This interstitial implant can be per-
formed in the same way but with HDR I92 Iridium
delivering 36–38 Gy in 10 fractions over 5 days in
case of iridium implant alone or 12–14 Gy in 3
fractions over 2 days in case of iridium implant
combined with EBRT or CRXT (Fig. 17.2).
165
m1: 5.00 Gy 41.1 cm^3
M1
0 2.00 4.00 6.00 8.00 10.0
Dose [Gy]
implant through a transverse axial plane, the 3D recon-
struction of the implant, and the dose-volume histogram
for the tumor volume
17.2.2 Contact X-Ray 50 kV (CXRT)
The technique was popularized in the 1950s by
Papillon using the Philips RT50™ machine [8]. It is
an ambulatory treatment. It necessitates a good
clinical practice of rigid proctoscopy. The dose is
delivered through a rectal applicator of 3 cm in
diameter. A dose between 15 and 40 Gy is delivered
under vision control in 1–3 min. Total dose depend-
ing on the clinical situation is between 50 Gy/3
Fr/3 weeks for postexcision CXRT to 90–130 Gy in
4 or 5 fractions over 5–8 weeks. Since 2009, a new
CXRT machine (Papillon 50™) has been designed
to replace the Philips RT50™. This new machine
allows direct vision of the tumor during treatment
and the use of 3 cm applicator but also smaller one
with 2.5 and 2.2 cm in diameter (Fig. 17.3).
166
Fig. 17.3 Contact X-ray 50 kV. Male patient of 74 years
referred by a surgeon for a distal rectal adenocarcinoma
staged T2N0. Patient treated in October 2010 with CXRT
(110 Gy in 4 fractions) and chemoradiotherapy CAP50
regimen (EBRT 50 Gy/25 F/5 weeks and concurrent
17.2.3 Intraoperative Brachytherapy
When patients present with T4 tumors, advanced
nodal metastases, or local recurrence in the pel-
vis, it is difficult to deliver radiation dose above
55 or 60 Gy. In case of nonradical surgery (R2
resection), local control is exceptional. To increase
safely the dose to gross residual (or R1 resection),
intraoperative radiotherapy (IORT) has been used
in various institutions. It is usually performed
with electrons but can also be done with iridium
192 [5] or in some anecdotal cases, with CXRT.
Although the relative role of IORT cannot be
determined with certainty as there exist no ran-
domized trial, very encouraging local control rate
J.-P. Gérard et al.
Xeloda 1,600 mg/m2 on radiation day). Treatment deliv-
ered with the Papillon 50 machine which allows direct
viewing of the tumor during irradiation. It is possible to
record the progressive shrinkage of the tumor until clinical
complete response. Patient alive and well in May 2011
suggests that this aggressive but well-tolerated
approach should be further investigated.
17.3 Clinical Results
17.3.1 Endoluminal HDR 192 Iridium
17.3.1.1 Preoperative Treatment
This technique can be used as an alternative to
EBRT for T3–4 Nx M0 tumors. It is not possible to
treat circumferential stenosing lesions. Between
1998 and 2008, Vuong has treated 285 patients
delivering a dose of 26 Gy in 4 fractions at the
periphery of the lesion. The immediate tolerance
17 What Is the Contribution of Brachytherapy in Tailoring Local Therapy?
was good in 95% of cases. Surgery was performed
4–6 weeks after (anterior resection: 60%). The rate
of sterilized operative specimen (ypCR) was 27%.
At 5 years, the rate of local relapse was 5% [12].
In Vejle, the endoluminal brachytherapy was
used after preoperative EBRT radiochemotherapy
(RT-CT). Out of 58 patients operated, the rate of
ypCR was 27%. Toxicity was low [6]. In
Clatterbridge, out of 29 patients treated with pre-
operative chemotherapy and a boost of 10 Gy
with HDR brachytherapy, 9 (31%) achieved a
ypCR [11].
17.3.1.2 Combined with EBRT Without
Surgery in Unfit Patients
Between 2005 and 2010, 41 patients were treated
in Montreal, McGill University (median age
82 years) without surgery. EBRT delivered
40–45 Gy/4–5 weeks followed by HDR endolu-
minal brachytherapy (30 Gy/3 F). With a follow-
up of 14 months, a local control was achieved in
76% (31/41). Tolerance was good with G3 rectal
bleeding in seven patients and rectal stenosis in
three patients [12].
17.3.2 Interstitial Iridium Implant
In very low rectal cancer close to the anal canal,
iridium implant either with low- or high-dose rate
combined with EBRT (± chemotherapy) and
CXRT is able to achieve 50% of long-term local
control inoperable patients presenting with early
T3N0 tumors [3].
17.3.3 Contact X-Ray 50 kV
17.3.3.1 CXRT Alone for T1N0
More than 1,300 patients with early rectal tumors
and strict selection were treated in different insti-
tutions in France, the UK, and North America
[3]. Local control was achieved in 80–90% of
cases with no toxicity and good bowel function
except in 10–20% of cases moderate rectal bleed-
ing due to radiation telangiectasia.
167
17.3.3.2 CXRT Alone (or with EBRT) After
Local Excision for Malignant
Polyp (T1N0)
In this adjuvant situation, a local control was
achieved in 90% of cases in different institutions
treating between 20 and 60 patients [2].
17.3.3.3 CXRT and EBRT for T2 Early T3N0
in Elderly Unfit Patients
These patients usually inoperable or elderly were
treated with curative intent. According to institu-
tion, the association was initiated with CXRT fol-
lowed by EBRT (± chemotherapy) or with EBRT
followed by CXRT. In T2 tumors, a 5-year local
control was achieved in 70–80% of patients and
in 45–55% for T3 lesions [1,10].
17.3.3.4 The Lyon R96.02 Randomized
Trial
Between 1996 and 2001, 88 patients (T2: 19 pts
– early T3: 69 pts) with a distal rectal cancer were
randomized between preoperative EBRT
(39 Gy/13 F/3 weeks) or the same EBRT with a
CXRT boost of 90 Gy/3 Fr. The main end point
was sphincter-saving treatment.
The clinical complete response (cCR) was 2%
in the EBRT alone group and 29% in the CXRT
group. After 10 years of follow-up, the colos-
tomy-free rate is 40% with EBRT alone and 84%
in the CXRT group. Out of 45 pts in the CXRT
group, 9 were able to preserve their whole rectum
(and anus) either with RT alone (seven patients)
or after transanal local excision (TLE) in two
patients [4].
17.4 Contribution of Brachytherapy
in Tailoring Treatment
• The advantages of brachytherapy in general
over teletherapy with external beam radiother-
apy are the following: excellent geographical
accuracy of dose distribution either image-
guided or eye-guided, no impact of tumor or
patient movements, and as the target volume is
small, the dose can be very high with a short
168
treatment time. The clinical consequence is a
high rate of clinical or pathological response
and a low toxicity. All these characteristics
allow safe hypofractionation which is more
convenient for the patient than long course of
5–7 weeks of EBRT.
• The endoluminal HDR iridium appears as an
alternative for operable patient to preoperative
EBRT especially when given with the short
course “nordic” 25 Gy/5 F regimen.
• It can also be used as a boost in T4 tumors to
escalate safely the dose.
• For inoperable patient, when the tumor is too
large to be treated with CXRT, it is an efficient
way to escalate the dose in association with
EBRT and to achieve long-term control and
cure with acceptable toxicity.
• Interstitial iridium implant
• It is well adapted to irradiate the rectal tumor
close to or extending into the anal canal
where it is better adapted than endoluminal
brachytherapy or CXRT.
CXRT is the more accurate technique to
irradiate under eye guidance accessible rectal
tumors not exceeding 4 cm in diameter. It can be
used either alone or after local excision for
T1N0. It can be used in combination with EBRT
(± chemotherapy) for inoperable patients with
T202 early T3N0 lesions. It is the only tech-
nique whose benefit was proven by a random-
ized trial.
17.5 Perspective
It an era of treatment individualization for rectal
cancer, brachytherapy should play an important
and increasing role mainly to improve the chance
of conservative treatment either in operable or
inoperable patients.
Prospective clinical trials phase II and if pos-
sible phase III such as the CONTEM trials using
CXRT should demonstrate the role of brachyther-
apy in the following situations after careful selec-
tion of the patients [7].
J.-P. Gérard et al.
17.5.1 In Fit Operable Patient
• Malignant polyp or T1N0 with first-line local
excision: postoperative “adjuvant” irradiation
with brachytherapy (± EBRT ± concurrent
chemotherapy) should keep safely the rate of
local recurrence below 10%. It can be per-
formed with CXRT or interstitial HDR iridium
implant for juxtarenal tumors.
• T1N0 <3 cm diameter
• Brachytherapy preferably with CXRT should
be able to cure 90% of these tumors.
• T2N0 <4 cm diameter
• A combination of chemoradiation with CXRT
should achieve cCR in 80%–90% of cases and
can be followed by either local excision or
watch and wait close follow-up. Salvage radi-
cal surgery should be proposed according to
clinical and pathological findings. The rate of
local relapse in the pelvis should be kept below
10%. Such an approach is still in the field of
clinical research.
• Early “good” T3a in the distal rectum
• Achieving cCR with a combination of chemo-
radiation and brachytherapy should increase
safely the chance of sphincter-saving surgery
and, if possible, organ preservation. A new
randomized trial to duplicate the results of the
Lyon R96.02 trial would be of great interest.
17.5.2 Inoperable Elderly Patient
Brachytherapy should play an important role to
cure some of these patients and sometimes to pal-
liate large radioresistant lesions. In case of tumor
exceeding 50% of circumference, endoluminal
brachytherapy usually combined with short-
course EBRT should play a predominant role.
To be able to run such important trials, radia-
tion oncologists must be trained to master clini-
cal examination of rectal tumors and especially
rigid proctoscopy. Proctoscopy should allow to
tatoo the tumor site, to take biopsy for response
evaluation, and to implant fiducial marker.
17 What Is the Contribution of Brachytherapy in Tailoring Local Therapy?
A quality assurance program of all these different
brachytherapy techniques is needed. A regular
cooperation with the other specialists is manda-
tory. Finally, informed patients should agree to
participate in these clinical trials or observational
studies.
Disclosure Jean-Pierre GERARD is the medical advisor
of the Ariane Medical systems company (UK).
References
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Treatment of rectal adenocarcinoma with endocavi-
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patients with localized tumors. Int J Radiat Oncol Biol
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2. Gérard JP, Chapet O, Romestaing P et al (2000) Local
excision and adjuvant radiotherapy for rectal adeno-
carcinoma T1–2N0. Gastroenterol Clin Biol
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3. Gerard JP, Romestaing P, Chapet O (2003) Radio-
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5. Goes RN, Beart RW Jr, Simons AJ et al (1997) Use of
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6. Jakobsen A, Mortensen JP, Bisgaard C et al (2006)
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8. Papillon J (1975) Intracavitary irradiation of early
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 Part V
Q&As on Chemotherapy
 Should Oxaliplatin Be Added
to Preoperative Chemoradiation? 18
Carlo Aschele

Contents 18.1 Disease Background

18.1 Disease Background ...................................... 173
Despite major improvements during the last
18.2 Rationale for Incorporating
Oxaliplatin in the Preoperative
20 years, the management of patients with locally
Treatment of Rectal Cancer ......................... 174 advanced rectal cancer is far from satisfactory
and mortality rates remain high. In particular,
18.3 Phase I–II Studies ......................................... 174
local recurrences have been substantially reduced
18.4 Phase III Studies ........................................... 175 with the combination of accurate surgery, pre- or
References ................................................................. 179 postoperative chemoradiation, and sequential
adjuvant chemotherapy but remain a major prob-
lem in subsets of patients with more advanced/
aggressive disease [2,3]. Distant metastases
develop in approximately 30–40% of rectal can-
cer patients. In contrast with local recurrence,
this figure has remained substantially unchanged
over the last 20 years with only minor improve-
ments achieved with postoperative fluorouracil-
based chemotherapy [2,3]. Now that local
recurrence rates are much lower due to optimized
local treatment, distant recurrence has thus
become the major form of failure in these patients.
In addition, more than 20% of clinically resect-
able patients are found to actually have a positive
circumferential resection margin after surgery
with a significantly increased risk of local recur-
rence and distant metastases and reduced 5-year
C. Aschele survival rates. Of note, this negative prognostic
Department of Medical Oncology,
effect is particularly marked for patients with a
Ospedale Sant’Andrea e del Felettino,
ASL 5 – Liguria, La Spezia, Italy positive circumferential resection margin after
e-mail: carlo.aschele@asl5.liguria.it neoadjuvant treatment [13].

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 173

DOI 10.1007/978-3-642-25005-7_18, © Springer-Verlag Berlin Heidelberg 2012
174
18.2 Rationale for Incorporating
Oxaliplatin in the Preoperative
Treatment of Rectal Cancer
5-Fluorouracil has been the mainstay of both
chemoradiation regimens and adjuvant chemo-
therapy programs for rectal cancer. Potentiation
of these regimens by incorporation of new drugs
active in colorectal cancer may improve the con-
trol of distant metastases.
Oxaliplatin is a diaminocyclohexane (DACH) –
platinum compound, active in several solid tumor
types, including some cisplatin/carboplatin
refractory neoplasm as colorectal cancer. The
main mechanism of action, like cisplatin, is medi-
ated through the formation of DNA adducts, but
DACH-platinum adducts are bulkier and more
hydrophobic than cisplatin adducts.
The improvement in disease free and overall
survival achieved when oxaliplatin was added to
5-fluorouracil as adjuvant treatment for com-
pletely resected intraperitoneal colon cancer [1]
suggests that incorporating this agent in the treat-
ment programs for rectal cancer may improve the
control of micrometastases at distant sites.
Oxaliplatin also increases the antitumor activ-
ity of 5-fluorouracil in metastatic colorectal can-
cer [8] and has been shown to be a radiation
sensitizer in preclinical models with optimal
efficacy when it is given concomitantly with radi-
ation, presumably by inhibiting postradiation
DNA repair [6]. Its combination with
5-fluorouracil and radiation in the preoperative
setting may thus improve also tumor shrinkage
before surgery. This may be particularly impor-
tant in low-lying tumors when sphincter preser-
vation is attempted and in patients with bulky T3,
T4, and tethered tumors where R0 resections are
difficult to achieve unless the tumor is adequately
shrunk before the operation.
Oxaliplatin has other pharmacological proper-
ties that are favorable for its incorporation in the
preoperative treatment of rectal cancer. In partic-
ular, the toxicity profile with a low incidence of
gastrointestinal toxicity makes this agent a good
drug for combination with pelvic radiotherapy
and concurrent infused 5-fluorouracil.
C. Aschele
18.3 Phase I–II Studies
Week 1 and 5 schedules of oxaliplatin in combi-
nation with 5-fluorouracil and radiation have
been initially evaluated in a series of phase I
studies of preoperative chemoradiotherapy in
the setting of locally advanced rectal cancer
[9,10,17]. These studies demonstrated the feasi-
bility of adding oxaliplatin to 5-fluorouracil and
standard preoperative pelvic radiation with a
high delivered dose intensity, acceptably low
gastrointestinal toxicity, neutropenia or early
postoperative complications. The optimal dose
on this 4-week schedule in combination with
infusional 5-fluorouracil and radiation therapy
was defined at 130 mg/m2 [9]. These initial stud-
ies also provided clinical evidence supporting
the preclinical rationale for the incorporation of
oxaliplatin in chemoradiation programs for rec-
tal cancer with rates of pathological complete
responses (pCRs) that have generally been
above 25% [9,10,17].
A weekly schedule of oxaliplatin administra-
tion concomitant to continuous infusion
5-fluorouracil and preoperative chemoradiation
has been developed by our group in Italy [2–4].
Weekly administration of oxaliplatin in combina-
tion with pelvic radiotherapy may present several
advantages compared to administration every
3–4 weeks. This schedule may in fact result in
reduced acute toxicity, thanks to dose fraction-
ation, and improved control of side effects, thanks
to better modulation of drug delivery. The high-
dose density of a weekly schedule of administra-
tion may also be optimal to maximize the
inhibition of sublethal, radiation-induced DNA
damage repair (advocated as the main mechanism
for the radiosensitizing effect of oxaliplatin) [7]
(Table 18.1).
Results from the pivotal phase I–II study of
this regimen have shown that the recommended
weekly dose of oxaliplatin (given for six times on
the first day of each week of treatment at escalat-
ing doses from 25 up to 60 mg/m2) in combina-
tion with pelvic radiotherapy (50.4 Gy – 28
fractions) and infused 5-fluorouracil (adminis-
tered for the entire duration of radiotherapy at
18 Should Oxaliplatin Be Added to Preoperative Chemoradiation?
Table 18.1 Phase I–II studies
of oxaliplatin and pelvic Regimen
radiation therapy
FU + OXA
CAPE/UFT + OXA
RTX + OXA
Abbreviations: pCR pathologic complete response, FU fluorouracil, OXA
oxaliplatin, CAPE capecitabine, UFT uracil/tegafur, RTX raltitrexed
225 mg/m2/day) is 60 mg/m2 given weekly ×6
[4]. The feasibility of this regimen and the rec-
ommended dose of weekly oxaliplatin previously
established in our study (60 mg/m2/week) were
confirmed in CALGB 89901 [16].
At the recommended dose, this regimen allows
therefore to deliver a total dose of oxaliplatin
(360 mg/m2 of over a 6-week time concomitant
to radiation) substantially higher compared to
other oxaliplatin-based chemoradiation programs
[9,10,17]. In addition, this oxaliplatin dose is poten-
tially active also systemically with a dose intensity
approximately 50% higher compared to the regi-
mens commonly used in the treatment of metastatic
colorectal cancer [8]. This schedule has therefore
an added advantage over a traditional week 1 and 5
chemotherapy program in that it incorporates a
dose and schedule of both oxaliplatin and
5-fluorouracil known to be systemically active.
This may be particularly important to optimize
both local control, with an enhanced chemoradia-
tion regimen, and the control of (micro)metastases
at distant sites with the concomitant administration
of systemically active combination chemotherapy.
18.4 Phase III Studies
There are four completed phase III randomized
clinical trials assessing the value of oxaliplatin
combined with fluoropyrimidines (FPs) and pre-
operative external-beam pelvic radiation in locally
advanced rectal cancer (Table 18.2). Infused
5-fluorouracil was the FP backbone in the STAR-
01 and CAO/ARO/AIO studies, while weekly
oxaliplatin was combined with capecitabine in
the French ACCORD trial and either capecitabine
or infused 5-fluorouracil in the NSABP study that
entailed a 2 × 2 factorial design.
175
Number Number Grades III–IV
of studies of patients pCR (%) toxicity (%)
15 450 7–36 6–39
14 616 6–29 6–33
4 160 14 7–23
Of note, all of these studies have used a
weekly schedule for oxaliplatin administration
building on the chemoradiation regimen origi-
nally generated by our group. Only our study
(the Italian STAR-01 trial), however, maintained
the six oxaliplatin courses as in the original regi-
men. Both the NASBP and the French study had
in fact five oxaliplatin administrations while
oxaliplatin was administered on days 1, 8, 22,
and 29 in the German study that prescribed a
chemotherapy break during the third week of
radiation.
As to control arms, the STAR-01, NSABP,
and French trials used exactly the same FP dose
and schedule as in the experimental arm, while a
shorter infusion with higher 5-fluorouracil daily
doses (mimicking the chemoradiation regimens
used in the treatment of anal cancer) was used in
the control arm of the German study.
Radiotherapy intensification was pursued
in the experimental arm in the French study
(45 Gy in the control arm vs. 50 Gy in the experi-
mental arm) while the planned radiotherapy dose
was 50.4 Gy for both arms in the other three
studies.
Data on safety, surgery, and response to preop-
erative chemoradiation have been reported for all
of these studies [5,11,14,15]. These results
confirm that weekly oxaliplatin can be added to
FP-based preoperative chemoradiation even
though toxicity is increased. Unexpected adverse
events were not reported, and there was no excess
treatment mortality in the oxaliplatin arms; over
95% of patients were operated as planned within
6–8 weeks from the end of chemoradiation inde-
pendent of the preoperative treatment they had
received, and surgical mortality was also low and
similar with or without oxaliplatin. Treatment
compliance was reduced with an apparent
176 C. Aschele

Table 18.2 Phase III randomized studies of FP-based preoperative chemoradiation ± oxaliplatin
Primary Postoperative
Study n endpoint Status Control arm Experimental arm treatment
ACCORD 598 pCR Reported Cape 1,600 mg/m2/
Cape 1,600 mg/m2/ Center choice
0405 (primary day d1–5 weekly day d1–5 weekly ×5;
endpoint) ×5; RT 45 Gy OXA 50 mg/m2 d1
weekly ×5; RT 50 Gy
STAR-01 747 OS Reported CI FU 225 mg/m2/ CI FU 225 mg/m2/ FU/LV
(secondary day d1–35; RT day d1–35; OXA (both arms)
endpoint) 50.4 Gy 60 mg/m2 d1 weekly
×6; RT 50.4 Gy
NSABP R-04 1,608 LR Reported CI FU 225 mg/m2/ CI FU 225 mg/m2/ Center choice
(secondary day or Cape day or Cape
endpoint) 1,650 mg/m2/d d1–5 1,650 mg/m2/d d1–5
weekly ×5; RT weekly ×5; OXA
46 Gy 50 mg/m2 d1 weekly
(+5.4–10.8 Gy) ×5; RT 46 Gy
(+5.4–10.8 Gy)
CAO/ARO/ 1,265 DFS Reported CI FU 1,000 mg/ CI FU 250 mg/m2 FU 500 mg/m2
AIO-04 (secondary m2/day d1–5, d1–14, 22–35; OXA day ×5 q 4 week
endpoint) 29–33; RT 50.4 Gy 50 mg/m2 d1, 8, 22, (4 cycles) vs.
29; RT 50.4 Gy mFOLFOX-6
(8 cycles)
PETACC-6 634 (1,090) DFS Accruing Cape 1,650 mg/m2/ Cape 1,650 mg/m2/ Cape 2,000 mg/
day d1–33; RT day d1–33; OXA m2/day d1–14 q
45 Gy (±5.4 Gy) 50 mg/m2 d1 weekly 3 week ± OXA
×5; RT 45 Gy 130 mg mg/m2
(±5.4 Gy) d1 q 3 week
(6 cycles)
Abbreviations: pCR pathologic complete response, OS overall survival, LR local relapse, DFS disease-free survival,
Cape capecitabine, RT pelvic radiotherapy, OXA oxaliplatin, CI continuous infusion, FU fluorouracil, mFOLFOX-6
modified FOLFOX-6

relationship between the oxaliplatin dose deliv-
ered concomitant to radiation and the proportion
of patients receiving a reduced radiotherapy dose
(6% in the German study where 200 mg/m2 of
oxaliplatin were delivered concomitant to radia-
tion, 13% in the French study with 250 mg/m2,
and 16% in the STAR-01 study with 360 mg/m2
of oxaliplatin added to 5-fluorouracil and radia-
tion). However, even in the STAR study that
entailed the highest added oxaliplatin dose, more
than 90% of the patients in the oxaliplatin arm
received at least 45 Gy and more than 80% had at
least 5 weekly administrations of oxaliplatin
(Tables 18.3 and 18.4).
The addition of oxaliplatin resulted in more
toxicity with grade III–IV events reported in
more than 20% of patients and rates of grade
III–IV diarrhea between 12% and 15% in all the
four studies. This increase in toxicity appears to
be less pronounced in the German study, possibly
because of the lower cumulative dose of oxalipla-
tin administered along with radiation. The higher
rate of severe toxicity in the control arm of this
study (22% compared to less than 10% in the
Italian and French studies) provides an alterna-
tive explanation for the less evident increment
observed with the addition of oxaliplatin.
Despite the promising phase II data (Table 18.1),
these randomized studies indicate that adding
oxaliplatin to preoperative 5-fluorouracil and
pelvic radiation does not improve primary tumor
response. pCR rates were identical, or nearly
identical, in the experimental compared to the
control arms in the STAR-01 and NSABP-R04
studies and numerically, but not significantly,
increased in the French study (that also entailed
intensified radiotherapy in the oxaliplatin-
containing arm). A 3.7% absolute difference in
18 Should Oxaliplatin Be Added to Preoperative Chemoradiation? 177

Table 18.3 Treatment compliance and safety of preoperative chemoradiation ± oxaliplatin in randomized
phase III studies
STAR-01 ACCORD 0405 NSABP R-04 CAO/ARO/AIO-04
Study arm, n Study arm, n Study arm, n Study arm, n
Ctr OXA Ctr OXA Ctr OXA Ctr OXA
379 352 293 291 622 631 624 613
RT full dose, % 92 84 100 87 nr nr 95 94
OXA full dose, % – 66a – nr – nr – 85c
Grade III–IV toxicity, %
Overall 8 24b 11 25b nr nr 22 23
Diarrhea 4 15b 3 13b 7 15b 8 12
Neuropathy (³G2) 0 8b 0.4 6b b
nr nr <1 2c
Abbreviations: ctr control arm, OXA oxaliplatin-containing arm, RT radiotherapy, CT chemotherapy
a
83% received at least 5 weekly courses
b
Statistically significant
c
Chemoradiation full dose

Table 18.4 Response to preoperative chemoradiation ± oxaliplatin in randomized phase III studies
STAR-01 ACCORD NSABP R-04 CAO/ARO/AIO-04
Study arm, n Study arm, n Study arm, n Study arm, n
Ctr OXA Ctr OXA Ctr OXA Ctr OXA
379 352 293 291 622 631 624 613
ypCR, % 16 16 14 19 19 21 13 17*
ypT0, % 18 19 14 20 nr nr 13 18
ypN+, % 26 29 30 28 nr nr 30 28
R0 resection, % 94 97 nr nr nr nr 92 90
CRM + (£1 mm), % 7 4 13 8 nr nr 6 5
SSS, % 78 79 75 75 64 60 71 69
Abbreviations: ctr control arm, OXA oxaliplatin-containing arm, ypCR pathological complete response, CRM circum-
ferential resection margin, SSS sphincter-saving surgery
*p = 0.045 (unplanned exploratory analysis)

favor of the oxaliplatin arm that reached statis-
tical significance in an exploratory unplanned
analysis was reported in the German study. Other
measures of response to preoperative chemoradi-
ation (including tumor regression grade, the pro-
portion of patients with residual tumor confined
to the muscular layer of the rectal wall, the rates
of node-positive disease found at surgery, and
the incidence of circumferential resection margin
positivity) were also similarly distributed among
patients treated with or without oxaliplatin in
the four studies ruling out any clinically relevant
effect on primary tumor response.
Although surgery details are not available for
NSABP-R04, in the three European trials, the
median number of examined lymph nodes was
between 12 and 15, less than 10% of patients did
not have TME surgery, and at least 90% had an
R0 resection. This may have contributed to lower
the pCR rate compared to initial phase II studies.
The quality of surgery and pathology indeed
affect the ability to detect residual tumor after
preoperative chemoradiation and is therefore
inversely correlated with the pCR rate.
The lower pCR rate observed with OXA in
these randomized studies probably reflects also
the better control for the multiple factors affect-
ing response to preoperative chemoradiation
and the larger sample size compared to phase II
assessment. This underlines the crucial impor-
tance of properly designed, adequately powered
randomized multidisciplinary studies with stan-
dardized and optimized radiological staging,
radiotherapy, TME surgery, and pathologic
178
evaluation to assess the effect of new treatment
strategies in rectal cancer.
This lack of improvement in tumor response
does not appear to be explained by a lower adher-
ence to the treatment program due to the increased
toxicity in the oxaliplatin arms. In the STAR-01
study, where all measures of compliance were
significantly reduced in the group randomized to
receive oxaliplatin compared to the control group,
pCR rates were similar between the two arms also
in exploratory analyses restricted to patients that
completed all the planned radiation and chemo-
therapy as assigned [5]. In addition, even in the
study that had the highest treatment compliance in
the oxaliplatin arm, with 85% of patients receiving
full-dose chemoradiation [14], a marginal, clini-
cally not relevant, although statistically significant,
4% increase in the pCR rate was observed.
These results indicate therefore that oxalipla-
tin is not a clinically effective radiation sensitizer
in rectal cancer (or at least that oxaliplatin does
not increase radiosensitization achieved with
5-fluorouracil or capecitabine administration
concomitant to radiation).
Of note, the pCR rates in the control arms of
these four studies appear to be higher than those
reported in less recent studies, probably thanks to
optimized radiotherapy techniques and higher
radiation doses. In particular, pCR rates in the
control arm were above 15% in the ACCORD-
PRODIGE, STAR-01, and NSABP R-04 trials all
involving continuous administration of the FP
(protracted 5-fluorouracil infusion or oral capecit-
abine) for all the duration of radiotherapy. It is
thus conceivable that optimal radiotherapy with
optimal radiosensitization by FPs already maxi-
mizes primary tumor response with little or no
room for further improvement with additional
radiation sensitizers.
Primary tumor response was the main endpoint
only for the French study, while the other studies
were designed to test the impact of oxaliplatin on
long-term efficacy endpoints (overall survival for
the STAR-01 study, local relapse in NSABP R04,
and disease-free survival for the German trial).
The lack of effect on primary tumor response does
not contradict this hypothesis. In rectal cancer,
there is in fact no evidence that differences in
C. Aschele
long-term outcome in a phase III trial are pre-
dicted comparing pCR rates between treatment
arms. The mechanisms of cytotoxicity and radio-
sensitization may in fact not be the same, and
local tumor regression does not necessarily pre-
dict responsiveness of disseminated tumor cells
toward the chemotherapy component of combined
modality treatment programs.
Of interest, in these studies, extrapelvic metas-
tases were found at surgery less frequently in
patients treated with oxaliplatin compared to those
receiving single-agent FP and radiation, although
statistical significance was reached only in the
STAR-01 trial.
Further follow-up is thus required to establish
if the early introduction of oxaliplatin in the man-
agement of locally advanced rectal cancer can
improve longer-term outcomes such as disease-
free and overall survival. At the present time,
however, oxaliplatin has no role in the neoadju-
vant radiochemotherapy of this disease and should
not be added to preoperative chemoradiation.
Single-agent FPs thus remain the standard che-
motherapy in this setting. Given this lack of effect
on primary tumor response, even future favorable
results in long-term efficacy should be weighed
against the increased toxicity observed when
oxaliplatin has been added to preoperative chemo-
radiation. The control of metastases at distant
sites could in fact be improved, also adding oxali-
platin in the postoperative setting at a lower toxic-
ity cost as successfully done in colon cancer.
Alternative strategies are thus required to
improve primary tumor response to preoperative
treatment in patients with locally advanced rectal
cancer. Induction chemotherapy and image-
guided radiotherapy techniques are actively
investigated at this end. Preclinical data also sug-
gest that the synergism between oxaliplatin,
5-fluorouracil, and radiation is restricted to cell
lines with specific gene expression profiles [12].
Future studies of novel therapies in rectal cancer
should thus include molecular profiling to indi-
vidualize therapy protocols and identify patients
that may achieve a good response even with
standard treatment and those demonstrating
aggressive biology that could benefit from a more
intensified approach.
18 Should Oxaliplatin Be Added to Preoperative Chemoradiation? 179

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 Should Biologic Targeted Agents
Be Combined with Preoperative 19
Chemoradiation in Rectal Cancer?

Pieter-Jan Cuyle and Eric Van Cutsem

Contents 19.1 Introduction

19.1 Introduction ................................................ 181
Over the last decades, the clinical management of
19.2 EGFR Inhibitors in Rectal Cancer........... 182
locally advanced rectal cancer (LARC) has
19.3 VEGF Inhibitors in Rectal Cancer........... 186 changed substantially. Improvements in preoper-
19.4 Combined EGFR and VEGF Inhibition ative staging techniques with magnetic resonance
in Rectal Cancer ......................................... 188 imaging (MRI) and endoscopic ultrasonography
References ................................................................. 189 (EUS), the use of neoadjuvant therapy, improved
and innovative surgical approach, and standard-
ized recommendations for histopathological
analysis (tumor regression grading (TRG) and
circumferential resection margin (CRM) involve-
ment) have gradually improved local control rates
and the outcome of patients with rectal cancer.
Preoperative radiotherapy with concomitant infu-
sional 5-fluorouracil (5FU) or oral capecitabine,
followed by total mesorectal excision (TME), has
become the standard of care for patients with T3/
T4 or lymph node positive rectal cancer in most
Western countries, reducing local failure rates to
<10%. The pathological complete response
(pCR), defined by an absence of residual tumor
in the resected specimen after preoperative ther-
apy, is reported between 0% and 31% in recent
phase II/III trials with these regimens. Despite
these advancements, the rate of distant metasta-
ses remains high: around 30–40%. Therefore, the
challenge remains to optimize further rectal can-
cer treatment. With the increased understanding
of molecular pathways that drive colorectal can-
P.-J. Cuyle • E. Van Cutsem (*) cer and the ongoing development of biological
Department of Digestive Oncology,
agents targeting these pathways, recent trials
University Hospital Gasthuisberg,
Leuven 3000, Belgium have investigated the role of targeted biologic
e-mail: eric.vancutsem@uzleuven.be agents in combination with cytotoxic drugs in

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 181

DOI 10.1007/978-3-642-25005-7_19, © Springer-Verlag Berlin Heidelberg 2012
182
preoperative chemoradiation regimens. By doing
so, it is the hope to further improve local control,
resectability, and sphincter preservation rates but
more importantly to decrease the risk of distant
recurrence and ultimately to improve overall sur-
vival. This manuscript discusses the integration
of epidermal growth factor receptor (EGFR) inhi-
bition and vascular endothelial growth factor
(VEGF) inhibition in neoadjuvant treatment
strategies for locally advanced rectal cancer.
19.2 EGFR Inhibitors in Rectal
Cancer
The epidermal growth factor receptor (EGFR,
HER1, or ErbB1) is a glycoprotein receptor, com-
prising of an extracellular ligand-binding domain,
a transmembrane region, and an intracytoplas-
matic domain with tyrosine kinase activity. Ligand
binding of the extracellular domain results in
homodimerization or heterodimerization with
other members of the EGFR family (HER2, HER3,
HER4) and subsequent initiation of downstream
signaling pathways by autophosphorylation. These
downstream signaling cascades include the mito-
gen-activated protein kinase (MAPK) pathway
and the phosphatidylinositol-3-kinase (PI3K)
pathway. EGFR regulates cellular growth, differ-
entiation, and survival, and abnormal EGFR acti-
vation can result in uncontrolled cell proliferation,
which makes this receptor an attractive target for
cancer treatment. Several EGFR inhibitors are
available for clinical use. Cetuximab (Erbitux;
ImClone/Bristol-Myers Squibb/Merck Serono)
and panitumumab (Vectibix; Amgen) are mono-
clonal antibodies directed against the extracellular
domain of the receptor, inhibiting ligand binding.
Gefitinib (Iressa; AstraZeneca) and erlotinib
(Tarceva; Genentech/OSI Pharmaceuticals) are
small-molecule tyrosine kinase inhibitors (TKI)
targeting the intracellular tyrosine kinase domain
of the receptor, preventing ATP binding and
autophosphorylation.
Several preclinical and clinical studies have
provided a strong rationale for integrating EGFR
inhibitors in the preoperative treatment of LARC.
EGFR is overexpressed in 60–80% of colorectal
P.-J. Cuyle and E. Van Cutsem
cancers, and overexpression is regarded as a
negative prognostic factor [1, 2]. Moreover, a ret-
rospective analysis has shown inferior results for
disease-free survival and pathological complete
response (pCR) rates in patients with EGFR-
expressing rectal cancer who were treated with
neoadjuvant radiotherapy [1]. The interaction of
ionizing radiation with different levels of the
EGFR pathway has been studied in preclinical
models, suggesting a synergistic effect for EGFR
inhibition with radiation therapy [3, 4]. Based on
their results, these authors suggested the use of
EGFR inhibitors as radiosensitizers in clinical
practice. A landmark phase III study in locally
advanced head and neck squamous cell carci-
noma combining cetuximab with standard high-
dose radiotherapy showed improved locoregional
control and reduced mortality, without increasing
the number of adverse events [5]. The clinically
significant activity of anti-EGFR targeting agents
in metastatic colorectal cancer has also been
demonstrated by a number of phase III clinical
trials [6].
Based on these data, several phase I and II
trials were undertaken, incorporating the use of
EGFR inhibitors in preoperative chemoradi-
ation for LARC, as summarized in Table 19.1.
Pathological complete response (pCR) was the
primary endpoint in the majority of reports. The
eligibility criteria for inclusion, including initial
tumor stage, varied considerably between stud-
ies. Also, a wide variation in drug regimen, dose,
treatment duration, and sequence was noticed
between study protocols. The number of reported
patients was often small and different methods of
assessing tumor response rates were used, mak-
ing it difficult to compare results or draw firm
conclusions. Cetuximab was integrated in 13 tri-
als [7–19], whereas panitumumab and gefitinib
each were used in two trials [20–23]. The reported
pCR ranged from 0% to 31%, 11% to 21%, and
0% to 30%, respectively. A loading dose of cetux-
imab or panitumumab was often administered 1
or 2 weeks prior to the start of chemoradiation.
The rate of (National Cancer Institute CTC) grade
3 or 4 (G3/4) adverse events was within the
expected range, with G3/4 diarrhea being reported
in 5–30% and G3/4 skin rash in 2–15% of patients
 19
Table 19.1 Published papers and abstracts reporting the use of EGFR inhibitors in preoperative chemoradiation in rectal cancer
Authors Chemoradiotherapy (CRT) Interval
[Ref.] Phase N Pre-CRT Target 5FU cap oxa iri RT (Gy) Post-CRT (weeks) pCR (%)
Cabebe et al. I 23 cet × × 50.4 cet NR 17
[ 7]
Chung et al. I 20 cet × 50.4 cet 1–3 12
[ 8]
Hofheinz I 20 cet × × 50.4 4–5 26
et al. [9]
Machiels I/II 40 cet cet × 45 6–8 5
et al. [10]
Mai et al. [11] I/II 47 cet × × 50.4 NR NR
Rödel et al. I/II 58 cet cet × × 50.4 6 9
[12]
Bertolini et al. II 40 cet cet × 50.4 6–8 8
[13]
Eisterer et al. II 28 cet × 45 4–6 0
[14]
Kim et al. II 39 cet cet × × 50.4 4–8 23
[15]
Horisberger II 50 cet × × 50.4 4–6 8
et al. [16]
McCollum II 67 cet cet × 50.4 cet 6–8 31
et al. [17]
Velenik et al. II 37 cap/cet cet × 45 4–6 8
[18]
Dewdney II 46 cap/oxa/cet cet × 54 6 11
et al. [19]
(continued)
Should Biologic Targeted Agents Be Combined with Preoperative Chemoradiation in Rectal Cancer?
183
Table 19.1 (continued)
184

Authors Chemoradiotherapy (CRT) Interval

[Ref.] Phase N Pre-CRT Target 5FU cap oxa iri RT (Gy) Post-CRT (weeks) pCR (%)
Czito et al. I 6 gef × 50.4 6–8 0
[20]
Valentini et al. I/II 41 gef × 50.4 7–8 30
[21]
Pinto et al. II 60 pan pan × × 50.4 7–8 21
[22]
Helbling et al. II 40 pan pan × 45 pan 3–5 11
[23]
N number of patients entering study, pre-CRT agents given before start of radiotherapy, target targeted agent used, 5FU 5-fluorouracil, cap capecitabine; oxa, oxaliplatin, iri
irinotecan, RT(Gy) radiotherapy dose, post-CRT agents given after completion of radiotherapy, interval therapy-free interval between the end of preoperative therapy and surgery
pCR pathological complete response, cet cetuximab, gef gefitinib, pan panitumumab, NR not reported
P.-J. Cuyle and E. Van Cutsem
19 Should Biologic Targeted Agents Be Combined with Preoperative Chemoradiation in Rectal Cancer?
receiving a cetuximab-containing regimen. Both
trials integrating panitumumab reported a high
incidence of G3/4 diarrhea, reaching up to 39%
of patients when combined with oxaliplatin, 5FU,
and radiation [22]. The association of gefitinib to
preoperative chemoradiation had a comparable
toxicity profile; however, G3 hepatic toxicity was
encountered in 26% of treated patients [21].
In summary, results of these phase I/II studies
confirm that combination of EGFR inhibitors
with neoadjuvant chemoradiation for rectal can-
cer is feasible with acceptable toxicity. However,
the rates of pCR achieved with this combination
are disappointingly low.
A number of possible explanations have been
proposed why these phase I/II trials are unable to
reproduce the benefit seen with EGFR-directed
therapy in concomitant radiotherapy for head and
neck cancer or in metastatic colorectal cancer.
Accelerated repopulation of tumor cells surviv-
ing irradiation is an adaptive mechanism produc-
ing radioresistance and can be suppressed by
EGFR inhibitors [2, 4]. This phenomenon, how-
ever, seems less important in the treatment of rec-
tal cancer, compared to head and neck cancer,
since radiation doses tend to be lower, concomi-
tant 5FU or capecitabine is usually administered,
and surgical resection generally follows treat-
ment [24]. Nyati et al. have clearly illustrated
possible interactions between EGFR inhibitors
and cytotoxic drugs, including 5FU, oxaliplatin,
and irinotecan [4]. The G1 cell cycle arrest,
caused by EGFR inhibitors through upregulation
of cyclin-dependent kinase inhibitors p27 and
p21, may in fact antagonize the cytotoxic activity
of other cell-cycle-dependent chemotherapeutic
agents. A well-considered sequence in the admin-
istration of different therapeutic agents and radio-
therapy may be the key to optimize synergy and
produce better outcome results. Morelli and col-
leagues have studied the antiproliferative activity
of cytotoxic agents and EGFR inhibitors in vitro
and have shown that a synergistic activity was
only obtained when chemotherapy administra-
tion preceded EGFR blocking treatment [25].
The administration of EGFR antagonists as a
maintenance after completion of chemoradia-
tion or induction chemotherapy, followed by
185
radiotherapy with concomitant EGFR inhibitors,
may be strategies worth exploring [3, 4].
On top of modifications in the drug schedule,
adequate patient selection appears to be crucial to
improve the treatment outcome in rectal cancer.
Currently, no predictive or prognostic biomarkers
that impact the individual treatment strategy
or outcome in preoperative treatment for rectal
cancer are universally accepted. EGFR protein
expression evaluated by immunohistochemistry
(IHC) is not predictive for response to cetuximab
in metastatic colorectal cancer, nor in locally
advanced rectal cancer [26]. The EGFR gene
copy number (GCN) determined by FISH
has been proposed as a more reliable marker.
However, in metastatic colorectal cancer, only a
fraction of patients with an increased EGFR GCN
responds [3]. In LARC, a significant relationship
between EGFR high GCN and high pathological
TRG was observed in patients treated with cetux-
imab and 5FU-based chemoradiation [26]. The
best probability to predict a high TRG in this
treatment group was achieved when the combina-
tion of a high GCN and KRAS wild type status
was present [26]. The same authors found no
such relation for EGFR GCN or KRAS mutation
status in patients who were treated with standard
chemoradiation without cetuximab [27]. KRAS
mutation is found in 30–40% of patients with
LARC, but no correlation between mutation sta-
tus and response to cetuximab-based chemoradi-
ation could be established in two separate studies
[26, 28]. However, these results could be due to
the small number of patients treated in these tri-
als. A recent retrospective pooled analysis by
Grimminger et al. suggested that pretreatment
intratumoral EGFR and VEGF mRNA expres-
sion levels, as well as KRAS mutation status, are
predictive markers of pathological response in
these patients [29]. Mutations in downstream
effectors of the EGFR pathway, such as BRAF
and PIK3CA, are rare in patients with KRAS
wild-type rectal cancer, and their predictive value
remains unclear [30]. Erben et al. found no cor-
relation between mRNA expression of platelet-
derived growth factor receptor-b (PDGFR-b) or
c-kit and tumor regression rate after cetuximab-
based chemoradiotherapy [31].
186
19.3 VEGF Inhibitors in Rectal
Cancer
Neoangiogenesis is crucial for tumor growth
and malignant progression. In the majority of
cancers, tumor vessels appear to be abnormal
in structure and function, leading to a hostile
microenvironment characterized by hypoxia, low
pH, and high interstitial fluid pressure [32]. On
the one hand, the escape of tumor cells through
leaky vessels is facilitated, and on the other hand,
transport and distribution of cytotoxics and oxy-
gen seem to be impaired. Blockade of VEGF sig-
naling by pharmacological agents can transiently
repair these vascular abnormalities, thus improv-
ing oxygenation and lowering interstitial fluid
pressure. This process is referred to as “vascular
normalization” [32]. Improving oxygenation can
sensitize tumors to the cytotoxic effects of irra-
diation, while a decrease in interstitial fluid pres-
sure improves cytotoxic drug delivery. Extensive
preclinical studies in human tumor xenograft
models have demonstrated tumor suppression
ability of VEGF blockade [2] as well as its radio-
sensitizing ability [33]. Willett and colleagues
have assessed the effect of a single administration
of bevacizumab (Avastin; Roche/Genentech), a
recombinant humanized monoclonal antibody to
VEGF, on vascular biology in human rectal can-
cer [34]. This study indicates that, even at low
doses, bevacizumab alone can decrease perfu-
sion, microvascular density, and interstitial fluid
pressure in a solid tumor. Addition of bevaci-
zumab to conventional chemotherapy in meta-
static colorectal cancer has resulted in significant
and clinically meaningful survival benefit in a
number of phase III trials [1].
The potential benefit of VEGF blockade was
further explored in a number of phase I and II
studies, summarized in Table 19.2. The reported
trials have integrated bevacizumab into preopera-
tive 5FU- or capecitabine-based chemoradiation
regimens for locally advanced rectal cancer [35–
46]. Five of them also used oxaliplatin as a sec-
ond cytotoxic agent during treatment [35, 39,
44–46]. Surgical intervention was usually delayed
until at least 4–6 weeks after the last dose of bev-
acizumab to prevent postoperative complications.
P.-J. Cuyle and E. Van Cutsem
Again, substantial differences were noted between
studies concerning the inclusion criteria and the
applied drug regimen, dose, treatment duration,
and sequence. The rate of a pathological com-
plete response, although difficult to compare,
tends to be somewhat higher with bevacizumab-
based regimens than seen with EGFR inhibitor
containing regimens, ranging from 13% to 36%
of patients.
The reported incidence of grade 3–4 diarrhea
ranged between 20% and 40% in most trials.
Other more typical bevacizumab-related adverse
events, such as hypertension, proteinuria, mucosal
bleeding, and arterial thrombosis, were reported
at rates similar to those seen in phase III trials of
bevacizumab in metastatic colorectal cancer.
Postoperative complication rates, including pel-
vic infection, delayed wound healing, anasto-
motic leak, and fistulae, were relatively high in a
number of trials, ranging between 36% and 63%
of cases [37, 39, 43–45]. On the other hand, a
recent report of Liang et al. investigated the tech-
nical feasibility of laparoscopic TME for low rec-
tal cancer after preoperative treatment with the
combination bevacizumab-oxaliplatin-5FU and
fractionated radiotherapy [46]. Although the
interval to surgery after the last dose of bevaci-
zumab was only 2–4 weeks, a R0 resection was
achieved in all 28 treated patients at a postopera-
tive complication rate of “only” 21.4%. Long-term
results after bevacizumab-containing chemora-
diation were only available for the study by
Willett et al. providing a 5-year actuarial overall
survival rate of 95.0%, a disease-free survival of
68.9%, and a local control rate of 91.7% [47].
In summary, results of these phase I/II trials
indicate that integration of VEGF inhibition, in
this case bevacizumab, into preoperative chemo-
radiation regimens is feasible at a manageable
toxicity rate but does not appear to dramatically
enhance pathological downstaging rates when
compared to more conventional preoperative reg-
imens. There are however no data available from
larger studies whether the addition of bevaci-
zumab decreases the rate of metastases in rectal
cancer, and some concerns may of course be
raised in view of the lack of benefit of bevaci-
zumab in improving the outcome of stage III
 19

Table 19.2 Published papers and abstracts reporting use of VEGF inhibitors in preoperative chemoradiation in rectal cancer
Authors Chemoradiotherapy (CRT) Interval
[Ref.] Phase N Pre-CRT Target FU cap oxa iri RT (Gy) Post-CRT (weeks) pCR (%)
Czito et al. I 11 bev × × 50.4 6–8 18
[35]
Blaszkowski I/II 21 bev/erl × 50.4 6–9 47
et al. [36]
Willett et al. I/II 32 bev bev × 50.4 7–10 16
[37]
Crane et al. II 25 bev × 50.4 6–10 32
[38]
Kennecke II 42 bev bev × × 50.4 7–9 18
et al. [39]
Nogué et al. II 47 cap/oxa/bev bev × 50.4 6–8 36
[40]
Resch et al. II 8 bev × 45 6–8 25
[41]
Spigel et al. II 35 bev × 50.4 2–8 29
[42]
Velenik et al. II 61 bev bev × 50.4 6–8 13
[43]
Dipetrillo II 26 FU/oxa/bev bev × × 50.4 4–8 20
et al. [44]
Hoehler et al. II 70 bev × × 50.4 NR 17
[45]
Liang et al. II 28 bev × × 45 FU/oxa/bev 2–4 25
[46]
N number of patients entering study, pre-CRT agents given before start of radiotherapy, target targeted agent used, FU 5-fluorouracil, cap capecitabine, oxa oxaliplatin, iri irino-
tecan, RT(Gy) radiotherapy dose, post-CRT agents given after completion of radiotherapy, interval therapy-free interval between the end of preoperative therapy and surgery,
pCR pathological complete response, bev bevacizumab, erl erlotinib, NR not reported
Should Biologic Targeted Agents Be Combined with Preoperative Chemoradiation in Rectal Cancer?
187
188
colon cancer [48]. Moreover, the high incidence
of postoperative complications has raised some
concerns about the safety of this approach.
So far, no molecular biomarkers reliably pre-
dicting response to VEGF inhibition therapy are
available in clinical practice. Pretreatment VEGF
concentrations in tumoral tissue and circulation
failed to correlate with outcome to therapy with
VEGF blocking agents [49], although some
recent studies suggested a potential predictive
role of serum VEGF-A, as determined with
newer assays, in some cancers including pancre-
atic and gastric cancer [50, 51]. Willett and col-
leagues have put considerable effort in identifying
the kinetic changes in tumor cell proliferation
and apoptosis indices in response to anti-VEGF
treatment. They found that bevacizumab admin-
istration increases levels of plasma VEGF and
placental-derived growth factor (PlGF) and
decreases levels of circulating endothelial cells
(CECs) and progenitor cells (CPCs) [37, 52].
This group also looked at soluble VEGF recep-
tor 1 (sVEGFR-1), which is an antiangiogenic
factor released by endothelial cells, playing an
important role in the process of vascular normal-
ization [49]. They noticed a striking association
of pretreatment plasma sVEGFR-1 concentra-
tions and both primary tumor response and tox-
icity after bevacizumab-based chemoradiation.
However, further evaluation of these markers is
needed in larger studies to confirm their predic-
tive and/or prognostic value. We are coordinat-
ing at the moment in our center a multicenter
randomized phase 2 study evaluating the combi-
nations of bevacizumab/capecitabine or bevaci-
zumab/capecitabine/oxaliplatin plus radiotherapy
in locally advanced rectal cancer, with a focus on
marker analysis and translational research (AXE-
BEAM study).
19.4 Combined EGFR and VEGF
Inhibition in Rectal Cancer
Despite evidence from preclinical data for a syn-
ergistic effect of EGFR and VEGF blockade,
results from phase III trials implementing this
P.-J. Cuyle and E. Van Cutsem
combination in treatment of metastatic colorectal
cancer demonstrated an inferior median progres-
sion-free survival at the cost of an unfavorable
toxicity profile [2]. A small phase I/II study by
Blaszkowski et al. investigated the combination of
bevacizumab and erlotinib in combination with
infusional 5FU and pelvic radiation in patients
with LARC [36]. This combination appeared to
be well tolerated, and a pCR of 47% was achieved
in 15 patients undergoing surgery so far.
Conclusions
Improving survival in locally advanced rectal
cancer, while minimizing treatment-related
comorbidity, remains challenging. Integration
of targeted therapy in preoperative chemora-
diation regimens is supported by a strong the-
oretical background, promising preclinical
data, and encouraging experiences with these
agents in metastatic colorectal cancer and
locally advanced head and neck cancer. Phase
I results have demonstrated that this approach
is feasible with an acceptable toxicity.
However, results from phase II studies, incor-
porating EGFR and VEGF targeting therapy,
have been unimpressive, showing no clear
response benefit by adding these agents to
standard therapy. No randomized phase III
studies are currently available. Consequently,
the use of these agents in the preoperative
treatment for rectal cancer remains experi-
mental. The use of the pathological complete
response as an endpoint remains controversial
since it is largely influenced by the initial size
of the tumor, the interval between radiother-
apy and surgery, and the quality of histopatho-
logical examination. The correlation between
pathological complete response and long-term
outcome has been variable in previous trials.
A better understanding of the mechanisms
responsible for the disappointing results in
these phase II trials is necessary before pro-
ceeding to phase III. Future strategies should
focus on accurate identification of biomarker-
defined subpopulations with high-risk rectal
tumors that will benefit most from a certain
treatment approach.
19 Should Biologic Targeted Agents Be Combined with Preoperative Chemoradiation in Rectal Cancer? 189

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 Should Upfront Chemotherapy
Precede Preoperative 20
Chemoradiation and Surgery?

Carlos Fernandez-Martos and Xabier Garcia

de Albeniz

Contents 20.1 Introduction

20.1 Introduction ................................................ 193
In North America and in many European countries,
20.2 Adjuvant Chemotherapy
in Colon Versus Rectal Cancer ................. 194
preoperative 5FU and radiation followed by total
mesorectal excision (TME) and postoperative
20.3 Induction Chemotherapy Followed
adjuvant 5FU is a standard treatment for locally
by Concomitant Chemoradiotherapy
and Surgery ................................................ 196 advanced rectal (stage II and III) cancer, resulting
in a 5-year cumulative rate of local relapse rate of
20.4 Appendix: Evidence to Proceed to
a Phase III Trial ......................................... 200 less than 10% and an incidence of distant metas-
20.4.1 Question to Answer ..................................... 200 tases of about 35% [5, 40].
20.4.2 Study Design ................................................ 200 The phase III studies published in the last
20.4.3 Biomarkers ................................................... 200 decade include patients with stage I, II and III
20.4.4 Randomization ............................................. 201
20.4.5 Sample Size.................................................. 201 [29] and clinically staged II and III [5, 20, 40].
The most important conclusion is that preopera-
References ................................................................. 201
tive treatment either with long-term radiotherapy
(RT) and chemotherapy (CT) or short-course RT
has a major impact on local control. However,
there has been no impact on DFS or OS. Since
survival is mainly determined by distant metasta-
ses, efforts should be directed towards preventing
systemic disease.
Comparing DFS in recent landmark trials in
adjuvant therapy in stage II and III colon cancer
versus stage II and III rectal cancer, the results
indicate a less favourable outcome for the latter
C. Fernandez-Martos (*)
Medical Oncology Department, group (Fig. 20.1).
Fundacion Instituto Valenciano de Oncologia, Although currently we do not have a definitive
Calle Gregorio Gea 31, Valencia 46009, Spain answer for this fact, the differences may be
e-mail: cfmartos@fivo.org
explained, in part, by the highest incidence of
X. Garcia de Albeniz local relapse and the limited and inconstant
Channing Laboratory, Cubicle 346F,
efficacy of adjuvant postoperative chemotherapy
Brigham and Women’s Hospital,
181 Longwood Avenue, Boston, MA 02115, USA in patients undergoing preoperative radio(chemo)
e-mail: xgarciad@hsph.harvard.edu therapy [8]. Furthermore, rectal and colon cancers

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 193

DOI 10.1007/978-3-642-25005-7_20, © Springer-Verlag Berlin Heidelberg 2012
194 C. Fernandez-Martos and X.G. de Albeniz

90
84.7% 83.7%
81.9%
79.9%
80 5FU/LV FOLFOX
5FU/LV
Control

70 68%
66.4% 65%
Postop
58.9% FOLFOX Preop FU/RT 59.4%
60 FU/RT FU 58.2%
Postop 55.5% Preop
5F/LV FU/RT Preop
FU 52.2% FU/RT
Preop Postop
RT Or RT
50 Postop
FU
Preop NO
FU FU/RT PostopFU
Or RT
NO
40 PostopFU

30

20

10

0
QUASAR MOSAIC MOSAIC CAO/ARO/AIO FFCD 9203 EORTC 22921
Stage II Stage II Stage III 94 Stage II/III Stage II/III Stage II/III

Fig. 20.1 5-year disease-free survival for landmark clini- EORTC 22921 [5] (Adapted from Ther Adv Med Oncol
cal trials in colon. Quasar [24]; MOSAIC [1] and rectal [3]. © Sage Publications, INC. London:SAGE)
cancer trials; CAO/ARO/AIO [40]; FFCD 9203 [20];

may be genetically different. Different levels of
microsatellite instability and mutations in BRAF
and NRAS have been described [19, 28, 39] and
can be of importance for the efficacy in the adju-
vant setting in these two different anatomic sites.
20.2 Adjuvant Chemotherapy
in Colon Versus Rectal Cancer
In colon cancer, adjuvant chemotherapy is rec-
ommended in stage III because, as demonstrated
in the MOSAIC trial, DFS at 5 years was
significantly better in the FOLFOX arm (66.4%)
when compared with those receiving 5FU/leu-
covorin (58.9%) P = 0.005. Overall survival at
6-year follow-up was also significantly increased
(72.9% vs. 68.7%; HR = 0.80; P = 0.023) [1].
The impact of adjuvant chemotherapy for
patients with stage II disease is much less clear.
An analysis of pooled data from seven random-
ized trials indicated that overall survival of
patients with resected early stage colon cancer
treated with 5FU-based adjuvant chemotherapy
was statistically significantly increased in the
subset of patients with positive regional lymph
nodes but not in patients with N0 disease when
compared to patients not receiving chemotherapy
[21]. Although results of a subset analysis of data
from the MOSAIC trial did not show a significant
DFS benefit of FOLFOX over 5FU/LV for patients
with stage II disease at a follow-up of 6 years, a
trend was observed for improved DFS in high-risk
stage II patients (i.e. disease characterized by at
least one of the following: T4 tumour, tumour per-
foration, bowel obstruction, poorly differentiated
tumour, venous invasion, £ lymph nodes exam-
ined) receiving FOLFOX compared to infusional
5FU/LV, suggesting that this patient population
may benefit from treatment with FOLFOX. No
benefit, however, of FOLFOX over 5FU/LV was
seen for patients with low-risk stage II disease in
the MOSAIC trial.
Although, to date, there has been no definitive
randomized study to identify the optimal post-
operative adjuvant treatment and the optimal
duration of therapy in rectal cancer [43], the
general recommendation is to give adjuvant
20 Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery?
chemotherapy to patients with stage II and III
[22, 35].
European Organization for Research and
Treatment of Cancer (EORTC) 22921 was a ran-
domized trial to evaluate the role of concurrent
chemoradiation in the neoadjuvant setting, along
with the role of adjuvant chemotherapy in patients
with resectable stage T3/T4 rectal cancer [5].
Patients (n = 1,011) were randomized to one of
four treatment arms:
1. Preoperative radiation (45 Gy over 5 weeks)
alone
2. Preoperative radiation plus two 5-day courses
of chemotherapy (5FU at 350 mg/m2/day and
leucovorin at 20 mg/m2/day in week 1 and 5 of
radiation therapy)
3. Preoperative radiotherapy plus four postoper-
ative courses of chemotherapy
4. Preoperative radiotherapy and chemotherapy
plus postoperative chemotherapy
The adjuvant chemotherapy used in this study
was 5FU (350 mg/m2/day) and leucovorin (20 mg/
m2/day) given on days 1–5, and this regimen was
given every 3 weeks for a total of four courses.
At the time of the initial analysis, which was
reported after a median follow-up of 5.4 years,
adjuvant chemotherapy did not appear to confer
benefit in terms of DFS or OS. There are, how-
ever, three important points to note. The first is
that 26.9% of patients randomized to receive
adjuvant chemotherapy actually never started the
treatment and only 43% received 95% of the
planned dose of chemotherapy. Data from other
modern phase II and phase III [18, 37, 40, 41]
trials are similar, showing that applying chemo-
therapy (5FU or capecitabine/oxaliplatin) after
preoperative chemoradiation and surgery is prob-
lematic and often not feasible with adequate dos-
ing. More recently, a National Comprehensive
Cancer Network (NCCN) analysis carried out on
810 stage II and III patients from eight specialty
cancer centres shows that 20% of patients treated
with neoadjuvant chemoradiation did not receive
any adjuvant CTX [30]. The most frequent
causes are the patient’s decision to abandon
treatment because of the fatigue following the
aggressive therapy schedule, toxicity, and physi-
cian’s recommendation due to comorbid illness.
195
By contrast, the adherence to the planned treatment
is higher in colon cancer trials. In the MOSAIC
trial, 98.6% of patients received at least one cycle
of fluorouracil/leucovorin and oxaliplatin and
98.9% received at least one cycle of fluorouracil/
leucovorin and 74.7% of patients in the group given
fluorouracil plus oxaliplatin and 86.5% in the FL
group received the planned 12 cycles [2]. This fact
could explain, at least in part, the lack of a clear
benefit to DFS or OS in the EORTC trial.
Second, this trial included clinically staged
T3/T4 patients [6], 35% of whom were recruited
after a clinical examination that included some
subjective criteria (i.e. clinical T3 had to have
one of the following at digital rectal examination:
a circular extension, a lateral or posterior fixity
and an anterior adhesion to the prostate or inva-
sion of the rectovaginal wall), and 60% were
ultrasound-staged T3, and as the German study
demonstrated, about 20% could be stage I [40].
Therefore, in this study, the methods used for
staging could have determined that the true popu-
lation would be made up of stages I, II and III.
Third, the survival curves for patients who
received postoperative adjuvant chemotherapy
begin to diverge after 2 years for DFS and after
4 years for OS when compared to those who did
not receive adjuvant chemotherapy, suggesting
that further follow-up is required to determine
whether these differences will continue.
An updated analysis was subsequently per-
formed to determine the long-term results of the
EORTC 22921 study [14]. The goal of this
exploratory multivariate analysis was to investi-
gate whether it was possible to identify a sub-
group of patients who would benefit most from
adjuvant chemotherapy in the long term. Adjuvant
chemotherapy did not improve DFS or OS for all
patients with resectable T3/T4 rectal cancer.
A subset analysis, however, revealed that patients
whose disease responded to neoadjuvant therapy,
specifically those patients whose tumours were
downstaged to ypT0–T2 compared with stages
ypT3–T4 with preoperative therapy, experienced
a survival benefit from adjuvant chemotherapy.
Exploring the same issue, more recently a
large retrospective analysis has been reported.
Two thousand seven hundred twenty-four
196
patients were included. Forty-one percent under-
went adjuvant chemotherapy, which consisted
mostly of 5FU-based chemotherapy. The aim of
that analysis was to determine whether patients
with pathological complete response, ypT1–T2
or ypT3–T4 tumour after CRT have different
benefits of adjuvant chemotherapy for DFS. The
HR with 95% CI for DFS for adjuvant chemo-
therapy was 0.94 (0.50–1.78) for patients with
pCR, 0.61 (0.40–0.92) for patients with ypT1–T2
tumours and 0.97 (0.75–1.25) for patients with
ypT3–T4 tumours. ypT1–T2N0 benefit most
from adjuvant CT, and for ypT3-T4 patients, pN-
stage did not alter benefit of adjuvant chemo [4].
20.3 Induction Chemotherapy
Followed by Concomitant
Chemoradiotherapy
and Surgery
Treatment of high-risk patients with fluoro-
pyrimidines and concurrent radiotherapy without
the addition of adequate doses and cycles of CT
appears to be less than optimal. Strategies to
improve adherence to the systemic component of
the treatment are necessary.
One approach to address this issue is to deliver
induction CT before preoperative CRT. Induction
CT may be associated with better treatment com-
pliance and may enable full systemic doses of CT
to be delivered. Other theoretical advantages of
induction CT include the possibility of shrinking
or downstaging a locally advanced tumour, thereby
facilitating more effective local treatment and early
treatment of micrometastasis. Disadvantages
include the delay in surgery and the reduced
efficacy of subsequent radiotherapy with selection
of radiotherapy-resistant clones [23].
The first study published with this strategy
was from the UK, in which 36T3/T4 and N×/+
rectal cancer patients were treated with 12 weeks
of induction protracted venous infusion of
fluorouracil and mitomycin C before standard
chemoradiation and surgery [12]. A high rate of
tumour downstaging was recorded without any
progressors during neoadjuvant chemotherapy,
and 82% of patients achieved microscopically
C. Fernandez-Martos and X.G. de Albeniz
clear (R0) resections despite nearly a third having
had tumours that were initially threatening or
involving the circumferential resection margin
(CRM). However, only one pathological com-
plete response was achieved.
More recently, investigators from the same
group have published the largest phase II trial
(first published in 2006 with 77 patients and
updated 2010 with 105 patients and median fol-
low-up of 55 months) which examined the use of
four cycles of induction, this time with capecit-
abine plus oxaliplatin (CAPOX) followed by
CRT with capecitabine [11, 13]. This trial
included poor-risk rectal cancer patients as
defined by magnetic resonance imaging (MRI).
Eligible patients must have tumours within 1 mm
of mesorectal fascia (i.e. circumferential resec-
tion margin threatened), T3 tumours at or below
levators, tumours extending 5 mm into perirectal
fat, T4 tumours and T1–4N2 tumours. There was
a clinically significant occurrence of cardiac/
thromboembolic (CTE) toxicity during neoadju-
vant oxaliplatin/capecitabine, which led to three
mortalities. This fact prompted a protocol amend-
ment, and more stringent criteria were added to
exclude entry of patients with a previous history
of stable angina, arrhythmia, acute coronary syn-
drome (even if controlled by drugs) or myocar-
dial infarction within the past 12 months. After
amendment of the protocol, only one further fatal
pulmonary embolism occurred.
High radiological response rates to preopera-
tive treatment were recorded (96% of assessable
patients), 20% pCR and no disease progression
during preoperative treatment. Three- and 5-year
failure-free survival (ITT population) was 68%
and 64%, respectively; 3- and 5-year overall sur-
vival was 83% and 75%, respectively. Clinical
results of these and other phase II trials are given
in Table 20.1.
On the basis of these encouraging results, we
designed a phase II, randomized trial to compare
this approach with conventional preoperative CRT
followed by surgery and postoperative adjuvant
CT [17] (Fig. 20.2). A total of 108 patients with
locally advanced rectal (LAR) cancer as defined
by magnetic resonance imaging (MRI) of the pel-
vis were randomly assigned to preoperative CRT
Table 20.1 Phase II studies with induction chemotherapy followed by chemoradiotherapy (CRT) with or without adjuvant chemotherapy in rectal cancer patients
20

Series n Inclusion criteria Treatment Toxicity pCR DFS

Chau et al. [12] 36 MRI or CT + DRE T3/ Induction CT PVI 5FU + MMC 12 weeks Induction CT: G3/4: 25% 2.7%
T4 N×/+ M0
CRT PVI 5FU during RT 50.4–54 Gy CRT: G3/4 28% (skin)
Surgery: 4–6 weeks after CRT Surgery: 1 death (anastomotic leak with multiorgan
failure)
Adjuvant 12 weeks. PVI 5FU, MMC
Chau et al. [11] 105 MRI: Induction CT: CAPOX 4 cycles Induction CT: 5 deaths 20%
(updated
T3 £1 mm to CRM CRT: Starting week 13, Cape during RT 54 Gy 1 neutropenic sepsis
Chua [13])
T3 at/below levators Surgery: 6 weeks after CRT 2 pulmonary embolus
T3 ³5 mm into fat; T4; Adjuvant Cape, 4 cycles 1 myocardial infarction
N2; M0
1 cardiac failure; G3–5 diarrhea 10%
CRT: G3–5: 42% skin
Surgery: no deaths within 30 days
Calvo et al. [9] 52 US T3/T4 or N+ M0 Induction CT: FOLFOX −4, 2 cycles Induction CT: G3: 6% N.R.
CRT: starting day 30, Tegafur during RT 45–50.4 Gy CRT: G3–4: 33% ypT0: 29%
Surgery: 4–6 weeks after CRT + IORTBoost Surgery: 31% postoperative complications
(10–15 Gy)
Adjuvant CT: left to the treating oncologist’s discretion
Koeberle 60 MRI or US T3/T4 Induction CT: CAPOX 1 cycle Induction CT: G3 17% diarrhea, 3% G4 infection, 1/60 23%
et al. [31] N×/+ M0 died 19 days after start of CT due to neutropenic sepsis
CRT: starting day 22, Cape and Oxa during RT 45 Gy CRT: G3 17% diarrhea
Surgery: 5–6 weeks after CRT Surgery: not given
Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery?

Adjuvan CT: left to the treating oncologist’s discretion

Gunnlaugsson 49 “Nonresectable” Induction CT: CAPOX 2 cycles Induction CT: G3/4: 11% diarrhea 13%
et al. [25] colorectal carcinoma
T4N × M0–1
41 pts rectal CRT: starting week 7, Cape and Oxa during RT 50.4 Gy CRT: G3/4: 24% diarrhea
Surgery: performed, if feasible 1 pt died due to myocardial infarction
Adapted from Rödel et al. [36]
197

5-FU 5-Fluorouracil, MMC Mitomycin C, pCR pathological complete response, CT chemotherapy, RT radiotherapy, MRI Magnetical Resonance Image, DRE Digital Rectal Examination,
US Ultrasonography, FOLFOX 5FU Leucovorin and Oxaliplatin, CAPOX Capecitabine and Oxaliplatin, N.R. Not reported
198 C. Fernandez-Martos and X.G. de Albeniz

Resectable rectal adenocarcinoma

RMI defined locally advanced rectal
cancer <12 cm anal verge

Stratification: center

Randomization
Cape: 825 mg/m2 × 2 Cape : 2,000 mg/m2 14 days. 1 week rest
5 days/ week-5 weeks Oxa: 130 mg/m2 day 1
Concomitant with RT 4 cycles
+
Oxa: 50 mg/m2 weekly × 5 Cape: 825 mg/m2 x2
Concomitant with RT 5 days/ week-5 weeks
+ Concomitant with RT
Pelvic RT : 5,040 cGys +
5 − 6 weeks Oxa: 50 mg/m2 weekly x 5
Surgery Concomitant with RT
+
Pelvic RT : 5,040 cGys
Cape : 2,000 mg/m2 14 days. 1 week rest 5 − 6 weeks
Oxa 130 mg/m2 day 1
Surgery
4 cycles

Fig. 20.2 Schema for randomized, Grupo Cáncer de Recto (GCR) 3, phase II study. Cape capecitabine, RT radiation
therapy, Oxa oxaliplatin

with capecitabine, oxaliplatin and concurrent
radiation followed by surgery and four cycles of
postoperative adjuvant capecitabine and oxalipla-
tin (CAPOX) or induction CAPOX followed by
CRT and surgery. MRI criteria for LAR cancer
were as follows: tumours extending to within
2 mm of, or beyond, the mesorectal fascia (i.e. an
involved or threatened circumferential resection
margin); lower third (£6 cm from the anal verge)
cT3 tumours; resectable cT4 tumours and any
cT3N+. The primary endpoint was pathologic
complete response rate (pCR). On an intention-
to-treat basis, the pCR for the standard strategy
(adjuvant CT) was 13.5% (95% CI, 5.6–25.8%)
and for the induction strategy 14.3% (95% CI,
6.4–26.2%) respectively. There were no statisti-
cally significant differences in other endpoints,
including downstaging, tumour regression and
R0 resection.
The most compelling results of this study
concern the secondary endpoints. In the course
of CRT, there were no differences between the
arms in the number of patients with grades 3–4
toxicity. However, during adjuvant/induction
CT, significantly more patients in adjuvant arm
than in the induction arm had grades 3–4 toxic-
ity (54% vs. 19%; P = 0.0004, respectively).
Furthermore, 25% of patients in the adjuvant arm
A did not begin treatment, and 51% received all
four cycles, whereas 100% of patients in the
induction arm began treatment, and 92% received
all four cycles. These differences reached statisti-
cal significance.
The updated results with a median follow-up
time of 39.3 months and 36 months DFS rates
were 68% (95% CI, 53–80%) for adjuvant arm
and 70% (95% CI, 55–80%) in the induction arm
(P = 0.97) (Fig. 20.3). Analyzing the subset of
patients at higher risk (i.e. patients with cT4, cT3
distal third or CRM + tumours), the 36 months
DFS was 62% for the adjuvant arm versus 70%
for the induction arm. Although the numbers are
small, this insignificant difference may indicate a
trend towards some benefit of the induction strat-
egy in the higher-risk population [16]. Further
evidence that induction chemotherapy can con-
tribute to better control of distant relapse comes
from the recently published NSABP R-03 phase
III trial [38]. This is the first trial to document a
significant improvement in disease-free survival
in patients undergoing neoadjuvant chemoradio-
therapy therapy. Patients enrolled in R-03 received
6 weeks of fluorouracil (500 mg/m2) and leuco-
vorin (500 mg/m2) before the start of radiotherapy
20 Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery? 199

1.00

0.75 69%
Survival probability

68%
0.50

Adjuvant arm
0.25 Induction arm
Subjects Event Censored Median (CL 95%)
Brazo A 52 29% (15) 71% (37) NA (NA, NA)
Brazo B 56 29% (16) 71% (40) NA (NA, NA)
Log−Rank 0.9704
0.00
0 6 12 18 24 30 36 42 48 54
Time from consent date (months)
Number of patients at risk
Brazo A 52 47 44 41 40 36 27 18 2 0
Brazo B 56 54 46 41 38 28 16 5 0

Fig. 20.3 3-year failure-free survival for all eligible patients in GCR 3 trial

(cycle 1). Two courses of chemotherapy (cycles 2
and 3) were administered during the first and fifth
week of radiotherapy and four courses (cycles
4–7) postoperatively. Perhaps a 6-week course of
induction chemotherapy and a greater total cumu-
lative dose of FU are more effective in control-
ling micrometastatic disease and improving
disease-free survival.
Conclusion
Several conclusions can be drawn based on the
studies discussed above. In colon cancer, the
recommended adjuvant treatment is based on
trials with an appropriate selection of patients
with pathological stages II and III, and one
important observation is that the benefit in
terms of DFS is more evident in high-risk
groups. Moreover, the patients are included in
clinical trials following surgery, including only
patients who are well recovered after surgery
and with a good performance status to receive
complementary treatment, allowing in this way
a high compliance with the planned treatment.
On the other hand, in cancer of the rectum, pre-
operative combined modality treatment with
5FU and radiation increases the pathological
complete response (pCR) rate over radiother-
apy alone and improve locoregional control
but to date have not demonstrated an improve-
ment in survival outcomes. The phase III stud-
ies published in the last decade include a
clinically staged population of heterogeneous
risk. Added to this, a frequently occurring fact
is that there is a poor adherence to the adjuvant
treatment with chemotherapy after surgery. In
this scenario, no randomized study has shown
that delivery of adjuvant chemotherapy in
patients undergoing preoperative radio(chemo)
therapy improves outcome as compared with
observation. Emerging evidence from several
phase II trials and, recently, randomized phase
II trials indicates that induction chemotherapy
for rectal cancer patients is feasible, does not
compromise pCR, or R0 resection rates, is
less toxic and enables chemotherapy to be
delivered in adequate dose and intensity.
Nonetheless, while these data are statistically
and potentially clinically meaningful, these
remarkable findings are regarded as hypothesis
generating. Given the fact that the predominant
200
site of failure after combined modality treat-
ment in rectal cancer is systemic rather than
local, we think that introducing a systemically
active combination chemotherapy prior to
CRT, in a high-risk population selected by
MRI, may well be the next step in phase III
testing in order to improve DFS (see proposal
for phase III trial in Appendix).
20.4 Appendix: Evidence to Proceed
to a Phase III Trial
The GCR-3 trial is relevant due to the following
points [17]:
• It addresses a relevant clinical question. A
priori, better compliance with the adjuvant
regimen can be translated in a better control of
micrometastatic disease.
• Less toxicity also translates into a better qual-
ity of life for the patient and lower expenses.
• It uses a legitimate endpoint for phase II
trials in rectal cancer, pathological complete
response.
• It is a randomized phase II trial with an appro-
priate control arm.
• It opens the door to explore a new strategy of
treatment delivery that may improve patient care.
20.4.1 Question to Answer
With this background, the question to answer
would be: ‘Does the new regimen (adjuvant che-
motherapy administered prior to CRT and TME)
improve the disease-free survival of patients with
resectable rectal cancer?’
20.4.2 Study Design
20.4.2.1 Primary Endpoint
Superiority in disease-free survival (DFS),
defined as the time from date of randomization
until disease progression, relapse or death from
any cause.
C. Fernandez-Martos and X.G. de Albeniz
20.4.2.2 Secondary Endpoint
Pathologic complete response, overall survival,
toxicity, genetic signature validation, tumour
regression grade and rate of local relapse.
20.4.2.3 Study Population
Further progress in the management of locally
advanced rectal cancer will require the ability to
define which patients may or may not benefit from
preoperative treatment and to develop new treat-
ment strategies for microscopic distant disease.
The extent of extramural tumour spread (EMS),
circumferential resection margin (CRM) and nodal
status as well as extramural venous invasion
(EMVI) have been identified as powerful predic-
tive factors for local recurrence, distant metastases
and overall survival in patients with rectal cancer
[26, 27, 33, 34]. Although currently a reliable ass-
essment of the pretherapeutic mesorectal regional
lymph node status is not possible by the present
imaging modalities [32], thin-slice high-resolution
MRI can identify accurately the extent of EMS,
the EMVI and the status of CRM [7, 42].
Main eligibility criteria:
1. Patient with rectal adenocarcinoma: Distal
border of tumour below the sacral promontory
2. Any T4 resectable
3. Any distal (less or equal to 5 cm to anal verge)
T3
4. T3 middle third tumours threatening or affect-
ing the mesorectal fascia (distance from
tumour to fascia £ than 2 mm)
5. T3 middle third and one or both of the
following:
(a) T3 >5 mm EMS
(b) Presence of EMVI
20.4.3 Biomarkers
A recent publication [10] showed that a 13-gene
signature could predict, with 86% accuracy, rec-
tal cancer patients that will respond to CRT. This
study was retrospective and validation in a differ-
ent population and prospectively is mandatory to
establish the clinical utility to such a signature.
20 Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery?
Therefore, we considered our study an ideal sce-
nario for such a validation.
20.4.4 Randomization
A blocked randomization with blocks of size 4
and 6 is proposed with the following stratification
factors:
• Institution
• Circumferential margin threatened or involved
versus neither
20.4.5 Sample Size
In order to ensure an appropriate power, an adap-
tive design will be used as recommended by the
FDA [15]. The strategy to maintain power is to
adjust the sample size if the overall event rate is
lower than initially anticipated, the variability of
the main outcome is greater than expected or the
adherence is low. In the case of ‘time-to-event’
main outcomes, this adaptive design is straight-
forward. As the power depends on the number of
events rather than on the number of patients
recruited, either the length of follow-up, the num-
ber of recruited patients or both can be increased
to achieve the desired power (event-driven trials).
Given that a time-to-event analysis is used,
instead of planning a specific sample size, patient
enrolment will be continued until the a priori
specified number of events occur. Two interim
analyses (a total number of looks of three) will be
performed to assess both efficacy and futility.
Assumptions:
Bilateral alpha level: 0.05
Power of 80%
Assigned fraction of treatment: 0.5
Planned number of looks (equally spaced): 3
Alpha and beta spending function: Lan-
DeMets
Subject accrual per month: 20
Length of patients’ accrual: 60 months
Based on preliminary data and literature review,
the expected 3-year DFS rate in the control arm
201
is 62%. The hazard ratio comparing the DFS in
the induction arm to the control arm is 0.78. This
is equivalent, based on design assumptions, to a
3-year DFS rate in the control arm of 62% versus
70% in the induction arm. Under these assump-
tions, a total of 1,028 patients would be needed.
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 How to Achieve Long-Term
Survival in Patients 21
with Metastatic Rectal Cancer?

Alexander Stein and Hans-Joachim Schmoll

Contents 21.6 Controversies About Preoperative

Treatment.................................................... 212
21.1 Introduction ................................................ 205 21.6.1 Complete Clinical Remission During
21.2 Management of Patients Preoperative Chemotherapy ......................... 212
with Metastatic Rectal Cancer.................. 206 21.6.2 Influence of Chemotherapy
on Perioperative Morbidity,
21.3 Selection of Patients Undergoing Mortality and Prognosis ............................... 212
Resection for Metastatic Disease .............. 206
21.7 Management of Limited Peritoneal
21.4 Management of Patients Disease with Cytoreductive Surgery
with Initially R0 Resectable (CRS) and Hyperthermic Intraperitoneal
Liver+/−Lung Metastases .......................... 207 Chemotherapy (HIPEC)............................ 213
21.4.1 Perioperative Treatment of Patients
with R0 Resectable Liver Metastases .......... 209 References ................................................................. 214
21.4.2 Postoperative Treatment of Patients
with R0 Resectable Liver+/−Lung
Metastases .................................................... 209
21.4.3 Peri- Versus Postoperative Treatment
of Patients with R0 Resectable
Liver+/−Lung Metastases ............................ 210
21.4.4 Local Treatment/Hepatic Artery Infusion
(HAI) After Resection of CLM ................... 211 21.1 Introduction
21.5 Management of Patients with Initially
Colorectal cancer (CRC) is the most frequently
Unresectable Metastases............................ 211
21.5.1 Current Developments ................................. 212 diagnosed cancer in Europe and one of the lead-
ing causes of cancer death worldwide [20, 29].
About 20–25% of patients with CRC present
with metastatic disease at time of diagnosis. The
majority of patients with metastatic rectal cancer
will have liver+/−lung metastases. All patients
A. Stein with metastatic rectal cancer should be discussed
University Cancer Center Hamburg, and managed within a multidisciplinary team to
University Medical Center Hamburg-Eppendorf, ensure selection of patients, which can be treated
Hamburg, Germany
with curative intent combining systemic (chemo-
H.-J. Schmoll (*) therapy) and local (surgery, radiotherapy) treat-
Department for Oncology/Haematology,
ment, although achievement of long-term survival
Martin-Luther-University Halle-Wittenberg,
Halle, Germany strongly depends on the biology and therefore
e-mail: hans-joachim.schmoll@medizin.uni-halle.de course of the metastatic disease.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 205

DOI 10.1007/978-3-642-25005-7_21, © Springer-Verlag Berlin Heidelberg 2012
206
Resection of liver metastases from colorectal
cancer (CLM) is a potentially curative treatment,
and reported 5-year overall survival rates
(5-yOSR) range from 20% to 40% [11, 66].
Further follow-up after resection of liver metasta-
ses from colorectal cancer revealed a rate of long-
term survival and finally cure for every fifth
patient even in the presence of poor prognostic
factors [1, 22, 58, 59]. Retrospective series
revealed profound improvements in outcome of
patients with colorectal cancer in the last 20 years
due to advancements in chemotherapy and dra-
matic increase in patients undergoing liver resec-
tion [35, 42].
Moreover, curative surgery can be per-
formed in CLM with extrahepatic disease.
Resection of lung metastases of colorectal can-
cer could result in a 5-yOSR of 45% in a
selected group of patients [28]. Several series
revealed promising 5-yOSR of 30–40% for the
resection of both liver and lung metastases
counted after the last organ resection [40, 45,
47]. Retrospective series of 186 patients with
CLM and extrahepatic disease (lung, lymph
node metastases and peritoneal metastases)
receiving perioperative chemotherapy and
resection demonstrated a 5-yOSR after first
pulmonary resection for patients with liver and
lung metastases (n = 88) of 37%, although one-
third of patients had bilateral pulmonary dis-
ease. In case of other sites of extrahepatic
disease, 5-yOSR was much lower (e.g., 18%
for lymph node metastases) [14]. Recent retro-
spective analysis of 112 patients undergoing
resection of both liver and lung metastases
demonstrated a 5-yOSR of 50%, which was
even better than 5-yOSR after resection of
CLM (40% in 1,148 patients) [9].
Furthermore, multimodality treatment includ-
ing cytoreductive surgery and perioperative intra-
peritoneal and systemic chemotherapy resulted in
a 5-yOSR of 27% in patients with localized perito-
neal carcinomatosis in a retrospective series of 523
patients (35% with synchronous disease) [16].
The following text refers to metastatic disease
with liver and/or lung or limited peritoneal
carcinomatosis.
A. Stein and H.-J. Schmoll
21.2 Management of Patients
with Metastatic Rectal Cancer
Prognosis of patients with metastatic disease
depends mainly on the course of metastatic dis-
ease; thus, primary treatment aim is to achieve
resectability of metastatic disease. In case of
either initial or secondary resectability, local
treatment according to stage for rectal primary
should be performed followed by resection of all
sites of disease. The choice of treatment sequence,
chemotherapy, radio(chemo)therapy and surgery
depends on characteristics of primary tumour
(local symptoms and stage) and metastatic dis-
ease (initially or potentially resectable after che-
motherapy). Possible treatment algorithms are
summarized in Figs. 21.1 and 21.2 for synchro-
nous metastatic disease including management of
primary tumour and in Fig. 21.3 for metachro-
nous disease.
21.3 Selection of Patients
Undergoing Resection
for Metastatic Disease
Risk factors for poor outcome after resection of
CLM were identified already 25 years ago, e.g.,
presence of positive portal lymph nodes, extrahe-
patic metastases, four or more hepatic metastases
or primary tumour stage Dukes’ C [26]. The scor-
ing system for CLM described by Fong and col-
leagues includes five risk factors: node-positive
primary, disease-free interval <12 months, > one
lesion, size >5 cm and CEA > 200 ng/m. Patients
with five risk factors had a 5-yOSR of 14% with a
median of 22 months compared to a 5-ySR of
44% and a median of 51 months in the presence of
one risk factor [22]. However, the ‘Fong score’
does not include contemporary variables like pre-
operative chemotherapy. Recently, the interna-
tional liver metastases survey, including data of
about 4,500 patients with preoperatively treated
CLM, confirmed the poor prognosis of patients
with lymph node positive primary, abnormal CEA
levels and number of CLM, although cut-off value
was three in the current analysis. Furthermore,
21 How to Achieve Long-Term Survival in Patients with Metastatic Rectal Cancer? 207

Synchronous rectal cancer with

intact primary and R0/R1
resectable metastases

<T3 NO ≥ T3 or N+

or
3 months Preop RT (5x5) 3 months
preop FOLFOX or CRT preop FOLFOX

3 months Preop RT (5x5)

preop FOLFOX or CRT

Resection of primary and met

Postop CRT or short course RT if T3, CRM+,

N+, perforation

6months postop
3 months postop FOLFOX
FOLFOX

Fig. 21.1 Treatment algorithm for resectable synchronous metastatic rectal cancer

more than one line and six cycles (3 months) of
preoperative treatment, incomplete macroscopic
resection (R2), concomitant extrahepatic metasta-
ses and progression during preoperative chemo-
therapy were associated with poor prognosis [1].
Whereas scoring for survival is broadly
accepted, criteria for resectability of CLM are
difficult to define. Although several approaches
were published, no consensus could be reached
yet [43, 49, 52, 62, 69]. In the EORTC 40983 trial,
patients with up to four potentially resectable liver
metastases and no evidence of extrahepatic dis-
ease were included [48]. Current clinical trials
include patients depending on resectability deter-
mined by a surgeon with hepatic surgery exper-
tise. Limitations for liver surgery are remnant
liver of less than 30%, unfavourable location, co-
morbidities excluding major surgery, aggressive
tumour biology and/or presence of extrahepatic
disease. Although number (more than 4) and size
(more than 5 cm) have an impact on prognosis
[69], patients could still be deemed resectable
with these characteristics. The ‘European Expert
Panel’ recently stated that the resection should
have the potential to be complete and macroscopi-
cally curative [49].
21.4 Management of Patients with
Initially R0 Resectable
Liver+/−Lung Metastases
The role of perioperative treatment in resectable
liver+/−lung metastases, especially the point
in time (pre- vs. postoperative), mode (systemic
vs. local) and intensity (monotherapy vs. combi-
nation), is still a matter of debate. Although
postoperative therapy after resection of liver
208 A. Stein and H.-J. Schmoll

Synchronous unresectable rectal

cancer with intact primary

Upfront chemotherapy

Resectability of mets achieved?

Yes No

Continue/change chemotherapy
< T3 N0 ≥ T3 or N+

Resectability of mets achieved?

Preop CRT or
short course RT

Yes No
Resection of primary
+ resection of metastases
Avoid radical and mutilating surgery
RCTx or short course RT for locally
advanced tumors
Resume initial treatment for a total
of 6 months

Fig. 21.2 Treatment algorithm for unresectable synchronous metastatic rectal cancer

Metachronous liver/lung
metastases

Clearly R0 resectable Borderline R0 resectable or

initially unresectable

Single, <2 cm FOLFOX Intensive chemotherapy

liver met 3 months preop 3-4(-6) months

Resection No resection

R0/1: FOLFOX R0/1: FOLFOX R0/1: complete periop. Escalate/change

6 months postop 3 months postop chemotherapy for total chemotherapy, than
of 6 months resection, if possible

Fig. 21.3 Treatment algorithm for metachronous metastatic rectal cancer

21 How to Achieve Long-Term Survival in Patients with Metastatic Rectal Cancer? 209

Table 21.1 EORTC trial 40983 of perioperative chemotherapy versus observation in patients with resectable colorec-
tal liver metastases: results by group of analysis
Perioperative Surgery Absolute difference for 3-year
Patients chemotherapy alone progression-free survival rate HR p-value
All 182 182 +7.3% (28.1–35.4%) 0.79 (0.62–1.02) 0.058
Eligible 171 171 +8.1% (28.1–36.2%) 0.77 (0.60–1.00) 0.041
Resected 151 152 +9.2% (33.2–42.4%) 0.73 (0.55–0.97) 0.025
HR hazard ratio, p-value significance level

metastases of colorectal origin CLM has become
an accepted standard of care in many parts of
the world, data on the benefit are limited. There
are only a few randomized trials comparing pre-
and/or postoperative intravenous chemotherapy
or hepatic artery infusion with or without intra-
venous chemotherapy to surgery alone.
Moreover, in adjuvant systemic chemotherapy,
none of the conducted clinical trials achieved
the recruitment goal, leading to solely prema-
ture data.
21.4.1 Perioperative Treatment of
Patients with R0 Resectable
Liver Metastases
The EORTC 40983 trial accrued 364 patients to
be randomized between surgery alone and che-
motherapy with 5-fluorouracil, leucovorin and
oxaliplatin (FOLFOX4 regimen), administered
3 months pre- and postoperatively [48]. Patients
had to be technically resectable (as stated by CT
scan) with a maximum of 4 CLM and no prior
treatment with chemotherapy. Despite favourable
patients`characteristics, with 50 % bearing only
one CLM and surgery at “high-quality” institu-
tions the 3-year progression-free survival rate
was relatively poor. A significant increase in pro-
gression-free survival rate at 3 years from 33.2%
to 42.4% was shown in the group of patients
(n = 171) receiving chemotherapy and resection
of CLM (HR 0.73, 95% CI 0.55–0.97). In the
randomized population (‘intent-to-treat analy-
ses’), the difference was not statistically
significant due to ineligibility of 6% of patients
(HR 0.79, 95% CI 0.62–1.02) but still favouring
the chemotherapy arm (Table 21.1). No unusual
toxicities occurred in the chemotherapy arm.
Nearly 80% of patients completed the preopera-
tive part. After resection, 76% of patients were
receiving postoperative treatment, with 52% of
patients (n = 80) completing six cycles.
During preoperative chemotherapy, main
grade 3/4 toxicities were nausea and vomiting
4%, diarrhoea 8%, stomatitis 7%, sensory neu-
ropathy 2% and neutropenia 18% (febrile 2%).
Postoperative reversible complications were
significantly higher (25% vs. 16%, p = 0.04) in
the chemotherapy group. Particularly intra-
abdominal infections, biliary fistulas with an out-
put of more than 100 ml/day for more than
10 days and hepatic failure with a bilirubin eleva-
tion grade 3/4 for more than 3 days occurred
more often in the perioperative group. There was
no impact on postoperative death rate (1% in both
arms). During postoperative chemotherapy, tox-
icities were similar, with a higher rate of grade 3
sensory neuropathy (10%) and other neurological
toxicities (12%) due to the higher cumulative
dose of oxaliplatin.
According to those data, this approach is
widely considered as a standard for patients with
resectable CLM.
21.4.2 Postoperative Treatment of
Patients with R0 Resectable
Liver+/−Lung Metastases
Despite being the standard of care in patients
with stage III disease, data for adjuvant treatment
after resection of stage IV disease are still limited.
Two randomized phase III trials have compared
adjuvant systemic chemotherapy with 5FU/FA
after resection of liver or lung metastases to
210
Table 21.2 Postoperative treatment after curative resection of liver+/−lung metastases
Postoperative
Trial Pat. (n) R0 treatment
Langer 129 nr 5FU/FA
et al. [36]
Portier 171 171 5FU/FA
et al. [51]
Ychou 321 321 LV5FU vs. FOLFIRI +1% (71.6% vs. 72.7%)
et al. [70]
Voest and 79 79 CAPOX (6 m)
Snoeren [64] vs. CAPOX
(6 m) + beva (12 m)
(n) number of patients, R0 (n) number of R0 resections, OS overall survival, OSR overall survival rate, HR hazard ratio, CI
confidence interval, p-value significance level, 5FU 5-fluorouracil, FA folinic acid, HAI: nr not reported, LV5FU leuco-
vorin and 5FU, FOLFIRI FA, 5FU and irinotecan, CAPOX capecitabine and oxaliplatin, beva bevacizumab, m months
surgery alone, but both closed prematurely due to
slow accrual. A small but significant improve-
ment in disease-free survival rate (DFSR) was
demonstrated in the FFCD trial at the time of clo-
sure, with a 5-year DFSR of 26.7% vs. 33.5%
(p = 0.028), favouring the group with adjuvant
treatment after resection of CLM [51]. Although
the 5-year overall survival rate (OSR) increased
from 41.1% to 51.1%, this difference was not
significant (p = 0.13). The ENG (EORTC/NCI-
CTG/GIVIO) trial, still not fully published, dis-
played a non-significant trend towards a prolonged
DFS with a median of 39 vs. 20 months (p = 0.35)
and an increased overall survival (OS) with a
median of 53 vs. 43 months (p = 0.39) in patients
with liver (n = 90) or lung (n = 13) metastases
[36]. However, a combined analysis of both trials
(n = 278) showed a non-significant prolongation
of the median disease-free survival (DFS) from
18.8 to 27.9 months (p = 0.058) and the OS from
47.3 to 62.2 months (p = 0.095) [41]. Both trials
were using a non-contemporary 5FU bolus regi-
men, which is more toxic and possibly not active
enough to reveal a significant increase in this lim-
ited number of patients. Postoperative treatment
with 5FU plus irinotecan in a prematurely
stopped, randomized phase III trial revealed no
additional benefit over 5FU alone in terms of OS
(3-year survival rate of 73% vs. 72%) [70].
Regarding median disease-free survival (DFS),
there was a non-significant increase of 3 months
(21.6 vs. 24.7 months, HR 0.90, 95% CI 0.67–
1.2, p = 0.47). The gain in DFS is possibly smaller
as to be detected with 150 patients per group.
A. Stein and H.-J. Schmoll
Absolute difference for
5yOSR or median OS HR (95% CI) p-value
+10 months (43 vs. 53) 1.30 (0.71–2.36) 0.39
+16 months (46.4 vs. 0.73 (0.48–1.10) 0.13
62.1)
1.09 (0.72–1.64) 0.69
(3yOSR)
+18% (52% vs. 70%) nr 0.074
(2-year DFS rate)
However, the lack of a clear benefit might also be
related to the relatively poor efficacy, as shown in
the adjuvant treatment of stage III colorectal dis-
ease with FOLFIRI [57, 61, 71]. Recently, results
of the prematurely closed Dutch HEPATICA trial
were presented, demonstrating a DFS benefit
after 2 years of 18% (70% vs. 52%) in favour of
12 months bevacizumab with 6 months chemo-
therapy with capecitabine and oxaliplatin com-
pared to the same chemotherapy alone after R0
resection of CLM in 79 patients [64]. Further
follow-up might reveal whether this benefit is
only transient, as recently seen with bevacizumab
after resection of stage II or III colon cancer
[2, 13]. However, it is questionable whether fur-
ther results regarding adjuvant chemotherapy will
be available, as most current postoperative trials
(ADHOC, NSABP C-09 and HEPATICA) were
closed due to insufficient accrual (Table 21.2).
21.4.3 Peri- Versus Postoperative
Treatment of Patients with R0
Resectable Liver+/−Lung
Metastases
Currently, available data seem to favour peri-
operative chemotherapy in clearly R0 resect-
able liver metastases, although OS data for the
perioperative approach are still lacking. In case
final analyses of the EORTC 40983 trial cannot
demonstrate a significant OS benefit, both
approaches (peri- and postoperative) would be
of similar evidence. However, preoperative
21 How to Achieve Long-Term Survival in Patients with Metastatic Rectal Cancer? 211

treatment offers the option of individual assess-
ment of tumour biology and response to chemo-
therapy and does therefore help to better select
patients for surgery and postoperative treatment;
e.g., patients with progressive disease during
preoperative chemotherapy will have no benefit
from liver surgery in case of extrahepatic spread
of disease, and even if still resectable, continua-
tion of same chemotherapy postoperatively
would not be meaningful. Furthermore, the peri-
operative approach enables administration of
chemotherapy to a higher rate of patients, as
postoperative treatment will not be feasible in
up to 20% as demonstrated in the EORTC 40983
trial, with 115 of 151 resected patients starting
postoperative FOLFOX and only 80 completing
6 cycles [48].
21.4.4 Local Treatment/Hepatic Artery
Infusion (HAI) After Resection
of CLM
Several trials were comparing postoperative
hepatic artery infusion combined with or without
systemic treatment to surgery alone after resec-
tion of CLM with diverging results [37, 55, 65].
The systematic review by Nelson et al. of 592
patients revealed a non-significant survival
advantage in favour of the control (non-HAI)
group of 8.9% (HR 1.089, 95% CI 0.887–1.334),
which is in contrast to a current meta-analysis
demonstrating a RFS benefit (HR 0.78, 95% CI
0.65–0.95; p = 0.01), although OS did not differ
(HR 1.0, 95% CI 0.84–1.21; p = 0.96) [46, 67].
Recently, a small phase II trial, evaluating the
addition of bevacizumab to HAI and systemic
chemotherapy with 5FU/FA and either oxalipla-
tin or irinotecan, demonstrated increased biliary
toxicity (p = 0.02) without any difference in RFS
or OS [31]. Regarding these results, application
of HAI may not be recommended as a standard
of care.
21.5 Management of Patients
with Initially Unresectable
Metastases
The group of patients with potentially resectable
metastases warrants a highly active, neoadjuvant
treatment aiming on conversion into resectabil-
ity, with tumour shrinkage as an important goal.
Regarding the reported RECIST overall response
rates (ORR) displayed in clinical trials in the
first-line treatment for metastatic colorectal can-
cer, either a chemo-doublet in combination with
a monoclonal antibody (e.g., cetuximab, panitu-
mumab or bevacizumab) or a three-drug chemo-
therapy (e.g., FOLFOXIRI) are possible options
[8, 15, 19, 27, 39, 56, 60]. However, the avail-
able large trials have included all patients with
metastatic CRC, and the bene fi t con fi ned to
CLM and ‘conversion rates’ cannot be assessed
(Table 21.3).
The CELIM included ‘potentially resectable’
CLM only. With RECIST response rates of
70% resulting from treatment with oxaliplatin- or

Table 21.3 Efficacy of first-line chemotherapy in unselected patients with metastatic colorectal cancer
R0 rate
Trial Treatment Pat. (n) RR (%) RR (‘liver only’) R0 rate all ‘liver only’
Van Cutsem et al. [60] FOLFIRI + cet 316* 57.3* 70.6* (n = 68) 5.1 13.2
Bokemeyer et al. [8] FOLFOX + cet 82* 57* 76* (n = 25) 7.3 16
Maughan et al. [39] 5FU/cape + oxali + cet 362* 64* nr nr nr
Douillard and Siena [15] FOLFOX + pan 593 57* nr nr 28
Hurwitz and IFL + beva 402 45 nr <2% nr
Fehrenbacher [27]
Saltz et al. [56] 5FU/cape + oxali + beva 699 47 nr 6.3 12.3
Falcone et al. [19] FOLFOXIRI 122 66 nr 15 36
*KRAS wildtype, (n) number of patients, R0 (n) number of R0-resections, 5FU 5-fluorouracil, cape capecitabine, oxali
oxaliplatin, irino irinotecan, beva bevacizumab, cet cetuximab, pan panitumumab, nr not reported
212
irinotecan-based chemotherapy in combination
with cetuximab in the KRAS wild-type population,
a conversion rate of 28% could be observed, leading
to R0 resection in 36% of patients [21]. In 45 CLM
patients with poor risk features (more than 4 CLM,
diameter >5 cm, synchronous disease), treatment
with capecitabine, oxaliplatin and bevacizumab
showed an ORR of 77%, leading to conversion to
resectability in 40% (12 of 30 initially unresectable
patients) in the BOXER trial [68].
Although tumour shrinkage is important in
order to achieve technical resectability, and
RECIST response rates are likely to correlate
well with the percentage of resected or ‘con-
verted’ patients, it has to be kept in mind that
prognosis of patients may (also) be determined
by the effect of treatment on tumour tissue.
Interestingly, good correlations of pathohistolog-
ical response to preoperative chemotherapy,
which seem to be increased with bevacizumab-
containing combinations, with overall survival
were reported from a cohort of patients after
resection of CLM [7, 33, 54]. Another issue of
defining the ‘optimal regimen’ is that in antian-
giogenic drugs, response to treatment may be
rather displayed in change of radiographic mor-
phology than in tumour shrinkage only [12].
21.5.1 Current Developments
Recent single-arm phase II trials in metastatic
colorectal cancer with four-drug regimens com-
bining either EGFR antibodies or bevacizumab
with fluoropyrimidines, oxaliplatin and irinote-
can demonstrated an ORR of 77–82% with a
complete response rate of about 12% [4, 10, 38].
In regard to a secondary R0 resection rate up to
26% in an unselected patient population, this
seems to be a promising approach for potentially
resectable patients. Although preliminary efficacy
of four-drug regimens seems to be similar for
EGFR antibodies and bevacizumab, toxicity
profile favours bevacizumab-containing regi-
mens, with rate of grade 3–4 diarrhoea of 52%
with the ERBIRINOX regimen (cetuximab and
FOLFIRINOX) compared to 14–18% with beva-
cizumab and FOLFOXIRI [4, 18, 38].
A. Stein and H.-J. Schmoll
21.6 Controversies About
Preoperative Treatment
One of the major drawbacks in neoadjuvant treat-
ment is the conversion into irresectability in case
of progression during chemotherapy. In the
EORTC 40983 trial, 12 (7%) patients experi-
enced progressive disease during preoperative
chemotherapy leading to irresectability in eight
patients, half of them presenting with new lesions
[48]. However, switch to irresectability reveals
aggressive tumour biology and predicts a worse
outcome even in case of resection [1].
21.6.1 Complete Clinical Remission
During Preoperative
Chemotherapy
The issue of complete radiological response has to
be kept in mind during neoadjuvant treatment, as
complete clinical response does not mean complete
pathological response [5, 23]. Therefore, patients
should be closely monitored during preoperative
chemotherapy and ideally resected before complete
remission [50]. If an anatomical resection can be
performed, complete response is not a major prob-
lem because resection will be based on initial sites
of liver metastases. In case of complete response on
CT and no option for anatomical resection, differ-
ent imaging methods might be used (MRI, PET
scan, contrast-enhanced US) or resection might be
delayed until relapse occurs.
21.6.2 Influence of Chemotherapy on
Perioperative Morbidity,
Mortality and Prognosis
Chemotherapy can result in severe damage of
liver tissue. Whereas oxaliplatin-based combina-
tions are associated with increased risk of vascu-
lar lesions, irinotecan-containing regimens have
been associated with increased risk of steatohep-
atitis, especially in obese patients with BMI over
25 kg/m2 [3, 6, 63]. The clinical impact of che-
motherapy-associated histological changes seems
to favour oxaliplatin in the neoadjuvant setting.
21 How to Achieve Long-Term Survival in Patients with Metastatic Rectal Cancer?
Increased risk of perioperative bleeding, postop-
erative complication rate and poorer functional
reserve was found to be associated with vascular
lesions. Although influence on morbidity is still
controversial, mortality was not affected [44, 63].
In the EORTC 40983 trial, the perioperative treat-
ment resulted in a similar postoperative death rate
as compared to surgery alone, with a significantly
higher rate of reversible postoperative complica-
tions (p = 0.04). Higher risk of complications and
an increased 90-day mortality (1.6% vs. 14.7%,
odds ratio (OR) 10.5) was reported for irinotecan-
associated steatohepatitis [34, 63]. The addition
of bevacizumab to neoadjuvant oxaliplatin-based
treatment is feasible and does not limit the ability
of liver regeneration [25, 53]. Duration of preop-
erative treatment seems to have major impact on
perioperative morbidity and prognosis and should
therefore be as short as possible in case of
initially unresectable disease [1, 3, 30, 32].
Duration of perioperative chemotherapy in case
of initially R0 resectable CLM should be either
6 months postoperatively or 3 months pre- and
postoperatively.
21.7 Management of Limited
Peritoneal Disease
with Cytoreductive
Surgery (CRS) and
Hyperthermic Intraperitoneal
Chemotherapy (HIPEC)
Peritoneal carcinomatosis as single lesion in
advanced colorectal cancer represents a special
biologic entity with poor prognosis under systemic
chemotherapy alone. Current data including one
randomized controlled trial and numerous pro-
spective and retrospective studies suggest a role of
CRS and HIPEC within the multimodal treatment
regimen and may improve PFS as well as OS for
selected patients with peritoneal carcinomatosis
[16, 17, 24]. The procedure can be performed with
acceptable morbidity and low mortality in special-
ized centres. Nevertheless, preoperative patient
selection is crucial for the success of the combined
treatment concept. Main selection criteria are good
general health status, limited intraperitoneal
213
tumour dissemination (peritoneal cancer index,
PCI < 20), limited small bowel disease and no
extra-abdominal metastasis. Furthermore localiza-
tion, histology and lymph node status of the pri-
mary tumour as well as response to systemic
chemotherapy should be considered.
Conclusion and Recommendations
Multidisciplinary management of patients
with metastatic rectal cancer is crucial in order
to select patients amenable for a curative
approach. In regard to long-term survival
achievable in liver+/−lung metastases or even
in localized peritoneal carcinomatosis, patients
eligible for a curative intent approach should
be transferred to specialized centres for hepatic
or peritoneal surgery.
Patients with synchronous metastatic rec-
tal cancer should be treated with primary
chemotherapy, followed by secondary local
treatment including surgical resection if fea-
sible according to extent of disease, response
to chemotherapy and co-morbidity with the
aim of long-term survival. Achievement of
resectability of metastatic disease is the main
treatment aim; therefore, the primary tumour
is less relevant. Only in case of symptomatic
rectal primary tumour local measures (e.g.,
insertion of a stent or stoma) and in specific
circumstances palliative surgical resection
should be performed.
For synchronous R0 resectable liver+/−lung
metastases, treatment approaches are as follows:
• For clearly R0 resectable metastatic dis-
ease, irrespective of primary tumour, peri-
operative chemotherapy (3 months pre- and
postoperative FOLFOX) should be applied
analogue to the EORTC 40983 trial [48].
• In locally advanced primary tumours (³T3
or N+): upfront chemotherapy with
FOLFOX for 3 months and local treatment
according to stage (or reverse sequence)
followed by resection of the primary (staged
or synchronous) followed by postoperative
FOLFOX for 3 months should be applied.
• In early primary tumours (<T3 N0): resec-
tion of primary and metastases followed by
postoperative treatment with FOLFOX for a
214
total of 6 months might be considered, and if
necessary (e.g., CRM+ or N+) postoperative
local treatment according to stage.
For patients with rectal cancer and synchro-
nous, potentially resectable metastatic disease
after chemotherapy, the most active available
induction treatment should be chosen. If metas-
tases become resectable, local treatment accord-
ing to stage for primary followed by resection
of primary and metastases should be performed,
followed by postoperative continuation of the
same regimen for a total of 6 months (including
preoperative). If metastases remain unresect-
able, treatment should be continued or switched,
depending on quality of response.
In case of metachronous disease, similar
treatment approaches should be applied.
• Cleary, R0 resectable liver+/−lung metasta-
ses should be treated with perioperative che-
motherapy (3 months pre- and postoperative
FOLFOX) and resection. In case of single
liver metastases with a size up to 2 cm, pri-
mary resection followed by postoperative
chemotherapy should be considered.
• For potentially resectable metastatic dis-
ease after chemotherapy, most active induc-
tion chemotherapy followed by secondary
resection, if feasible, should be performed.
Acknowledgments The manuscript was prepared with-
out any funding or contribution of persons not mentioned
in the authors’ section.
Conflict of Interest AS honoraria: Roche, Merck
Serono. HJS: consultant or advisory role: Roche hono-
raria: Roche; research support: Roche and Merck Serono.
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folinic acid with FOLFIRI in patients following com-
plete resection of liver metastases from colorectal
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71. Ychou M, Raoul JL et al (2009) A phase III ran-
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Accord02/FFCD9802). Ann Oncol 20(4):674–680
 Will Adjuvant Chemotherapy
Improve Outcome After 22
Preoperative Chemoradiation?

Bengt Glimelius and Peter Nygren

Contents 22.1 Introduction

22.1 Introduction ................................................ 217
In colon cancer, there is high scientific evidence
22.2 Retrieval of Published Data ...................... 218
for significant gains in both disease-free survival
22.3 Summary of Published Data ..................... 218 (DFS) and overall survival (OS) from adjuvant
22.3.1 Adjuvant Chemotherapy Following biochemically modulated 5-fluorouracil (5-FU)
Surgery Alone .............................................. 218
22.3.2 Adjuvant Chemotherapy Following or capecitabine [15, 20, 44]. Large randomized
Surgery and Postoperative RT or CRT ......... 219 trials show that addition of oxaliplatin to 5-FU/
22.3.3 Adjuvant Chemotherapy Following leucovorin or capecitabine further improves DFS
Preoperative RT and Surgery ....................... 219 and possibly OS [4, 30, 35]. The relative reduc-
22.3.4 Adjuvant Chemotherapy Following
Preoperative CRT ......................................... 219 tion in recurrences by fluoropyrimidines is in the
22.3.5 Adjuvant Chemotherapy Before order of 30–35% and further 15–20% by the
and After CRT and Surgery ......................... 220 addition of oxaliplatin, totally resulting in a rela-
22.4 Discussion ................................................... 220 tive reduction of 40–45%. Based on these results,
adjuvant systemic chemotherapy is standard
References ................................................................. 223
treatment in stage III and in stage II if the risk of
recurrence is high.
As opposed to colon cancer, traditionally, many
recurrences have occurred loco-regionally in rectal
cancer, and although systemic recurrences were
also common, the loco-regional recurrences domi-
nated the clinical situation for many patients due
to their severe symptoms prior to death. With
improved surgery, based on the total mesorectal
B. Glimelius (*) excision (TME) concept and increasing use of
Department of Radiology, Oncology and Radiation preoperative radiotherapy (RT) and chemoradio-
Science, University of Uppsala, Akademiska sjukhuset, therapy (CRT), the risk of a local recurrence has
SE-751 85, Uppsala, Sweden
diminished substantially, from about 30–40%
Department of Oncology and Pathology, down to less than 10% considering the entire pop-
Karolinska Institutet, Stockholm, Sweden
ulation with a new rectal primary [42].
e-mail: bengt.glimelius@onkologi.uu.se
In rectal cancer, the scientific evidence for
P. Nygren
convincing gains in DFS and OS from adjuvant
Department of Radiology, Oncology and Radiation
Science, University of Uppsala, Akademiska sjukhuset, chemotherapy is much less than in colon cancer.
SE-751 85, Uppsala, Sweden The large adjuvant trials in this field have included

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 217

DOI 10.1007/978-3-642-25005-7_22, © Springer-Verlag Berlin Heidelberg 2012
218
comparatively few patients with rectal cancer or
have focused on colon cancer alone. Most patients
with rectal cancer receive loco-regional treatment
with RT or CRT, either after or, currently more
common, before surgery, whereas this is rarely
done in colon cancer. This more complex treat-
ment scenario has made the effect of systemic
adjuvant chemotherapy in rectal cancer more
difficult to study, and the evolvement over time of
the local treatment strategies has added further to
this complexity.
The low level of scientific evidence for a
benefit from adjuvant chemotherapy in rectal
cancer is acknowledged in authoritative treatment
guidelines and by expert groups that still often
conclude that such treatment should be consid-
ered based on the principles used for colon can-
cer [25, 40, 51]. In a recent systematic review, it
was concluded that adjuvant chemotherapy after
surgery for rectal cancer following RT or CRT is
not ‘evidence-based’ [7]. In this review, where
the key findings from the pivotal clinical trials
performed in this field are summarized, we dis-
cuss how to interpret the current state of knowl-
edge to be able to answer the question posed in
the title and related questions.
22.2 Retrieval of Published Data
Although the recent systematic review by Bujko
et al. concentrated on its role following CRT, the
literature search covered all treatment settings
and was performed through August 2009 [7].
The current review is based on the literature
retrieved by Bujko et al., updated with the addi-
tional relevant data published from August 2009
through May 2011. The PubMed and Cochrane
databases were searched using the keywords
‘rectal cancer and adjuvant chemotherapy’. In
addition, abstracts and conference reports from
the scientific meetings of the American Society
of Clinical Oncology and the European Society
of Medical Oncology and smaller focused meet-
ings 2009–2011 relevant to the field were
retrieved. We limited our report to data from tri-
als in which treatment allocation was randomized
and to patients operated on with curative intent.
B. Glimelius and P. Nygren
22.3 Summary of Published Data
The published data on the role of adjuvant chemo-
therapy in rectal cancer derive from several
decades during which the loco-regional treatment
has undergone considerable changes. The data are
divided based on whether surgery was the only
treatment or was accompanied by RT or CRT and
whether such treatment was given before or after
the surgery. Very few studies about the value of
adjuvant chemotherapy for rectal cancer have
been performed after preoperative CRT followed
by TME, i.e. the focus of this review.
22.3.1 Adjuvant Chemotherapy
Following Surgery Alone
This treatment setting, in most cases not rele-
vant today to the treatment of rectal cancer in
the Western world, except for the early stages,
has mostly been studied in Japan, and the
fluoropyrimidine used was mostly uracil/tegafur
administered for 1–2 years, sometimes also
together with mitomycin C. Several Japanese tri-
als, including more than 5,000 patients, showed
statistically significant benefit from adjuvant che-
motherapy in DFS and/or OS with risk reductions
in the 15–40% range [31, 32, 45, 46]. Similar
observations were also observed in two western
world trials, including the QUASAR trial which
explored the value of adjuvant folinic-acid-
modulated 5-FU in patients with colon cancer or
rectal cancer where the benefit of adjuvant chemo-
therapy was considered uncertain [43].
Of 3,239 patients in the QUASAR trial, 984
had rectal cancer. In this group, a survival benefit
from adjuvant chemotherapy was shown with a
5-year OS of 78% compared with 74% in the
control group (HR 0.77; p = 0.05). Subgroup
analysis with patients divided into those with sur-
gery alone (n = 549) or pre- (n = 198) or postop-
erative (n = 201) RT was presented separately
[27]. This analysis showed no significant hetero-
geneity between the groups, which separately
were too small to show statistically significant
differences, but all showed point estimates indi-
cating benefit from adjuvant chemotherapy.
22 Will Adjuvant Chemotherapy Improve Outcome After Preoperative Chemoradiation?
A joint analysis of Nordic trials showed no
statistically significant benefit in OS at 5 years in
stage II/III rectal cancer (n = 691) from 4 to
12 months of various types of 5-FU-based che-
motherapy [26]. A separate analysis of the
Norwegian study where 5-FU + levamisole was
used for 12 months did similarly not reveal any
benefit in rectal cancer after surgery alone [13].
An OS gain was seen in colon cancer stage III. In
addition, smaller studies showed no benefit in
DFS or OS [24, 28, 29].
22.3.2 Adjuvant Chemotherapy
Following Surgery and
Postoperative RT or CRT
Four moderately sized trials in this treatment set-
ting showed no benefit in DFS or OS [9, 22, 37,
49]. In these trials, the adjuvant chemotherapy
was 5-FU for 6–12 months. This treatment set-
ting was also part of the QUASAR trial (see
above), with 201 patients randomized [27, 43].
The hazard ratios indicated benefit from adjuvant
chemotherapy for OS and DFS in this subgroup
of patients, although the differences were not sta-
tistically significant.
22.3.3 Adjuvant Chemotherapy
Following Preoperative
RT and Surgery
This treatment setting was investigated as part
of the 2 × 2 factorially designed EORTC 22921
trial, in a subgroup of patients in the QUASAR
trial and preliminary data have also been pre-
sented from three trials still ongoing or finished
early. In the EORTC 22921 trial, a total of 1,011
patients were randomized to preoperative RT or
CRT and then to postoperative adjuvant chemo-
therapy or observation only [6]. The adjuvant
chemotherapy was 5-FU, but only for 3 months.
Adjuvant chemotherapy tended to provide
benefit in DFS and OS following preoperative
RT or CRT, but the differences were not statisti-
cally significant, and hazard ratio for OS was
0.85 (95% confidence interval 0.68–1.04) and
219
for DFS 0.87 (0.72–1.04). However, in patients
given adjuvant chemotherapy, the local recur-
rence rate was reduced from 17% to 9%
(p = 0.002). OS and DFS were not reported sep-
arately for the RT and CRT groups. In the
QUASAR trial, 198 patients had preoperative
RT and were then randomized to adjuvant che-
motherapy or not [27, 43]. In this subgroup,
there was an obvious trend to benefit from adju-
vant chemotherapy with hazard ratios for OS
and DFS close to 0.5. These differences were
not statistically significant due to the small
sample size.
Early interim data from the ongoing PROCTOR/
SCRIPT trial in which patients following short-
course RT and immediate surgery are randomized
to 6 months folinic-acid-modulated 5-FU (n = 177)
or capecitabine (n = 183) or observation only and
joined with data (n = 107) from the Chronicle trial,
with randomization after preoperative CRT to
observation or adjuvant capecitabine and oxalipl-
atin, have been presented at a conference [53].
Based on these 470 patients, there were no signs
of benefit in OS but numerically a minor advan-
tage in terms of local recurrence and rate of dis-
tance metastasis. The follow-up time of the
patients was not presented, but likely short since
some patients were recently included. The
PROCTOR/SCRIPT is still ongoing and has been
expanded to also include patients having preop-
erative long-course CRT.
22.3.4 Adjuvant Chemotherapy
Following Preoperative CRT
This setting was investigated as part of the
EORTC 22921 trial as presented above, and the
addition of adjuvant chemotherapy to preopera-
tive CRT had no effect on local recurrence [6]. In
a similar Italian trial, still only reported as an
abstract [11], 635 patients had preoperative CRT
and were then randomized to 4.5 months of adju-
vant folinic-acid-modulated 5-FU or observation
alone. OS was essentially identical, and there was
also no difference in local recurrence rate. The
results of the small Chronicle trial (see above)
have not been separately reported.
220
22.3.5 Adjuvant Chemotherapy Before
and After CRT and Surgery
This setting could be considered experimental
and is currently being studied, and no mature data
are available. Phase 2 trial data show high
response rates in the rectal cancer primary from
chemotherapy with 5-FU/capecitabine and oxali-
platin and better tolerance and compliance from
adjuvant chemotherapy starting before CRT and
surgery vs. CRT, surgery and adjuvant chemo-
therapy [10, 18].
More relevant to the current issue of adjuvant
effects is the randomized phase 2 Expert-C trial
(n = 164) in which all patients with high-risk
operable RC were treated with 3 months of
capecitabine combined with oxaliplatin (Capox),
then had CRT with capecitabine followed by
surgery and finally three more months of postop-
erative Capox. The patients were randomized to
addition of the EGFR antibody cetuximab to
the pre- and postoperative chemotherapy and the
CRT or not. Efficacy data were presented at the
2011 ASCO Conference [17]. Interestingly, in
addition to significantly higher local tumour
response, addition of cetuximab also provided a
statistically significant benefit in OS (hazard ratio
0.27; p = 0.035) and a trend towards better DFS
(hazard ratio 0.81; p = 0.668) in the subset of
patients with KRAS wild-type tumours.
22.4 Discussion
The level of scientific evidence in favour of
benefit from adjuvant chemotherapy in rectal
cancer after curative surgery is considerably
weaker than that in colon cancer. Not only are the
overall efficacy data far from convincing but they
often derive from old trials using adjuvant che-
motherapy schedules not in current use, and little
data are from treatment settings in which optimal
surgery and preoperative short-course RT or CRT
have been applied.
Adding 5-FU-based adjuvant chemotherapy
to surgery alone seems to provide meaningful
benefit in terms of OS and DFS and perhaps also
local recurrence rate, although not all study data
B. Glimelius and P. Nygren
are positive. The overall data for this setting
support the notion that rectal cancer, in corre-
spondence with colon cancer, is possible to tar-
get with adjuvant chemotherapy. From a clinical
practice point of view, however, this has limited
relevance since probably very few patients today
with more advanced rectal cancer go to surgery
without preoperative (C)RT.
In addition to being interesting from a princi-
ple point of view, this knowledge is of use in a
situation in which a patient has been operated
without prior (C)RT based on favourable clinical
and radiology findings at staging, but with unex-
pected high-risk features in the histopathological
report. In this situation, adjuvant chemotherapy
may be reasonable to consider as an alternative to
postoperative CRT since adjuvant chemotherapy
may provide both improved local and systemic
control. If the high-risk features indicate a com-
parably high risk of local failure (e.g. crm+), it
may be difficult for many to accept removal of
the (C)RT component used for decades. If the
features rather indicate high risk of failing sys-
temically (e.g. extramural vascular invasion with
clear crm), adjuvant chemotherapy only maybe
considered acceptable. It is acknowledged,
though, that these data are not strong and are also
unexpected from a pharmacological point of
view. A beneficial effect from adjuvant chemo-
therapy on local recurrences is also supported by
population-based data [36] and in an analysis of
data from five European clinical trials [52].
The overall picture gets complicated when
(neo)adjuvant (C)RT has been used. For such
therapy given postoperatively, most data show
that addition of adjuvant chemotherapy pro-
vides no major benefit, notably with the data
from the QUASAR trial as an exception.
However, in practice, this situation is less rele-
vant to discuss since there is now little support
for (C)RT after surgery [40, 51]. Most data
indicate that when preoperative (C)RT has been
given, the benefit from adding adjuvant chemo-
therapy is likely to be very small or absent,
again with the QUASAR trial as an exception.
Although the Chronicle/PROCTOR/SCRIPT
data are early and based on an interim analysis
only, the lack of indication of a benefit from
22 Will Adjuvant Chemotherapy Improve Outcome After Preoperative Chemoradiation?
adjuvant chemotherapy is troublesome, given
the use in these trials of up-to-date neoadjuvant
(C)RT, high-quality surgery and adjuvant che-
motherapy of current standard (5FU/leucovorin,
capecitabine or capecitabine/oxaliplatin).
By comparison with the efficacy of adjuvant
chemotherapy in colon cancer and in rectal can-
cer when adjunctive (C)RT has not been given, it
might be concluded that by adding (C)RT, which
has an obvious effect on small tumour deposits as
indicated by reduced local recurrence rate from
its addition to surgery, the effect from adjuvant
chemotherapy is in some way reduced. In the
case of CRT, the chemotherapy added to RT
could theoretically have an adjuvant systemic
effect although this is unlikely considering the
lack of benefit in OS and DFS from preoperative
CRT compared with RT alone [6, 8] and the low
total systemic exposure to chemotherapy in this
setting compared with conventional adjuvant
chemotherapy.
Theoretically, the finding of an attenuated
effect from adjuvant chemotherapy when given
after (C)RT could be explained if the untreated
primary rectal cancer is an important source of
tumour cells that preoperatively spread and later
developed into metastases. However, in that case,
(C)RT should provide some benefit over no (C)
RT in terms of OS and development of metasta-
sis, which has not been observed, unless short-
course RT was given in the pre-TME era [21, 48].
On the other hand, the very complex view of the
primary tumour, metastasis and microenviron-
ment ecology emerging [38] may open for yet
unknown distant interactions between the pri-
mary and the metastases that speculatively could
depend on the local treatment.
Another possibility is a lower sensitivity of
rectal cancer compared with colon cancer in the
adjuvant setting based on differences in tumour
biology. Similar activity of chemotherapy in
terms of tumour response rates and benefit in PFS
and OS as well as the spectrum of drug activity in
the metastatic setting argue against this possibil-
ity. However, colon cancer differs from rectal
cancer in several aspects relevant to tumour biol-
ogy [1, 23, 39, 47], and although such differences
may not materialize in the metastatic setting, they
221
may be important in putative tumour ‘stem cells’,
responsible for establishment and growth of
metastasis. Furthermore, the pattern of metastatic
spread differs between colon cancer and rectal
cancer, and theoretically, ‘stem cells’ deposited
in e.g., the lungs may be less drug sensitive than
those in the liver or lymph nodes due to differ-
ences in the interaction between tumour cells and
stroma [33, 38]. However, the finding of an adju-
vant effect in rectal cancer following surgery only
does not support this possibility.
Yet, another explanation to the small or absent
effect from adjuvant chemotherapy in rectal can-
cer treated with preoperative (C)RT would be tim-
ing of adjuvant chemotherapy, i.e. that adjuvant
chemotherapy is starting later than in colon can-
cer due to the time spent on the (C)RT and waiting
for surgery and/or postoperative complications
leading to postponed start of adjuvant chemother-
apy compared with the situation in colon cancer.
This might be relevant since in colon cancer, the
efficacy of adjuvant chemotherapy is attenuated
by time of start after surgery [5, 16]. However, the
indication of a lack of effect from adjuvant che-
motherapy also in the PROCTOR/SCRIPT study,
in which the delay to adjuvant chemotherapy was
likely small, argues against a major effect from
timing. Another and related explanation could be
the mostly lower compliance with the adjuvant
chemotherapy in rectal cancer compared with
colon cancer. In this context, presentation of study
data both based on intention to treat and per pro-
tocol would be valuable. Although Swedish popu-
lation data show that OS after short-course RT,
TME and adjuvant chemotherapy is significantly
better than if adjuvant chemotherapy is not given
[50], patient selection could have influenced the
outcome since treatment allocation was not by
randomization.
The relevance of the timing effect could be
approached by starting with the systemic rather
than the local treatment in rectal cancer. The
apparently favourable findings in the Expert-C
trials indicate that this approach may be
beneficial [10, 17]. This approach seems fea-
sible and well tolerated [10, 18] and will be
investigated in the Nordic/Dutch RAPIDO
trial, in which patients with poor prognosis
222
rectal cancer will be randomized to conven-
tional CRT followed by surgery and optional
adjuvant chemotherapy or short-course RT fol-
lowed immediately by neoadjuvant chemother-
apy and finally surgery.
Subgroup analyses of the EORTC 22921 trial
have indicated that patients with tumour down-
staging to pT0–2 compared with those with
tumours remaining as pT3–4 following (C)RT had
better prognosis but they also showed benefit
from adjuvant chemotherapy [12]. However, this
effect from adjuvant chemotherapy seemed
restricted to preoperative RT but not to CRT and
was, surprisingly, not related to the nodal status
after treatment. These findings contrast to other
subgroup analysis on this issue [19] and the gen-
eral observations of better effect from adjuvant
chemotherapy in colon cancer in more advanced
disease [4, 35]. Additional methodological prob-
lems with the EORTC trial subgroup analysis
were discussed by Bujko et al. [7]. Thus, although
response to neoadjuvant (C)RT provides strong
prognostic information in rectal cancer, it cannot,
based on current knowledge, be used to predict
the efficacy of adjuvant chemotherapy.
The notion that rectal cancer may successfully
be targeted in the adjuvant setting, as shown in the
early trials adding adjuvant chemotherapy to sur-
gery only, but that a substantial effect is somehow
lost or at least severely attenuated when combined
with preoperative (C)RT points to the use in adju-
vant chemotherapy of drugs more active against
subclinical disease than 5-FU or its analogues
alone. The addition of oxaliplatin to 5-FU
improves the adjuvant effect in colon cancer [4,
30, 35] and needs to be studied also in rectal can-
cer. Unfortunately, effects in the metastatic situa-
tion cannot be extrapolated to the adjuvant setting
as illustrated by the recent negative trial data on
the VEGF and EGFR antibodies in colon cancer
[2, 3, 14]. Thus, there is a need for preclinical
models of subclinical disease relevant to colon
and rectal cancer to optimize the selection of can-
didate drugs to be included in clinical trials on the
adjuvant effects in these tumour types.
In many, perhaps even most, centres treating
rectal cancer, adjuvant chemotherapy in this
tumour type is a non-issue; colon cancer and rectal
B. Glimelius and P. Nygren
cancer are regarded as one disease entity essen-
tially separated only by an anatomical border.
Consequently, the role of adjuvant chemotherapy
in rectal cancer following (C)RT and surgery is
conveniently and pragmatically extrapolated
from colon cancer and from the old, mainly US
studies in rectal cancer where adjuvant chemo-
therapy with adjuvant chemoradiotherapy was
tested [41], without too much consideration of
the evidence basis for this approach. The NCCN
guidelines clearly state the adjuvant chemother-
apy should be given to those at risk for recurrence
[40]. In a recent exploration of the use of adju-
vant chemotherapy in a large US population
registry, suboptimal use was noticed. It was con-
cluded that even at specialty cancer centres, a
sizeable minority of rectal cancer patients treated
with curative intent neoadjuvant CRT do not
complete postoperative chemotherapy. Strategies
to foster adherence to the third and final compo-
nent of curative intent treatment were considered
necessary [34]. However, for those with a more
puristic view on the scientific basis of cancer
treatment, associated with considerable costs
both in terms of health-care funding and individ-
ual patient suffering from adverse effects, this
approach is clearly disturbing.
In routine care, any treatment should be given
if it is proven that it is sufficiently effective and
that the negative effects and costs do not counter-
balance this. Since many patients with rectal can-
cer recur, there is a need for adjuvant therapies
that decrease the risk. After surgery alone, the
data indicate that adjuvant chemotherapy may
have sufficient effects, but this is presently not
the case after CRT. The answer to the question
‘will adjuvant therapy’ posed in the title is ‘well,
it should’. But, does it? No, we do not know.
Should it be given? Basically not. Will it be
given? Well, in many, but not all health-care sys-
tems it will, and even strongly recommended in
official guidelines. When the use was quality
controlled, the doctors were almost ‘banned not
to have followed the guidelines’ [34]. In every
health-care system, doctors and patients must
weigh pros and cons in every clinical situation.
Considering the weak scientific evidence, with
comparably small gains in the positive trials and
22 Will Adjuvant Chemotherapy Improve Outcome After Preoperative Chemoradiation?
lack of signs of gain in other trials, it may actually
be very sound that not all patients get treatment,
even if recommended.
The lack of convincing data showing a benefit
from adjuvant chemotherapy in rectal cancer
argues for participation in well-designed clinical
trials in currently used treatment settings.
Unfortunately, the trials ongoing in this field are
not designed to answer the fundamental question
whether adjuvant chemotherapy provides any
benefit over no adjuvant systemic treatment at all,
since no non-treatment control arms are included.
In this light, the PROCTOR/SCRIPT trial is
important to finalize.
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presentation
 Part VI
Q&As on Surgery
 How to Evaluate the Quality
of Surgery? Suggestions 23
for Critical Reading of Surgical
and Pathological Reports

Lars Påhlman

Contents 23.1 Introduction

23.1 Introduction ................................................ 229
The differences in outcome between surgeons are
23.2 Volume ........................................................ 230
sometimes great and cannot only be explained by
23.3 The Pathologist’s Evaluation stage of disease and patients’ co-morbidity but
of Surgical Quality ..................................... 230
merely of the fact that the quality in the surgical
23.4 How to Access Quality of Surgery? .......... 230 technique differs among surgeons [1].
References ................................................................. 231 In rectal cancer, this phenomenon has been
discussed extensively. In the early 1980s, when
preoperative radiotherapy was introduced to
reduce the often unacceptable high local recur-
rence rate, some centres reported results regard-
ing local recurrences better than standard surgery
combined with radiotherapy [2–4]. All these
reports pinpointed the importance of good surgi-
cal quality, and the TME technique (total mesorec-
tal excision), i.e., dissection in the embryological
plane, should be the gold standard [2]. As a con-
sequence, several countries started training pro-
grammes, and in Scandinavia, not only the surgical
technique changed but also a concentration to
fewer centres has been carried out [5–7].
With a careful examination of the specimen, it
is possible for the surgeon but also by the pathol-
ogists to grade the quality of surgery. If the sur-
geon has followed the embryological plane,
which has been shown to be a barrier for local
spread, no tears in the mesorectal fascia can be
seen.
L. Påhlman This chapter will describe the importance of
Department of Surgical Sciences,
surgical standardization and quality registration
Uppsala University,
SE 751 85, Uppsala, Sweden but also a structured evaluation of the specimen
e-mail: lars.pahlman@surgsci.uu.se by the pathologists.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 229

DOI 10.1007/978-3-642-25005-7_23, © Springer-Verlag Berlin Heidelberg 2012
230
23.2 Volume
One important question has been raised in the
surgical community and also among health-care
providers and that is the volume for units or indi-
vidual surgeons. Rectal cancer is a rather com-
mon disease with an incidence in Europe of
approximately 15–20 new cases per 100,000
inhabitants. Therefore, a unit taking care of
500,000 up to 1 million inhabitants will have
around 100 rectal cancers a year, which is prob-
ably a sufficient volume to require good knowl-
edge and treatment in all level, including surgery,
nursing, follow-up, etc. This is, however, not the
case in the majority of countries in Europe. At
several hospitals, not more than 10–20 rectal
cancers are treated by more than one surgeon
giving the numbers rather small. There are data
from literature supporting that volume is impor-
tant, but it is difficult to interpret the literature,
mainly due to so many confounding factors like
co-morbidity, stage of disease, social depriva-
tion, etc. [8].
23.3 The Pathologist’s Evaluation
of Surgical Quality
The pathologist has the ultimate position to eval-
uate the surgical quality. If the specimens are sent
fresh to the pathology laboratory, it is possible to
grade the quality of the specimen but also have
photo documentation in the files. Different termi-
nology has been proposed to classify the speci-
men where three groups have been proposed
including a perfect specimen, rather well and a
poor specimen. Professor Quirke, a pathologist
from Leeds, has proposed that the three planes
should be classified as follows [9]:
(a) Mesorectal plane, indicating that the whole
mesorectal fascia is intact
(b) Intra-mesorectal plane, with minor tears in
the mesorectal fascia
(c) Muscularis propria plane, which is a speci-
men where lots of mesorectum is left behind
and the muscle tube of the bowel can be seen
macroscopically
L. Påhlman
When applying such a grading on the whole
material in the MRC CR07 trial, on radiotherapy
in rectal cancer, the quality of the specimen pre-
dict not only local recurrence rate but also sur-
vival [9]. For a more specific way of treating the
specimen, see the chapter by Nigel Scott.
Therefore, although not yet recommended, all
pathological reports should ideally have photo
documentation of the specimen but also a judge-
ment of the quality of the specimen. Based upon
this grading, a constructive feedback can be given
to the surgeon at the postoperative MDT confer-
ence. Moreover, by combining this grading with
the preoperative MRI stage, important end point
for a positive outcome, like the circumferential
resection margin, can be better evaluated.
23.4 How to Access Quality
of Surgery?
The shape and quality of the specimen is of
utmost importance and can be evaluated by the
pathologist as described above. However, there
are several other parameters that will differ and
also are indications on differences in quality.
Based upon data emanated from quality assur-
ance registries in the Scandinavian countries
during the last 15 years, it is possible to evalu-
ate the ‘overall’ outcome. Those registries are
national based with participation from all hos-
pitals. With more or less transparent reports
and honest discussions among surgeons, the
improvement has been dramatic in the coun-
tries involved [5–7].
Data collected in these registries are surgical
procedure, level of vessel ligation, type of recon-
struction and outcome in terms of complications
to surgery but also cancer-related end points like
local control and survival. Moreover, the diag-
nostic process preoperatively is registered
together with the follow-up routines and the use
of neo-adjuvant and/or adjuvant use of chemo-
therapy and radiotherapy. In some, registries also
register co-morbidity and health-related parame-
ters like smoking, BMI, etc. Also, prospective
registration of the preoperative tumour stage
23 How to Evaluate the Quality of Surgery?
based upon imaging as well as postoperative
tumour stage based upon pathological examina-
tion exists.
The registries have annual reports with data
divided upon hospitals but also showing chang-
ing’s and trends in each country. Most of the reg-
isters have been enlarged based upon the need for
new items to be register and studied. Once a new
parameter is involved in the registration, i.e.,
lymph node retrieval, the first year registration
often shows unaccepted differences between
units, but with transparent reports and discus-
sions among the surgical communities in the
country, the next years’ registration will often
show an increase to the better, and within some
years it reaches acceptable levels. Subsequently,
a quality register not only guarantees good assur-
ance that the level of care is acceptable but also
acts as a vehicle for quick introduction of new
treatment standards.
The experience from the Scandinavian countries
has led to the same project in many European coun-
tries. In an effort to have similar programmes,
ECCO has sponsored together with European
Society of Surgical Oncology (ESSO) and Euro-
pean Society of Coloproctology (ESCP) a collabo-
ration with all countries with quality registration,
the EURECCA project (European Registration of
Cancer Care) [10]. Countries involved so far, as
national registries or regional, are Belgium,
Denmark, Germany, Italy, the Netherlands, Norway,
Spain, Sweden and the UK.
Other important end points to be evaluated are
specific complications which can be results of
non-optimal surgical technique. Well-known
complications or merely dysfunctions are sexual
impairment, urinary dysfunctions and bowel
problems [11, 12]. In all, this is a whole spectrum
of quality of life. To add this in a quality registra-
tion, prospective validated questionnaires have to
be used.
Regarding the sexual problems and also uri-
nary impairments, modern more precise surgery
will prevent such complications in the majority of
the cases. Today, with good preoperative staging,
surgeons should know if the normal plane of dis-
section could be followed. If that is the case, the
231
risk of damage of the nerves should be minimal.
However, if the tumour is growing outside the
normal plane of dissection, the risk of nerve dam-
age is obvious. By registering such outcome
together with the knowledge of tumour stage, it is
possible to increase the quality.
Conclusion
Quality in surgery has become an important
topic in rectal cancer treatment. Lots of data
support that provided surgery is done in an
optimal way, one can reduce the use of radio-
therapy and perhaps also reduce the use of
chemotherapy. To have an immediate feed-
back to the surgeon whether or not the surgi-
cal procedure has been done in an optimal
way, photo documentation of the specimen is
essential and grading by the pathologist of the
macroscopic view of the specimen is also
crucial. With a quality assurance programme,
the whole treatment of rectal cancer can be
evaluated.
References
1. Mc Ardle CS, Hole D (1901) Impact of variability
among surgeons on postoperative morbidity and mor-
tality and ultimate survival. BMJ 302:1501–1505
2. Heald RJ, Husband EM, Ryall RDH (1982) The
mesorectum in rectal cancer surgery: the clue to pel-
vic recurrence. Br J Surg 69:613–616
3. Enker WE, Thaler HT, Cranor ML, Polyak T (1995)
Total mesorectal excision in the operative treatment of
carcinoma of the rectum. J Am Coll Surg 18:
335–346
4. Moriya Y, Hojo K, Sawada T, Koyama Y (1989)
Significance of lateral lymph node dissection for
advanced rectal carcinoma at or below the peritoneal
reflection. Dis Colon Rectum 32:307–315
5. Wibe A, Møller B, Norstein J, Carlsen E, Wiig JN,
Heald RJ, Langmark F, Myrvold HE, Søreide O,
Norwegian Rectal Cancer Group (2002) A national
strategic change in treatment policy for rectal cancer –
implementation of total mesorectal excision as routine
treatment in Norway. A national audit. Dis Colon
Rectum 45:857–866
6. Påhlman L, Bohe M, Cedermark B, Dahlberg M,
Lindmark G, Sjödahl R, Öjerskog B, Damber L,
Johansson R (2007) The Swedish rectal cancer regis-
try. Br J Surg 94:1285–1292
232
7. Bülow S, Harling H, Iversen LH, Ladelund S, Danish
Colorectal Cancer Group (2009) Survival after rectal
cancer has improved considerably in Denmark. Ugeskr
Laeger 171:2735–2738
8. Kressner M, Bohe M, Cedermark B, Dahlberg M,
Damber L, Lindmark G, Öjerskog B, Sjödahl R,
Johansson R, Påhlman L (2009) The impact of hospi-
tal volume on surgical outcome for rectal cancer – a
survey of the Swedish Rectal Cancer Register. Dis
Colon Rectum 52:1542–1549
9. Quirke P, Steele R, Monson J, Grieve R, Khanna S,
O’Callghan C, Sun Myint A, Bessell E, Thompson
LC, Parmar M, Stephens RJ, Sebag-Montefiore D
(2009) Effect of the plane of surgery achieved on local
recurrence in patients operated with operable rectal
cancer: a prospective study using data from the MRC
L. Påhlman
CR07 and NCIC-CTGCO16 randomised clinical trial.
Lancet 373:821–828
10. van Gijn W, van de Velde CJH, and on behalf of the mem-
bers of the EURECCA Consortium (2010) Improving
quality of cancer care through surgical audit. Eur J Surg
Oncol 36:S23–S26
11. Dahlberg M, Glimelius B, Graf W, Påhlman L (1998)
Preoperative irradiation for rectal cancer affects the
functional results after colorectal anastomosis –
results from the Swedish Rectal Cancer Trial. Dis
Colon Rectum 41:543–551
12. Marijnen CA, van de Velde CJ, Putter H et al (2005)
Impact of short-term preoperative radiotherapy on
health-related quality of life and sexual functioning in
primary recta caner: report of a multicentre trial.
J Clin Oncol 23:1847–1858
 How Is Nerve-Sparing Surgery
Well Performed? 24
Zoran Krivokapic and Ivan Dimitrijevic

Contents 24.1 Introduction

24.1 Introduction ................................................ 233
Major goals of rectal cancer treatment are
24.2 The Importance of Pelvic
Vegetative Nerve Preservation .................. 233 improving of overall survival rates by minimiz-
ing the percentage of local and distant recurrence.
24.3 Physiological Considerations .................... 235
Efforts are also made in attempt to further reduce
24.4 Anatomical Consideration in the Context the percentage of permanent stomas as well as to
of Function Preservation ........................... 235 improve the life quality of patients treated for this
24.4.1 Pelvic Vegetative Nerve Structures .............. 235
24.4.2 Anatomy of Denonvilliers’ Fascia ............... 237 disease. Until around 20 years ago, there was a
24.4.3 The ‘Lateral Ligaments’ of the Rectum ....... 237 lot of space for improvement of surgical results.
24.4.4 Pudendal and Levator Ani Nerve ................. 238 The percentage of permanent stomas in around
24.5 Important Points of Nerve 55%, 5-year survival of around 50%, local recur-
Preserving TME ......................................... 238 rence in 30–40%, and distant recurrence in more
24.5.1 Mobilization of the Left Colon than 60% made situation with rectal cancer treat-
and Ligation of the Inferior
Mesenteric Artery ........................................ 238
ment very upsetting. After the introduction of
24.5.2 Division of the Sigmoid Colon .................... 239 total mesorectal excision (TME) in 1982, by Bill
24.5.3 High Posterior and Lateral Dissection ......... 239 Heald, significant improvement was noted in all
24.5.4 Distal Posterior and Lateral Dissection ....... 240 fields of the surgical treatment of rectal cancer.
24.5.5 Anterior Dissection ...................................... 241
24.5.6 Mobilization of the Most Caudal
Five-year local recurrence rate was reduced to
Portion of the Mesorectum .......................... 243 only 5%, and 5-year overall survival was 80%,
24.5.7 Laparoscopic TME in the Context of Nerve according to Mr. Heald’s results [18].
Identification and Preservation .................... 245
References ................................................................. 245
24.2 The Importance of Pelvic
Vegetative Nerve Preservation

Having in mind the importance of life quality of

patients operated for rectal cancer, systematic
identification and preservation of pelvic vegeta-
Z. Krivokapic • I. Dimitrijevic (*) tive nerves was applied in wide surgical practice
Colorectal Department, Institute for Digestive Diseases, simultaneously with the introduction of TME.
Medical School of Belgrade University,
High percentage of postoperative sexual and uri-
First Surgical Clinic, Clinical Center of Serbia,
Belgrade, Serbia nary dysfunctions was well-known phenomenon
e-mail: scpy@beotel.yu in the early years of modern rectal cancer surgery.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 233

DOI 10.1007/978-3-642-25005-7_24, © Springer-Verlag Berlin Heidelberg 2012
234
Goligher, Bernstein and Weinstein [2, 63, 67]
published the papers where significant percent-
age of patients operated for rectal cancer had
sexual and urinary dysfunction. In one meta-
analysis that dealt with quality of life of patients
operated for rectal cancer in the second half of
the twentieth century, sexual dysfunction was
observed in 39% and urinary dysfunction
occurred in 27% of patients [4]. Fortunately, with
the introduction and popularization of the TME,
the things changed for better [16]. Besides men-
tioned oncological benefits, identification and
preservation of vegetative nerves has become
easier [18]. By abiding the main principles of
TME technique, i.e. sharp dissection under the
direct control of vision, we have almost no bleed-
ing, and by following the correct dissection plane,
there is minimal risk of serious vegetative nerve
damage. Additionally, we obtain adequate resec-
tion margins, especially important circumferen-
tial resection margin, good specimen and ability
to perform high percentage of sphincter-preserv-
ing operations.
Sympathetic vegetative nerve structures are
generally situated more proximally and are easier
to identify and preserve. According to literature
data, by conducting proper TME, identification
of these structures is possible in 80–94% [13]
in males and in even 96% [21] in females. The
situation with identification and preservation of
parasympathetic structures differs. They are
placed deep in the pelvis, in delicate fascial lay-
ers of closely situated pelvic organs and are much
more difficult to identify and preserve. There is
a lot of discrepancy in literature data on this
subject. The percentage of preservation and
identification of these structures varies between
53% and 96% [21, 39, 44].
In almost all studies published on this sub-
ject, the operation type proved to be a significant
factor of influence. In cases where surgeons pre-
formed the transection of mesorectum, situation
was very good as presented by some [42]. On
the other hand, when performing more challeng-
ing procedure, TME, the results tend to be
worse. Unfavourable functional results were
noted in patients where abdominoperineal resec-
tion (APR) was performed, compared to those
Z. Krivokapic and I. Dimitrijevic
with sphincter-saving procedures [13, 27, 31,
41, 59, 66]. These results are in a way obvious
since the abdominoperineal resection (APR) is
more mutilant in its nature, and presence of a
stoma has a significant psychological influence
on these individuals. Mr. Heald stressed that
injury to the neurovascular bundle of Walsh is
likely to happen during the perineal act due to
poor visibility and the fact that statistically more
advanced tumours are found in this group of
patients [15].
As it is clearly apparent, the sex of patient
significantly affects the percentage of nerve
identification and preservation as well as patients’
constitution (obese individuals, narrow ‘male’
pelvis) [56]. Neo-adjuvant therapy can also be a
factor that influences nerve identification and
preservation. Nevertheless, literature data are
inconsistent due to different inclusion criteria,
and research methods and this subject deserve to
be further investigated [27, 32]. Tumour stage
and localization as well as operation type also
have significant influence on the degree of
identification and preservation of vegetative
nerves [27, 31]. The factor that significantly
affects nerve preservation and identification is
surgeons experience and training in this field.
Learning curve showed to be independent factor
that predisposed the degree of nerve preservation
and identification [27].
Nevertheless, the good postoperative results
published by highly specialized rectal surgeons
have not been achieved in larger studies [38, 43].
Concerning sexual function, age showed to be
a very, if not the most, important predictive fac-
tor after rectal cancer operations [19, 29, 59].
Patients over 60 years of age have a significantly
higher risk of loss of sexual function postopera-
tively than younger patients [13]. The difference
in the upper age limit between a number of stud-
ies can explain various rates of sexual dysfunc-
tion reported.
Some investigators, in order to further
improve and facilitate the nerve preservation,
attempted to employ neurostimulation and mea-
surement of penile tumescence or intravesical
pressure. Using these methods, the percentage
of identification of pelvic vegetative nerves rises
24 How Is Nerve-Sparing Surgery Well Performed?
from standard 70–80% to almost 100% [7, 58].
The initial results are promising but deserve fur-
ther research.
Concerning all postoperative functional deficits
and recovery rates in the follow-up period, we can
conclude that if preoperative function is intact, the
likelihood of complete recovery is fair.
24.3 Physiological Considerations
The sympathetic and parasympathetic nervous
systems act as an integral system in the coordina-
tion of urinary and sexual function. Sacral para-
sympathetic fibres carry the impulses that mediate
dilatation of the vascular inflow to the cavernous
bodies which results in erection. The neuronally
triggered vasodilatation responsible for erection
is mediated by nitric-oxide-induced relaxation of
the cavernosal sinusoids. The damage to these
structures results in impotence, the most severe
sexual deficit in men.
On the other hand, sympathetic fibres are
responsible for emission of semen from the semi-
nal vesicles into the urethra. Sympathetic fibres
also innervate the vasa, prostate, urethra and the
internal urethral sphincter. Coordinated sympa-
thetic activation of these structures, together with
somatically innervated bulbospongiosus and
ischiocavernosus muscles, results in ejaculation.
The sacral segment of spinal cord is responsible
for the coordination of the sexual response.
Damage to these structures most commonly
causes the absence of ejaculation or a case of a
retrograde one due to denervation of internal ure-
thral sphincter. Male sexual dysfunction is pres-
ent in around 10–35% of cases after rectal cancer
operations [13, 34, 39]. Enker reported that spon-
taneous postoperative erection was possible in
85% of the patients [9], and similar results were
achieved by other specialized surgeons [14, 48].
In women, parasympathetic impulses trigger
the release of vasoactive intestinal polypeptide
from nerve endings in the vaginal wall that results
in intensive vaginal transudation of fluid which
together with secretion of Bartholin glands allows
good lubrication of vagina. As in males, parasym-
pathetic impulses are responsible for vascular
235
engorgement of the clitoris and labia. Disruption
of the autonomic nerves in females may cause
dyspareunia and vaginal dryness. Reviewing the
literature, we see that postoperative sexual dys-
function is present in the range between 3% and
57% [19, 49]. Dyspareunia is the most common
symptom after rectal cancer surgery and some-
times even before the operation [13]. Disturbances
of the pelvic anatomy can explain some of the
female sexual problems. APR results in higher
incidence of dyspareunia and is almost always
present if the posterior wall of the vagina is
removed.
Urinary bladder is also innervated with both
components of the autonomic system. The base
of the bladder is supplied by sympathetic
impulses, and the detrusor muscle is innervated
by parasympathetic fibres. These two systems
together with centres in the spinal cord and pons
coordinate the cycle of filling and empting of the
bladder. Damage to the parasympathetic fibres
causes non-coordinated action of the detrusor
and overactive sympathetic stimulation of the
bladder base. As a result, we have the most com-
mon consequence of the damaged vegetative
innervation, flaccid bladder with high intravesi-
cal pressure. Patients in this situation experience
urinary retention. Infrequently, due to the isolated
sympathetic denervation or a lesion of levator ani
nerve, which is a somatic structure, patients can
experience urinary incontinence [28, 62]. Urinary
dysfunction after rectal cancer operations is pres-
ent in 4–28% of the cases [27, 37, 48]. In males,
urinary disturbances are rather frequent, occur-
ring in around 40%. On the other hand, urinary
incontinence is infrequently reported [27, 37].
24.4 Anatomical Consideration
in the Context of Function
Preservation
24.4.1 Pelvic Vegetative Nerve
Structures
24.4.1.1 Sympathetic Innervation
The sympathetic impulses to the pelvis are gener-
ated in the intermediolateral grey matter of the
236
Fig.24.1 Schematic presentation of pelvic autonomic
system
spinal cord in the level of T12 to L2(3) (Fig. 24.1).
The preganglionic fibres come out of the spinal
cord through spinal nerve and through white
ramus communicans into the sympathetic para-
vertebral chain. The lumbar splanchnic nerves
are predominantly preganglionic sympathetic
structures that join preaortic plexus that covers
the full length of anterior side of the abdominal
aorta. The logical continuation of this structure is
inferior mesenteric plexus, localized opposite the
inferior mesenteric artery. These nerve fibres
form two filaments that lead to the anterior sur-
face of the aorta that join together in the level of
sacral promontory where superior hypogastric
plexus is formed [6, 40]. Many of these pregan-
glionic fibres make synapses at this point. Besides
these, this plexus contains ascending parasympa-
thetic filaments that innervate descending colon
as well as afferent fibres from the pelvic organs.
Distally, superior hypogastric plexus divides
into two filament-like structures, around 4–7-
mm wide called hypogastric nerves. These
nerves lead inferolaterally medial to the ureter,
beneath the peritoneum. They are also placed
inside the internal iliac vessels and in close
Z. Krivokapic and I. Dimitrijevic
contact with mesorectal fascia. Individual dif-
ferences in the size of these structures are rather
great; sometimes, they are thick voluminous
structures, but in some cases, they are filament
like, barely visible.
Distally hypogastric nerves join parasympa-
thetic errigent nerves to form inferior hypogastric
(pelvic) plexus.
24.4.1.2 Parasympathetic Innervation
The parasympathetic nerve supply to the pelvis
derives from sacral parasympathetic ganglia
located in the S2–S4 segments of the spinal cord.
Preganglionic fibres pass through second, third
and fourth sacral foramina, going anterolaterally,
just close to piriform muscle towards the hypo-
gastric nerves piercing the pelvis sidewall facia,
and after joining with these sympathetic struc-
tures, they form inferior hypogastric (pelvic)
plexus [28].
There are certain variations in the type and
number of errigent nerves that participate in for-
mation of pelvic plexus. They most frequently
are from S3 and S4 (60%), sometimes from S2
(40%) and rarely from S5 roots of the spinal
cord [40].
24.4.1.3 The Pelvic Plexus
The pelvic plexus is the major centre for coordi-
nation of the vegetative innervation of the pelvis.
It is placed between thick pelvic sidewall fascia
and much thinner mesorectal fascia, which makes
it in some individuals very difficult to properly
visualize.
This plexus in males is described as a rectan-
gular structure, around 5 cm long and 3 cm wide,
with its midpoint at the tip of the seminal vesicles
[62]. It is located in the sagittal plane on either
side of the rectum and pierced by a number of
vessels that supply rectum, bladder, seminal ves-
icles and prostate [53].
On the other hand, in females, pelvic plexus, by
some authors, is described as a triangle, with a
posterior base and an anterior inferior top which is
at the ureter’s point of contact where it perforates
the posterior layer of the broad ligament [40].
Besides its main tributaries, hypogastric and
errigent nerves, in 30% of the cases, sympathetic
24 How Is Nerve-Sparing Surgery Well Performed?
afferences exist, most commonly from a single
branch of the second, third or fourth sacral gan-
glion [40].
24.4.1.4 Efferences of the Pelvic Plexus
In females, the vaginal branches distally come out
of the top of the pelvic plexus through branches
leading to the bladder, vagina and the rectum. These
branches come from two stalks just beneath the
point where ureter crosses uterine artery. One trunk
that innervates bladder is distally, down to the ure-
ter, divided into further two branches – lateral and
medial trigonal. The other trunk innervates vagina
and goes along with uterine artery. This branch, at
the lateral edge of vagina, is divided into further
two fibre groups. Some of these fibres perforate the
posterior vaginal wall and can be found in the rec-
tovaginal septum [40].
In males, the most prominent and important
efferent of the pelvic plexus is the urogenital neu-
rovascular bundle. From its origin, at the most dis-
tal part of the pelvic plexus, it goes posterolaterally
to the prostate and continues laterally on the both
sides of the urethra. Approximate thickness of this
structure is around 10–12 mm. It contains ganglia
as well as nerve fibres together with connective tis-
sue. This structure is situated between two layers
of the lateral pelvic fascia (levator and prostatic
fascia). The neurovascular bundle branches
through parietal pelvic fascia and medially through
Denonvilliers’ fascia to the prostate and urinary
bladder. The rest of the fibres (cavernous nerves)
pass around the base of the prostate base and con-
verge in a ‘pincer-shaped’ formation, close to ure-
thra. Distally, these nerves pierce through pelvic
floor muscles and course to genital organs [6, 54].
Nevertheless, this structure is far from being well-
defined. Some authors [30] found distinct neuro-
vascular bundle in only 48% of the cases. In the
remaining 52%, nerve fibres were spread all along
the lateral side of the prostate.
24.4.2 Anatomy of Denonvilliers’ Fascia
During the rectal mobilization, this structure is
sometimes easily visible as a membrane, but some-
times, it can be very thin and fragile. Denonvilliers’
237
fascia can sometimes be more obvious in patients
thatunderwentneo-adjuvanttreatment.Nevertheless,
in most of the cases, this layer is thicker than the
mesorectal fascia [5].
Histologically, it is constituted of collagen,
elastic and smooth muscle fibres. As mentioned,
these longitudinal smooth muscle fibres are
accompanied by delicate nerve filaments [1, 55].
Prostate and seminal vesicles in males and vagina
in females are situated anteriorly [1, 35].
Posteriorly, mesorectal fascia, thin mesorectum
and rectal wall are found. This structure is contin-
ued to the perineal body caudally [8].
On the matter of adherence of this structure to
the surrounding organs, there is no current con-
sensus. Sex differences are present, and generally
in females, it is less adherent to the anterior organs
opposed to males, especially distally. Some
authors state that adherence is generally stronger
to the anterior organs, but others have opposite
opinion [5, 23].
According to Bill Heald and a number of other
authors [17, 45] Denonvilliers’ fascia is a part of
the mesorectum anteriorly, thus suggesting that
during the dissection, this structure should be left
on the mesorectal specimen. According to them,
a distinct plane of dissection exists between sem-
inal vesicles and Denonvilliers’ fascia. Applying
this approach mentioned, authors managed to
maintain good sexual and urinary function post-
operatively, which suggests that we can avoid
damage to vegetative nerve structures if we fol-
low the so-called mesorectal plane [15, 36].
Others state that this structure has two leaves,
suggesting that appropriate dissection plane
should be through the Denonvilliers’ fascia [47].
Some more recent histological studies show
that this fascia is more adherent to the anterior
organs, and the reason for leaving it on the rectal
side is more oncologic than anatomic one, in cases
of low anteriorly placed rectal carcinomas [35].
24.4.3 The ‘Lateral Ligaments’
of the Rectum
These ligaments have been described in some
papers and textbooks as a structure that arises
238
from the endopelvic fascia of the pelvic sidewall
that goes anteromedially as it approaches to the
rectum. Miles, Goligher and some other older
authors suggested ‘clamping’ or ‘hooking on the
finger’ of this structure [11].
Also, it has been suggested that these liga-
ments contain fatty tissue, nerves and vessels
(middle rectal artery), which present oncological
danger for the rectal cancer patients; thus, these
should be clamped near the lateral pelvic side-
wall [11]. This approach proved to be devastating
in the terms of preservation of pelvic vegetative
nerves, since according to recent studies, impor-
tant pelvic ganglia are contained in this area,
especially in its lateral third [6].
With the advances in this field of surgery,
especially since the introduction of TME in 1982,
by Bill Heald [18], situation changed. Heald and
others state that there is no such structure and
sharp dissection just close to mesorectal fascia is
adequate and oncologically sufficient. Resent
anatomical studies supported this opinion [25].
In addition, studies have shown that middle rectal
artery exists in only 25–50% of cases and its
diameter is rarely greater than 2 mm [25, 52],
which makes diathermy perfectly safe method in
transection of this structure.
24.4.4 Pudendal and Levator Ani Nerve
Not only autonomic nerves play an important
role in sexual and urinary function. Two somatic
nerves are responsible for certain aspect of these
functions. Those are pudendal nerve and levator
ani nerve.
In the infralevatory compartment, pudendal
nerve arises from S2–S4 roots of the sacral plexus
and runs through ischioanal fossa to the genital
area giving sensory and motor branches, i.e., dor-
sal penis or clitoris nerve. In males, pudendal
nerve gives motoric impulses for ischiocaverno-
sus and bulbospongiosus muscle, important for
rigid phase of erection [6]. The damage to puden-
dal nerve can cause faecal incontinence. Relatively,
recent papers have re-emphasized another somatic
nerve that innervates levator muscles. That is leva-
tor ani nerve that arises from S3–S4 roots of the
Z. Krivokapic and I. Dimitrijevic
sacral plexus, separately from pudendal nerve.
The levator ani nerve approaches levator ani mus-
cle from within the pelvis on the superior surface
of the pelvic floor. Its position makes this struc-
ture amenable to accidental damage during TME.
This nerve gives substantial innervation to levator
muscle as mentioned, and its injury can explain
certain proportion of postoperative faecal and uri-
nary incontinence [61].
24.5 Important Points of Nerve
Preserving TME
The basic concept of the TME procedure is to
follow embryologically defined layers. According
to Mr. Bill Heald, the founder of this method, ‘the
corollary to the perfect specimen and cure is
the perfect preservation of the layers surrounding
the mesorectum which, are formed by the auto-
nomic nerves and plexuses’ [15].
During the nowadays standard operation for
rectal carcinoma of the middle and lower third
of rectum (TME), there are a number of points
where a surgeon can easily damage some of the
mentioned vegetative nerve structures. We will
go through these steps and try to ascertain
mechanisms of vegetative nerve injury and their
prevention.
24.5.1 Mobilization of the Left Colon
and Ligation of the Inferior
Mesenteric Artery
Proper mobilization of the left colon involves
finding the right plane between two leaves of
Toldt’s fascia, leaving retroperitoneal surface
with gonadal vessels, ureter and preaortic sym-
pathetic fibres intact. This is done by dividing
the white (Toldt’s) line of the sigmoid colon
from the peritoneum of the lateral abdominal
wall (Fig. 24.2). By gently lifting upwards meso-
colon together with so-called pedicle package,
we reveal a correct dissection plane (Fig. 24.3).
Performing this, we can easily identify and pre-
serve already mentioned two preaortic sympa-
thetic trunks going around inferior mesenteric
24 How Is Nerve-Sparing Surgery Well Performed?
Fig.24.2 The division of the Toldt’s white line of the
sigmoid colon
Fig. 24.3 Mobilized left colon with visible ‘pedicle
package’, superior rectal artery, vein and para-aortic plexus
artery. Additionally, this plane of dissection is
continued distally with the extrafascial plane of
dissection of mesorectum, leaving its fascia
intact [15, 28].
With completely mobilized and lifted left
colon, it is easy to identify the proximal end of
the pedicle package. It is advisable to separately
ligate inferior mesenteric vessels (Fig. 24.4).
Ligating of inferior mesenteric artery can be
safely done 1–2 cm distally to the aorta in order
to avoid conflict with preaortic sympathetic
nerves. On the other hand, the vein is usually
divided close to the lower edge of pancreas.
When performing APE, it is satisfactory to ligate
239
Fig. 24.4 Ligated inferior mesenteric artery and vein
inferior mesenteric artery as described, but the
vein can be divided nearby.
24.5.2 Division of the Sigmoid Colon
Sigmoid colon along with its mesentery should
be divided on the safe distance proximally to the
tumour. This step may appear insignificant, but
its importance is in the optimal mobility of the
specimen which provides clear and direct visual-
ization of the plane of dissection around mesorec-
tal fascia where important vegetative nerve
structures are situated.
24.5.3 High Posterior and Lateral
Dissection
The traction of the transected sigmoid colon
‘towards the ceiling’ reveals shiny posterior side of
mesorectal fascia. Visualizing the fascia usually
precedes identification of vegetative nerve struc-
tures (Fig. 24.5). Superior hypogastric plexus is
situated on the sacral promontory, and hypogastric
240
Fig. 24.5 Posterior surface of mesorectal fascia and areolar,
avascular tissue preceding superior hypogastric plexus
Fig. 24.6 Superior hypogastric plexus and hypogastric
nerves (With permission of Bill Heald)
nerves, by leaving it, form a ‘wishbone-like’ struc-
ture (Fig. 24.6). Accidental damage to these struc-
tures is avoided by traction and counter-traction
together with sharp dissection keeping the nerves
in view all the time. The hypogastric nerves are
placed just beneath the level of the peritoneal
reflection, and by incising the peritoneum more lat-
erally than optimal, surgeon can easily transect
them. Also, hypogastric nerves are relatively adher-
ent to the mesorectal fascia, and by traction of the
specimen to the left, nerves can be ‘tented up’ and
accidentally injured. To avoid this, one must care-
fully ‘peel off’ the nerves from mesorectal fascia.
Bilateral sacrifice of hypogastric nerves almost cer-
tainly leads to ejaculatory failure [37, 56].
Z. Krivokapic and I. Dimitrijevic
Fig. 24.7 Recto-sacral (Waldeyer’s) fascia partially
transected
24.5.4 Distal Posterior and Lateral
Dissection
Further distal posterior dissection is an important
step of the TME. It is mandatory to follow the
right plane as one proceeds downwards. At a
strict posterior plane, there are no important veg-
etative nerve structures, but sharp dissection of
the areolar, avascular tissue together with the
transection of the recto-sacral (Waldeyer’s) fascia
gives a surgeon correct plane for lateral and even-
tually anterior dissection (Fig. 24.7). Also, by
mobilizing the posterior aspect of the mesorec-
tum, proper traction and counter-traction can be
achieved in order to perform correct visualization
of the lateral vegetative nerve structures, which is
one of the main advantages of open surgery to
laparoscopic approach [12, 15, 24, 50, 51].
Lateral dissection is one of the most important
phases of the nerve-preserving TME. It involves
strict following of the plane obtained posteriorly,
with further ‘peeling off’ of the hypogastric
nerves to the level of the ‘lateral ligaments’
(Fig. 24.8). Already mentioned errigent nerves
are during the lateral dissection seen as ‘errigent
pillars’ [15]. These structures are placed laterally
outside the parietal fascia which they penetrate,
going towards the pelvic plexus in posteroante-
rior direction. Though we already mentioned that
there are most frequently three errigent nerves,
intraoperatively, we usually identify one or some-
times two of these nerve structures (most fre-
quently from S3 component), making a nerve
24 How Is Nerve-Sparing Surgery Well Performed?
Fig. 24.8 Proximal lateral dissection with visible
hypogastric nerves adherent to mesorectal fascia
Fig. 24.9 ‘Lateral ligament’ of the rectum, i.e. inferior
hypogastric plexus with visible ‘errigent pillar’ (With
permission of Bill Heald)
root from the front of the S3 part of the main
sacral plexus (Fig. 24.9).
The traction to the rectum is most likely
responsible for pillar-like appearance of errigent
nerves, which makes them easily recognizable.
This may be an explanation why it is easier to
identify these nerves during open surgery, despite
magnification that is available during laparo-
scopic approach that lacks in sufficient traction to
the rectum.
Further anteriorly, the dissection plane is
extended to the vesicles with the hypogastric
plexus neural plate placed with its centre on the
tips of the seminal vesicles. At this point, one
has to be extremely careful. Namely, between
mesorectal fascia and pelvic plexus, an area of
adherence exists, in the place where nerve fibres
241
and small blood vessels penetrate mesorectal
fascia. Once more, it is important to stress that
main constituents of the so-called lateral liga-
ment are vegetative nerve fibres and ganglia,
whereas middle rectal artery is found only in
around 28% in anatomical studies [33, 52, 57],
bilaterally present in only one-third of the cases.
The diameter of this artery is only around 1.3 mm
and gradually deceasing during the course to
mesorectal fascia, thus becoming barely visible
at the point where it pierces it. Therefore, it is
practically impossible to identify lateral liga-
ments during the correct TME procedure. Also,
it is perfectly safe to follow the mesorectal plane
with absolutely no need to clamp or ligate any
vascular structures [33, 52, 57].
If one tends to proceed with the dissection
more laterally, injury to the pelvic plexus may
occur, especially if one applies too much traction
to the rectum, displacing the plexus superiorly
and medially [46]. At this point, if the pelvic
plexus is damaged, both sympathetic and para-
sympathetic functional deficits may occur.
On the other hand, if a surgeon tries to stay far
away from the pelvic plexus and ‘cones in’ the
mesorectum, a need for ligation of the vessels is
frequently possible. These vessels are actually a
part of the mesorectal envelope and should be left
intact. Otherwise, an oncological quality of the
operation is diminished by leaving a part of the
mesorectum within the pelvis [15].
24.5.5 Anterior Dissection
This phase of the TME is probably the most
demanding in terms of vegetative nerve preserva-
tion. As mentioned, the dissection is conducted
in a very thin area between rectum and seminal
vesicles and prostate or vagina where anterior
mesorectum, mesorectal fascia and Denonvilliers’
fascia are situated (Fig. 24.10). There is still no
absolute consensus in terms where to proceed
with the dissection plane in this area [35].
According to Bill Heald, dissection anteriorly
and anterolaterally should follow the plane
obtained during posterior and lateral phase.
Proximally, peritoneum should be incised in a way
242
Fig. 24.10 The area of anterior dissection after two thirds
of posterolateral dissection performed
Fig. 24.11 Proper incision of the peritoneum reflection at
the beginning of anterior dissection
to encompass peritoneal reflection that should
remain on the specimen (Fig. 24.11). Entering this
plane enables us to clearly visualize anterior
organs, seminal vesicles and vagina. Good retrac-
tion of these structures in most cases reveals avas-
cular, areolar tissue and relatively straightforward
dissection plane distally which leaves shiny,
smooth anterior side of the specimen (Fig. 24.12).
This smooth surface on the specimen is actually
Denonvilliers’ fascia. As one proceeds distally,
comes to a point where Denonvilliers’ fascia
becomes adherent to the posterior capsule of
the prostate. Here, fascia should be divided
Z. Krivokapic and I. Dimitrijevic
Fig. 24.12 The correct plane of anterior dissection with
visible Denonvilliers’ fascia posteriorly and seminal vesi-
cles anteriorly
Fig. 24.13 Specimen after performed TME with lower
edge of Denonvilliers’ fascia transected in the level of the
lower third of prostate
transversely (Fig. 24.13). This is a crucial step in
the preservation of delicate neurovascular bundles
that present distal continuation of the inferior
hypogastric plexus and practically invisible cav-
ernous nerves that pass anterolaterally to the rec-
tum on the way through urogenital diaphragm
before entering cavernous bodies [10, 16]. Once
again, in order to properly preserve neurovascular
bundles of Walsh, it is mandatory to be aware of its
correct anatomical position, especially in males
(Fig. 24.14). From the distal part of the pelvic
plexus, it travels caudally, under the pelvic floor
fascia. The neurovascular bundle pierces this
24 How Is Nerve-Sparing Surgery Well Performed?
Fig. 24.14 View on the posterior side of prostate, with
present Denonvilliers’ fascia transected in the lower third
and intact neurovascular bundles posterolaterally, after
performed ‘face down’ APR (With permission of Bill
Heald)
fascia, and part of the nerves goes through
Denonvilliers’ fascia towards prostate and urinary
bladder. The rest of the fibres courses around the
prostate base, then through pelvic diaphragm
towards genital organs.
Having in mind these anatomical consider-
ations, it is obvious that the dissection plane
described above has several advantages. First, the
plane one follows is avascular, thus visualization
is optimal; second, from oncological point of
view leaving the Denonvilliers’ fascia on the
specimen, the risk for oncologically insufficient
operation is minimal; and third, by transecting
the rectogenital fascia at the mentioned level, we
avoid collision with often invisible vegetative
structures [20].
Nevertheless, different opinions considering
the right plane in the anterior dissection exist.
Some advocate taking the entire Denonvilliers’
fascia [45], using as some would say ‘extrame-
sorectal plane’ [35, 36]. This approach is onco-
logically safe, but risk of the damaging vegetative
nerves is too high. On the other hand, some advo-
cate ‘mesorectal’ plane, which is immediately
outside the mesorectal fascia, practically the con-
tinuation of the plane obtained during posterior
and lateral dissection thus leaving entire
Denonvilliers’ fascia on the anterior organs [35,
36]. This plane is however difficult to follow and
not always readily visible. Additionally, if we
have a low, anteriorly placed tumour, oncologi-
cally it might not be safe to go so close to the
243
malignant tissue. Another possible approach is
‘close rectal plane’, which lies immediately on
the rectal musculature. This is not an anatomical
plane, and the dissection through the tissue of
anterior mesorectum is often bloody and difficult
since numerous blood vessels cross this plane
before entering the rectal wall [5]. In the mind of
most colorectal surgeons today, when we are
talking about malignant disease, there is little
doubt that this approach is not safe. Still, some
[35, 36] advocate that in cases of posteriorly
placed non-advanced tumours, we can use this
approach since the risk of damaging vegetative
nerves is minimal and oncological safety is satis-
factory since there is little risk of tumour spread-
ing in this area of mesorectum. Then again, there
is data that if we, even in cases of benign disease,
use close rectal dissection plane, we do not
improve vegetative nerve preservation, compared
to TME [34].
24.5.6 Mobilization of the Most Caudal
Portion of the Mesorectum
The anatomical relations of the most distal
mesorectum and surrounding organs are often very
difficult to visualize and comprehend because
the traction, counter-traction and upward traction
distorts actual situation. However, a clear percep-
tion of the cone-like pelvic floor together with
globular bilobed mesorectum is necessary in
order to preserve delicate nerve structures placed
around it.
It is well established that there is higher per-
centage of sexual and urinary dysfunction after
APR compared to sphincter-saving procedures
[13, 37, 63, 67]. This can be explained by the
damage to the neurovascular bundles and cavern-
ous nerves during the perineal act of the proce-
dure. It is often difficult to enter the correct plane,
especially anteriorly where all delicate structures
are placed. Additional difficulty presents an effort
not to ‘cone in’ the specimen and start the perineal
phase early enough. In order to avoid this, some
authors advocate ‘face down’ position and plac-
ing the clips on the most distal vegetative nerve
structures visible during the abdominal phase of
244
Fig. 24.15 Specimen after
correctly performed TME with
coloured mesorectal fascia and
cross sections to inspect
specimen quality
the operation. Removing of the coccyx which is a
standard part of this procedure enables the sur-
geon to properly visualize neurovascular bundles
and posterior part of the prostate, much easier
than during standard abdominoperineal proce-
dure [3, 22, 64, 65].
Additionally, in cases of very low rectal carci-
nomas when performing APR or intersphincteric
resection, it is rather difficult to find a correct
plane or one can encounter venous bleeding in
the area of anorectum passing levator hiatus.
Some anatomical studies showed that this can be
explained by existence of rectourethral muscle
Z. Krivokapic and I. Dimitrijevic
[60]. This is a smooth muscle situated in the
levator hiatus, in the place where Denonvilliers’
fascia ends. It is connected to the external anal
sphincter, as well as with muscle layer of the rec-
tum. Cavernous nerves pierce this structure, and
it is surrounded with tortuous anorectal veins. If
we tend to dissect through this structure during
the perineal act of APR, we can transect cavern-
ous nerves and mentioned veins can be damaged.
Afterwards, in an attempt to control the bleeding,
we can also do the damage to vegetative nerves
during the mass ligation of the anterior structures
(Fig. 24.15).
24 How Is Nerve-Sparing Surgery Well Performed?
24.5.7 Laparoscopic TME in the Context
of Nerve Identification and
Preservation
In recent years, laparoscopic approach is gaining
ground in this field of surgery. It would be logical
that better magnification facilitates the visualiza-
tion and identification of nerve structures within
the pelvis. A number of studies addressed the
issue of postoperative sexual and urinary func-
tion after laparoscopic TME. A few authors
achieved excellent results, of only 6% urinary
and sexual dysfunction [26]. Still, majority state
that postoperative urinary and sexual function
was worse compared to open technique. Quah
and co-workers noted significant percentage of
sexual and urinary deficits especially in patients
with low and bulky rectal tumours [50]. To the
similar conclusion came Rullier in a study that
dealt only with distally placed rectal carcinomas
[51]. This can be explained by insufficient trac-
tion and counter-traction in the areas where this
manoeuvre helps us to differentiate minute nerve
structures placed between thicker fascial struc-
tures and organs. Also, present laparoscopic
instruments do not allow adequate manipulation
in the distal parts of the pelvis. Mentioned trend
confirms multicentre randomized trial that com-
pared short-term results of open versus laparo-
scopic-assisted surgery for colorectal cancer.
Severe change in sexual function was noted in
41% of patients in the laparoscopic group com-
pared to 26% of patients in the open group. These
data are to be taken with caution, because groups
were not well matched due to higher number of
TME procedures in laparoscopic group caused
by inability to correctly locate the tumour and
perform transection. Additionally, conversions
took place due to excessive bleeding that pre-
vented visualization of nerve structures [12].
Conclusion
Functional deficits after rectal cancer surgery
are still present in significant percentage of
cases. The way to improve functional results is
to advance surgical training and knowledge in
this area. Exact identification of all pelvic veg-
etative nerve structures is not always possible
245
even with expert rectal surgeons. Thus, in
words of Mr. Bill Heald, ‘specimen-oriented
surgery’ may be the clue. If we obtain a perfect
specimen, with no defects of extra tissue on the
mesorectal fascia, it can be expected, with a
certain amount of certainty, that functional
result of the operation will be favourable. A
careful TME with proper reconstruction is a
complex procedure, and with careful nerve
preservation takes 3–5 h according to the
patient’s and tumour characteristics; a conven-
tional APE was often completed in 1 h.
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 Is Laparoscopic Rectal Surgery
the Gold Standard? 25
David Jayne and Laeeq Khan

Contents 25.1 Introduction

25.1 Introduction ................................................ 249
The last two decades have seen a gradual but
25.2 Evolution of Laparoscopic
Colorectal Surgery ..................................... 250
shifting enthusiasm for laparoscopic general sur-
gery. A better appreciation of the laparoscopic
25.3 Future Developments in Laparoscopic
approach with adaptation of open surgical tech-
Rectal Cancer Surgery ............................... 255
niques and improvements in instrumentation has
References ............................................................... 255 helped this transition. A realization of the patient
benefits that can be gained from laparoscopic sur-
gery in benign disease has increased interest in its
application in cancer surgery. Colorectal surgery,
by its very nature, is challenging for the laparo-
scopic approach, involving multi-quadrant dis-
section, manipulation of bulky tissues and a
dependency on assistants for retraction. In rectal
cancer, the situation is made more difficult by the
confines of the bony pelvis, the proximity of vital
structures and the precision demanded to achieve
complete tumour resection with an intact
mesorectum and preservation of pelvic auto-
nomic nerves. For colon cancer, there has been a
D. Jayne (*)
John Goligher Colorectal Unit, general recognition for some time that laparo-
University of Leeds, scopic surgery can produce oncological outcomes
Leeds, UK at least equivalent to open surgery, but with the
Level 7 Clinical Sciences Building, added advantages of quicker patient recovery and
St James’s University Hospital, shorter hospital stay. In this chapter, we will
Leeds LS9 7TF, UK
explore the evolution of laparoscopic colorectal
e-mail: d.g.jayne@leeds.ac.uk
surgery, with particular emphasis on rectal can-
L. Khan
cer, and ask whether laparoscopic rectal cancer
John Goligher Colorectal Unit,
Leeds Teaching Hospitals NHS Trust, surgery has acquired the same acceptance as
Leeds, UK colon cancer to become the new ‘gold standard’.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 249

DOI 10.1007/978-3-642-25005-7_25, © Springer-Verlag Berlin Heidelberg, 2012
250
25.2 Evolution of Laparoscopic
Colorectal Surgery
Laparoscopic techniques were introduced into
colorectal practice in the late 1980s, and it
soon became apparent that the benefits seen in
other general surgical procedures (cholecystec-
tomy, fundoplication, hernia repair, etc.) could
also be achieved following colectomy. Several
studies reported improved outcomes compared
to conventional open surgery with reduced
post-operative pain, less analgesic requirement,
shorter hospital stay, better cosmesis and quicker
return to normal function. A desire to replicate
these outcomes in cancer patients led to the
uptake of laparoscopic techniques for colon and,
subsequently, rectal cancer. Initial clinical enthu-
siasm, supported to some extent by commercial
drivers, was tempered by unease expressed by
many that the widespread adoption of hitherto
untested laparoscopic techniques might risk
inferior oncological outcomes. This view found
support with the reporting of high rates of port-
site metastases and led to calls for laparoscopic
cancer surgery to be abandoned. The response
from national bodies at that time was reserved,
with the National Institute for Clinical Excellence
in the UK advising ‘For colorectal cancer, open
rather than laparoscopic resection should be the
preferred surgical procedure’, and ‘Laparoscopic
surgery should only be undertaken for colorectal
cancer as part of a randomised controlled clini-
cal trial’ [1].
In response, several groups took the initiative
to undertake randomized controlled trials to
address the safety and efficacy of laparoscopic
surgery for colorectal cancer. The first group to
report their findings was the Clinical Outcomes
of Surgical Therapy Study Group (COST),
who published the results of a US multi-centre
randomized controlled trial (RCT) comparing
laparoscopic and open surgery for colon cancer
in 2004 [2]. In their study of 872 patients recruited
from 48 centres and followed up for a median of
4.4 years, they showed benefits for laparoscopic-
assisted surgery, including less analgesic require-
ment, shorter hospital stay (lap, 5 days; open,
6 days; p < 0.001) and similar morbidity, mortality
D. Jayne and L. Khan
and readmission rates. There was no difference in
survival outcomes, with local recurrence rates of
16% and 18% and overall 3-year survival rates of
86% and 85% for the laparoscopic-assisted and
open groups, respectively. Importantly, recurrence
rates in surgical wounds were 1% for both the
laparoscopic-assisted and open groups, indicating
that abdominal wound metastasis was not peculiar
to the laparoscopic approach.
The first randomized control trial to address
the issue of rectal cancer was the UK MRC-
CLASICC (Conventional versus Laparoscopic-
Assisted Surgery for Colorectal Cancer) trial [3].
Recruitment commenced in 1996 and, over the
next 6 years, accumulated a total of 794 patients
from 32 surgeons across the UK, randomized on
a 2:1 basis in favour of the laparoscopic approach.
Of the 794 patients, 381 had rectal cancer, with
252 randomized to laparoscopic-assisted surgery
either by anterior resection or abdominoperineal
excision. Uniquely at that time, the CLASICC
trial included a centralized review of pathology
that included assessment of the quality of surgi-
cal plane. The early results from CLASICC were
reported in 2005 and showed no significant dif-
ference in the short-term end points, which
included morbidity, mortality and pathological
surrogate markers for oncological outcome. Time
to resumption of normal diet and time to first
bowel movement were no different between
laparoscopic-assisted and open arms, but length
of hospital stay was 2 days shorter in the laparo-
scopic group, and for successful laparoscopic
resections, hospital stay was 3 days shorter than
for converted cases. Pathological analysis was
generally encouraging with high-quality surgery
observed in both laparoscopic-assisted and open
arms, similar longitudinal resection margins and
lymph node yields comparable to the best results
reported in other large series (median lymph node
yield: 12 (IQR: 8–17) lap vs. 13.5 (IQR: 8–19)
open). However, the data did raise two important
concerns. In patients undergoing laparoscopic-
assisted anterior resection, there was a higher rate
of circumferential resection margin involvement
(CRM positivity: 12% lap vs. 6% open, 95% CI:
−2.1%, 14.4%, p = 0.19), although this was not
statistically significant. The other issue was a
25 Is Laparoscopic Rectal Surgery the Gold Standard? 251

1.0

0.9

0.8

0.7
Proportion surviving

0.6 Open

0.5 Laparoscopic

Conversion
0.4

0.3

0.2
P–value for Longronk test = 0.0017
0.1
P–value for Wilcoxon test = 0.0004
0.0
0 6 12 18 24 30 36

Number at risk Time from randomisation (months)

Open 280 255 234 210 195 178 163
Lap 343 323 307 290 266 244 217
Con 144 120 110 98 92 88 79

Fig. 25.1 Three-year overall survival by actual procedure: open, laparoscopic and converted. A significant difference
is observed with worse outcomes for the converted patients

high conversion rate of 34% for laparoscopic-
assisted surgery. This was a reflection of both a
learning curve effect, as demonstrated by a fall
in conversion rates throughout the study period,
but also the increased technical difficulty associ-
ated with rectal cancer as compared to colon
cancer surgery. The main reasons for conversion
were excessive tumour fixity or uncertainty of
tumour clearance (41% of conversions), obesity
(26%), anatomical uncertainty (21%) and inac-
cessibility of tumour (20%). Importantly, conver-
sion appeared to have a negative influence on
early post-operative morbidity and mortality,
with a significant difference in those patients who
were converted and those who completed a lap-
aroscopic resection (Fig. 25.1). Three factors
were subsequently found to be independent pre-
dictors for conversion to open surgery, namely,
body mass index, male sex and extent of tumour
spread from the muscularis mucosa [4]. Thus, the
obese male patient with a locally advanced rectal
cancer is much less likely to undergo a successful
laparoscopic operation, a fi nding that makes
intuitive sense.
Disappointingly, CLASICC failed to show
any difference in quality of life between laparo-
scopic-assisted and open surgery, a feature that
has also been reported in other trials. The reason
for this is unclear as the earlier recovery demon-
strated by shorter hospital stays is a consistent
finding. It is perhaps related to the quality of life
instruments used, which may be insensitive to
subtle differences in physical and psychological
well-being, or to the timing of the investigation,
missing early benefits which occur within the
first 2 weeks following surgery. One area of con-
cern, specifically related to laparoscopic rectal
cancer surgery, has been the reporting of impaired
post-operative bladder and sexual function [5].
Although this is a recognized complication fol-
lowing open surgery, with reported rates of blad-
der and sexual dysfunction between 0–15% and
10–35%, respectively, the incidence of sexual
dysfunction following laparoscopic surgery in
252
male patients in particular seems to be increased
(overall sexual function: difference lap vs. open
−11.18; 95% CI: −10.94, −0.74; p = 0.063).
Adequate training in laparoscopic total mesorec-
tal excision with attention to preservation of the
pelvic autonomic nerves is therefore important if
optimal functional outcomes are to be achieved.
In 2006, NICE updated its guidance for lap-
aroscopic colorectal cancer surgery, stating ‘lap-
aroscopic (including laparoscopically assisted)
resection is recommended as an alternative to
open resection for individuals with colorectal can-
cer in whom both laparoscopic and open surgery
are considered suitable’ [6]. This statement was
qualified by the caveat that ‘laparoscopic colorec-
tal surgery should be performed only by surgeons
who have completed appropriate training in the
technique and who perform this procedure often
enough to maintain competence’. The NICE state-
ment failed to distinguish between laparoscopic
surgery for colon and rectal cancer, with the two
entities being merged under the same ‘colorectal’
umbrella. This was taken by many surgeons as a
‘green light’ to progress with laparoscopic rectal
cancer surgery and indeed was informally embod-
ied into the 2006 Department of Health initiative
to promote laparoscopic colorectal cancer surgery
in the UK [7].
A summary of the published data on laparo-
scopic rectal cancer surgery up to 2006 is shown
in Table 25.1 and includes a total of 44 studies.
The conversion rates range from 0% to 33% with
only two studies reporting rates greater than 20%.
Three studies reported a significant reduction in
morbidity with the laparoscopic approach, with
11 studies showing no significant difference; no
study reported an increase in morbidity from
laparoscopic surgery. The duration of surgery
was consistently longer with the laparoscopic
approach, with no obvious differences in short-
term survival measures.
Two meta-analyses specifically addressing
laparoscopic rectal cancer surgery have attempted
to collate the available evidence. In 2006, Aziz
et al. reported their meta-analysis, including 20
studies and 2,071 patients with 44% undergoing
laparoscopic and 56% open surgery for rectal
D. Jayne and L. Khan
cancer [8]. Significant benefits in favour of the
laparoscopic approach were found for time to
stomal function, first bowel movement, feeding
solids and length of hospital stay. Additional
benefit was found for those undergoing laparo-
scopic abdominoperineal resection in terms of
decreased post-operative analgesic requirements
and less wound infections. No difference was
found between the laparoscopic and open groups
in extent of oncological clearance. In 2008,
Anderson et al. reported a meta-analysis focusing
on the oncological outcomes following laparo-
scopic rectal cancer resection [9]. Over 3,000
patients from 24 studies were compared for dif-
ferences in oncological outcome between laparo-
scopic and open surgery. At 3 years, no significant
difference was seen between the two treatment
groups: radial margin positivity was 5% (lap)
versus 8% (open), overall survival was 76% (lap)
versus 69% (open) and local recurrence was 7%
(lap) versus 8% (open). The authors concluded
that there was no oncological difference between
laparoscopic and open resections for primary rec-
tal cancer. This conclusion accords with the
recently published long-term results from the
CLASICC trial [10]. Initial concerns regarding
the higher rate of circumferential margin involve-
ment following laparoscopic anterior resection
failed to translate into a difference in local recur-
rence, overall survival or disease-free survival.
The most recent evidence to emerge is that
from the COLOR II study. This multi-centre study
involving 30 centres across the world and recruit-
ing 1,103 rectal cancer patients over the period
2004–2010 has recently presented its initial results
at the European Society of Surgical Oncology
(ESSO) conference in Stockholm in 2011 (unpub-
lished). Patients undergoing laparoscopic rectal
cancer resection had less blood loss but longer
operations than those undergoing open surgery.
Conversion to open operation was still observed
in 16.4% of cases. There was no difference in the
circumferential or longitudinal resection margins
or the number of retrieved lymph nodes. However,
laparoscopic surgery had the advantage of earlier
recovery of bowel function, less analgesic require-
ment and shorter hospital stay.
Table 25.1 Published series for laparoscopic rectal cancer surgery
25

Procedure 5-year Duration of Lymph nodes Hospital stay Local

n (%) Conversion survival (%) Morbidity (%) surgery (min) removed (days) recurrence (%) Follow-up
Study author Year Lap Open LAR APR rate (%) Lap Open Lap Open Lap Open Lap Open Lap Open Lap Open (months)
Barlehner 2005 194 – 92 8 1 88 – 20 – 174 – 25 – – – 4 – 46
Bretagnol 2005 144 – 100 0 14 – – 34 – – – 10 – – – 1.4 – 18
Dulucq 2005 218 – 100 0 12 67 – 25.6 – 138 – 25 – 6 – 6.8 – 57
Yamamoto 2005 31 – 100 0 0 – – – – 267 – – – 8 – – – –
Delgado 2004 220 – 80 19 20 – – 26 – 179 – 14 – 6.8 – 5.4 – 18
Law 2004 102 – 86.7 13.3 3 75 – 27 – 202 – 8 – 11.9 – – – 36
Leung 2004 203 200 100 0 23.2 75.3 78.3 19.7 22.5 190* 144* 11.1 12.1 8.2* 8.7* – – 49.2
Wu 2004 18 18 61 39 0 – – 5.6* 27.8* 189* 146* 7.8 8.2 – – – – –
Zhou 2004 82 89 100 0 – – – 6.1* 12.4* 120* 106* – – 8.1* 13.3* – – –
Anthube 2003 101 334 77 23 11 – – 11 25 218 218 12* 22* 14 20 – – –
Feliciotti 2003 81 43 74 26 12.3 62.5 60.6 – – – – 10.3 9.8 – 20.8 20.8 – 43.8
Morino 2003 100 – 100 0 12 63 – 36 – 250 – 12.8 – 16.6 – 4.2 – 45.7
Is Laparoscopic Rectal Surgery the Gold Standard?

Rullier 2003 32 – 100 0 9 – – 31 – 420 – 10 – 9 – 0 – –

Tsang 2003 44 – 100 0 0 – – 38.6 – 180 – – – 8 – 4.5 – 15
Baker 2002 28 61 – 100 8 – – – – – – 6 5 13* 18* 33 33 36
Chen 2002 8 – 100 0 – – – 25 – 210 – – – 13 – 0 – 14
Lezoche 2002 42 26 71 29 19 – – – – – – – – – 24.1 25 – 49.4
Pietrabissa 2002 16 – 100 0 0 – – 19 – 233 – – – 6.6 – – – –
Poulin 2002 80 – 65 35 18.25 72.1 – 40 – 200 – – – 6.5 – 3.75 – 31
Reis Neto 2002 32 – 100 0 3.1 – – – – – – 12.3 – 5.12 – 3.12 – 14
Scheibach 2002 308 – 60.8 39.2 6.1 – – 37.6 – 208 – 13 – – – 6.6 – 24.8
Yamamoto 2002 70 – 94.3 5.7 2.9 92.1 – 18.6 – – – 14.3 – 8 – 2.8 – 23
Chung 2001 5 – 100 0 – – – – – 208 – – – 10.6 – 0 – 13
Hartley 2001 21 22 71 29 33 – – 28.5 18 180* 125* 6 7 13.5 15 5 4.5 38
Hu 2001 20 25 100 0 0 – – 0 8 227* 146* – – 18.3 18 – – 8
Pasupathy 2001 11 22 100 0 – – – 18 9 97.5 90 – – 6.5 6 – – 12
Vithiananthan 2001 27 17 100 0 – – – 26* 28* – – 12 11 6.1* 11.1* – – –
Leung 2000 25 34 0 100 8 – – 48 62 215* 166* 10 12 16* 25.5* – – 28.3
Kockerling 2000 119 – 0 100 3.4 – – 34.4 – 226 – – – 21.6 – 9.5 – 16
253

(continued)
Table 25.1 (continued)
254

Procedure 5-year Duration of Lymph nodes Hospital stay Local

n (%) Conversion survival (%) Morbidity (%) surgery (min) removed (days) recurrence (%) Follow-up
Study author Year Lap Open LAR APR rate (%) Lap Open Lap Open Lap Open Lap Open Lap Open Lap Open (months)
Schiedeck 2000 259 – 60.6 39.4 6.6 – – 26.4 – 235 – 12.1 – 14.4 – 1.9 – 26
Wantanabe 2000 7 – 100 0 – – – – – 280– – – – – – – – –
450
Weiser 2000 21 – – – – – – – – 300 – – – – – 0 – –
Fleshmann 1999 42 152 100 0 21 54 60 76 50 234 209 9.7 7.9 7.4* 11.9* 21.4 – 55
Idani 1999 5 – 100 0 – – – 20 – 177 – – – 16.2 – 0 – 3
Schwander 1999 32 32 59.3 40.7 0 – – 31.3 31.3 281* 209* 13 13 15.3* 21.9* 3.1 0 32
Bokey 1997 10 – 2 8 – – – – – 342 – 10 – 16 – 0 – 29
Bruch 1997 20 – 30 70 10 – – – – 315 – 12 – 16 – 5 – 46
Goh 1997 20 20 100 100 0 – – – 90 73 20 19 5 5.5 – – 38
Ramos 1997 18 18 0 100 10 – – 44 66 229 208 11.1 7.8 7.4* 12.9* 6 17 20
Seow–Choen 1997 16 11 0 100 – – – – – – – 10 10 6.5* 8* 0 0 12 vs. 33
Wu 1997 14 – 0 100 14 – – 42 – 240 – – – – – 7 – 17
Darzi 1995 12 16 0 100 0 – – 33 56 195 104 9.5 6 11 17.5 – – –
Larach 1993 4 – 0 100 20 – – 40 – 323 – 4.75 – 12.3 – – – –
Tate 1993 11 14 100 0 – – – 45 29 205* 123* 10 13 12.3 14.3 – – –
Lap laparoscopic, LAR laparoscopic anterior resection, APR abdominoperineal resection
Data not reported marked with ‘–’. Values marked with ‘*’ were reported as being statistically significant (p £ 0.05)
D. Jayne and L. Khan
25 Is Laparoscopic Rectal Surgery the Gold Standard?
Two other trials of laparoscopic rectal cancer
surgery are currently still in progress: a US trial
of laparoscopic-assisted versus open resection
for rectal cancer (ClinicalTrials.gov Identifier:
NCT00726622) and the Australasian A La Cart
trial (www.australiancancertrials.gov.au). The
results of these trials are eagerly awaited.
25.3 Future Developments
in Laparoscopic Rectal
Cancer Surgery
The last two decades have seen much improve-
ment in laparoscopic techniques and technol-
ogy. The use of modified approaches, such as
medial-to-lateral dissection, combined with bet-
ter instrumentation has facilitated the perfor-
mance of laparoscopic surgery, making it safer
and encouraging wider adoption. It is likely that
this trend will continue, driven by increased
patient demand, pressure from commercial
sources and greater acceptance by health-care
providers. Current estimates of penetration for
laparoscopic colorectal surgery are around
30% in the UK and Australasia in 2011, so there
remains the potential for considerable growth,
particularly in rectal cancer. However, there
is probably a ceiling beyond which laparo-
scopic surgery in its current form cannot extend.
This is governed by the inherent limitations of
laparoscopy, namely, the fulcrum effect of the
ports, two-dimensional imaging and limited
instrumentation. The introduction of robotics
into surgical practice offers to overcome at least
some of these limitations. Currently, there is
only one commercially available robotic system,
the da Vinci® surgical system (Intuitive Surgical,
Sunnyvale, CA). Several personal series and one
small randomized controlled trial testify to the
safety and feasibility of robotic-assisted rectal
cancer surgery, with initial indications of short-
term benefit with low conversion rates to open
surgery and reduced rates of circumferential
resection margin involvement. Whether these
indicators bear out in future long-term studies
and randomized controlled trials, and whether
255
they can be clinically justified in terms of
cost-effectiveness given the capital cost of the
robotic system, remains to be seen. But, there is
an inevitability that new technologies and tech-
niques will continue to be incorporated into
laparoscopic practice, enabling current bound-
aries to be surpassed with benefits to both
patients and health-care providers.
Conclusion
Is laparoscopic surgery the current gold stan-
dard? Based on the current available evidence,
it is still probably a little too premature to make
such a bold statement. A gold standard is a
level that can be attained by the majority. It
cannot be judged on the results of personal
series from enthusiastic centres of excellence,
but rather we must await the results of the large
randomized clinical trials that are still yet to
report. But there is no reason to believe that
they will show any real difference from that
already observed, i.e. the laparoscopic approach
for rectal cancer produces oncological results
similar to open surgery, but with the advantage
of better short-term outcomes. If this proves to
be the case, then it will be safe to conclude that
a new gold standard for rectal cancer surgery
has been established.
References
1. National Centre for Clinical Excellence (2000)
Technology Appraisal Guidance No 17: Guidance on
the use of laparoscopic surgery for colorectal cancer.
www.nice.org.uk. Accessed March 2012
2. The Clinical Outcomes of Surgical Therapy Study
Group (2004) A comparison of laparoscopically
assisted and open colectomy for colon cancer. N Engl
J Med 350:2050–2059
3. Guillou PJ, Quirke P, Thorpe H, Walker J, Jayne DG,
Smith AMH, Heath RM, Brown JM, for the MRC
CLASICC trial group (2005) Short-term end-points
of conventional versus laparoscopic-assisted surgery
in patients with colorectal cancer (MRC CLASICC
trial): multicentre, randomised controlled trial. Lancet
365:1718–1726
4. Thorpe H, Jayne DG, Guillou PJ, Quirke P, Copeland J,
Brown JM, for the Medical Research Council Con-
ventional versus Laparoscopic-Assisted Surgery in
Colorectal Cancer Trial Group (2008) Patient factors
256
influencing conversion from laparoscopically assisted
to open surgery for colorectal cancer. Br J Surg 95:
199–205
5. Jayne DG, Brown JM, Thorpe H, Walker J, Quirke P,
Guiloou PJ (2005) Bladder and sexual function fol-
lowing resection for rectal cancer in a randomized
clinical trial of laparoscopic versus open technique.
Br J Surg 92:1124–1132
6. (2006) NICE Technology Appraisal Guidance
105: Laparoscopic surgery for colorectal cancer.
www.nice.org.uk/TA105. Accessed March 2012
7. LAPCO: National Training Programme in Laparo-
scopic Colorectal Surgery. www.lapco.nhs.uk. Acces-
sed March 2012
D. Jayne and L. Khan
8. Aziz O, Constantinides V, Tekkis PP, Athanasiou T,
Purkayatha S, Paraskeva P, Darzi AW, Heriot AG
(2006) Laparoscopic versus open surgery for rectal
cancer: a meta-analysis. Ann Surg Oncol 13:413–424
9. Anderson C, Uman G, Pigazzi A (2008) Oncological
outcomes of laparoscopic surgery for rectal cancer: a
systematic review and meta-analysis of the literature.
J Cancer Surg 34:1135–1142
10. Jayne DG, Thorpe H, Copeland J, Quirke P, Brown
JM, Guillou PJ (2010) Five year follow-up of the
Medical Research Council CLASICC trial of laparo-
scopically assisted versus open surgery for colorectal
cancer. Br J Surg 97:1638–1645
 Is a Diverting Stoma Always
Necessary for a Low Anterior 26
Resection of a Rectal Cancer?

Geerard L. Beets

Contents 26.1 Background: Anastomotic

26.1 Background: Leakage
Anastomotic Leakage ................................... 257
26.2 Rationale and Evidence
The main surgical complication of a low anterior
for Diverting Stoma ...................................... 258 resection of the rectum with a low anastomosis is
pelvic sepsis. Pelvic sepsis is most often due to
26.3 Routine or Selective
Diverting Stoma? .......................................... 258 poor anastomotic healing and can have different
manifestations: anastomotic leakage, presacral
26.4 Ileostomy or Colostomy? .............................. 258
abscess, rectovaginal fistula, etc. The symptoms
References ................................................................. 259 can occur as early as a couple of days after the
operation or as late as several weeks after dis-
charge, and the severity can range from minor to
life threatening. The reported incidence of pelvic
sepsis is variable, ranging from 2% to as high as
39%. A large part of this variability is most likely
due to a lack of standardized definition, a lack of
standardized reporting and inclusion of different
types of patients and operations. The newly
formed International Study Group of Rectal
Cancer recently proposed a simple and practical
grading system that includes abscesses near the
anastomosis and that is focused on the conse-
quences for the patient [1]. Grade A is basically
an asymptomatic leak, Grade B a leak or abscess
that can be managed without relaparotomy and
Grade C one that requires a relaparotomy. The
reported mortality after a leakage/pelvic sepsis
ranges from 2% to 24%, with the variability most
likely related to the previously mentioned lack of
standardization in definition. Additional to the
G.L. Beets immediate morbidity and mortality, there are
Department of Surgery,
also long-term functional consequences for the
Maastricht University Medical Centre,
Maastricht, The Netherlands patient. Many patients will suffer from poor
e-mail: g.beets@mumc.nl anorectal function due to ongoing low-grade

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 257

DOI 10.1007/978-3-642-25005-7_26, © Springer-Verlag Berlin Heidelberg 2012
258
infection or pelvic fibrosis, and a substantial num-
ber of patients will end up with some form of
definitive colostomy. Some older reports also sug-
gested a worse long-term oncological outcome,
with a higher rate of local recurrence. A recent
study on pooled data from five large randomized
trials on rectal cancer showed a 5-year overall sur-
vival rate of 66% in patients who had an anasto-
motic leak, compared to 74% in patients who had
an uneventful anastomotic healing [2]. This 8%
long-term survival difference was, however, not
due to a higher relapse rate but to a higher mortal-
ity in the postoperative period.
26.2 Rationale and Evidence
for Diverting Stoma
A diverting loop ileostomy or colostomy has long
been used by surgeons with the intention to both
reduce the incidence and the severity of anasto-
motic leakage. By decreasing the faecal load at
the site of the leakage, it is hoped that less bacte-
rial contamination results in a less severe clinical
course or even in a complete subclinical leakage.
A recent Cochrane review of six randomized tri-
als evaluating a routine diverting ileostomy or
colostomy versus no diverting stoma after low
anterior resection for rectal cancer shows a two-
thirds reduction of clinical leak rate from 19.6%
to 6.3% and a three-fourths reduction in urgent
reoperation rate from 16.1% to 3.9% [3]. The
reduction in mortality was not significant. Two
earlier reviews that included also nonrandomized
series basically had come to the same conclusion,
with the additional finding that in the nonran-
domized series, the mortality was significantly
lower in the patients who were given a diverting
stoma [4, 5].
26.3 Routine or Selective Diverting
Stoma?
Although a temporary diverting stoma dimin-
ishes the incidence and severity of anastomotic
leakage, it does require a second procedure for
G.L. Beets
reversal and has its own morbidity in the form of
stoma-related complications and the decreased
quality of life that is inherently associated with a
stoma. A valid question is, therefore, whether all
patients should be given a diverting stoma or only
those at high risk for an anastomotic problem.
Many papers have described risk factors for anas-
tomotic leakage, and the most important risk fac-
tor without question is the height of the
anastomosis: the lower the anastomosis, the
higher the chance of leakage. When the entire
mesorectum is removed in a total mesorectal
excision, the anastomosis is always very low and,
therefore, at increased risk for leakage. Other risk
factors that are often mentioned in reports are
peripheral vascular disease, male patients, meta-
static or advanced disease, smoking, low albu-
min, diabetes, high age, blood transfusion and
technical mishaps during the operation. It is
unclear whether or not neoadjuvant therapy
increases the risk for anastomotic problems. In
the large randomized trials, the rate of anasto-
motic leakage is generally the same in patients
with and without neoadjuvant therapy, while
multivariate analyses of large cohort series some-
times suggest an increased risk. In practice, it
remains difficult to predict which group of
patients is at risk, and given the evidence on the
routine use of a diverting stoma in the random-
ized trials, it seems prudent to use a routine rather
than a selective policy.
26.4 Ileostomy or Colostomy?
An additional question is which diverting stoma
is to be preferred, ileostomy or colostomy. This is
a topic for discussion among colorectal surgeons,
and strong personal opinions are often expressed.
It is more a matter of personal choice than a
choice based on evidence. There is a Cochrane
review of five randomized trials and a meta-anal-
ysis that adds seven observational studies. In the
Cochrane review, the only significant finding is a
higher rate of stoma prolapse with a colostomy
[6]. The other meta-analysis confirms this and
also found an increased risk of infectious
26 Is a Diverting Stoma Always Necessary for a Low Anterior Resection of a Rectal Cancer?
complications with the colostomy [7]. The ileos-
tomy, on the other hand, was more associated
with dehydration and late intestinal obstruction
after closure. There is, therefore, no compelling
evidence to prefer one to the other.
Conclusion
A diverting stoma decreases both the incidence
and the consequences of anastomotic failure
after a low anterior resection for rectal cancer.
The available evidence supports a routine
diverting stoma for all patients rather than a
selective approach. There is no solid evidence
favouring either ileostomy or colostomy.
References
1. Rahbari NN, Weitz J, Hohenberger W et al (2010)
Definition and grading of anastomotic leakage follow-
ing anterior resection of the rectum: a proposal by the
259
International Study Group of Rectal Cancer. Surgery
147(3):339–351
2. den Dulk M, Marijnen CA, Collette L et al (2009)
Multicentre analysis of oncological and survival
outcomes following anastomotic leakage after rectal
cancer surgery. Br J Surg 96(9):1066–1075
3. Montedori A, Cirocchi R, Farinella E, Sciannameo F,
Abraha I (2010) Covering ileo- or colostomy in
anterior resection for rectal carcinoma. Cochrane
Database Syst Rev 12(5):CD006878
4. Huser N, Michalski CW, Erkan M et al (2008)
Systematic review and meta-analysis of the role of
defunctioning stoma in low rectal cancer surgery. Ann
Surg 248(1):52–60
5. Tan WS, Tang CL, Shi L, Eu KW (2009) Meta-
analysis of defunctioning stomas in low anterior
resection for rectal cancer. Br J Surg 96(5):462–472
6. Guenaga KF, Lustosa SA, Saad SS, Saconato H, Matos
D (2007) Ileostomy or colostomy for temporary
decompression of colorectal anastomosis. Cochrane
Database Syst Rev (1):CD004647
7. Rondelli F, Reboldi P, Rulli A et al (2009) Loop ileo-
stomy versus loop colostomy for fecal diversion after
colorectal or coloanal anastomosis: a meta-analysis.
Int J Colorectal Dis 24(5):479–488
 Will Extralevator Abdominoperineal
Excision Become the New Gold 27
Standard?

Ingrid Martijnse, Nicholas West, Phil Quirke,

Richard Heald, Cornelius J.H. van de Velde,
and Harm Rutten

Contents 27.6 How Should Surgery in the Supine

Position Be Performed? ............................ 265
27.1 Does a Patient After Abdominoperineal
Excision Have a Worse Prognosis 27.7 What Are the Advantages and Pitfalls
Than After (Low) of Performing an Extralevator APE
Anterior Resection? .................................. 261 in the Prone Position? ............................... 266

27.2 How Does Preoperative Imaging Result 27.8 How Should Surgery in the Prone
in Better Surgery?..................................... 262 Position Be Performed? ............................ 267

27.3 Is Selective Use of Preoperative 27.9 Which Surgical Technique Should Be

Radio(−Chemo)Therapy Effective Performed? ................................................ 267
in Patients with Low Rectal Cancer? ...... 262 27.10 What Role Do Pathologists Play
27.4 How to Decide on Which Surgical in the Treatment of Rectal
Procedure to Perform? ............................. 263 Cancer Surgery? ....................................... 269

27.5 What Are the Advantages and 27.11 Is a New Standard for
Limitations of Performing an Extralevator Abdominoperineal Excision
APE in the Supine Position? .................... 264 Necessary? ................................................. 270

References ............................................................... 271

I. Martijnse
Colorectal Surgery, Catharina Hospital Eindhoven,
The Netherlands
N. West • P. Quirke
Pathology and Tumour Biology, Leeds Institute of
27.1 Does a Patient After
Molecular Medicine, University of Leeds, Abdominoperineal Excision
United Kingdom Have a Worse Prognosis Than
R. Heald After (Low) Anterior Resection?
Pelican Cancer Foundation, Basingstoke,
United Kingdom The introduction of TME surgery led to the real-
C.J.H. van de Velde ization that the quality of surgery significantly
Colorectal Surgery, Leiden University Medical Center, influences the prognosis of rectal cancer patients
Leiden, The Netherlands
and has resulted in a huge improvement in sur-
H. Rutten (*) gery and its outcome [1]. On a population-based
Colorectal Surgery, Catharina Hospital Eindhoven,
level, an improved survival of more than 10%
Michelangelolaan 2 5623EJ Eindhoven,
The Netherlands was realized in countries adopting TME as the
e-mail: harm.rutten@cze.nl standard surgical technique [2, 3].

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 261

DOI 10.1007/978-3-642-25005-7_27, © Springer-Verlag Berlin Heidelberg, 2012
262
However, patients with low rectal cancer did
not seem to benefit from this improvement [4, 5].
After more than 20 years of widespread TME
surgery, the difference between patients undergo-
ing APE or AR still persists [6–8]. It has been
demonstrated that it is not the tumor biology
which heralds a worse outcome, but an increased
number of positive circumferential resection
margins (CRM) and iatrogenic perforations, both
of which are avoidable and confer a poor progno-
sis [9–13]. The latest analysis of the Dutch TME
study shows that when radical surgery is per-
formed, APE patients share the same prognosis
as AR patients [14].
Besides the change in surgical approach, the
introduction of TME surgery has been associated
with improved preoperative staging, proper selec-
tion of preoperative treatment, and feedback on
the quality of surgery by pathologists.
27.2 How Does Preoperative
Imaging Result in Better
Surgery?
At the beginning of the TME era during which
the anatomical planes became increasingly
important for surgery, preoperative MRI was not
widely used for local staging. Current guidelines
are based on patients often operated upon with
only a rectal examination and endoscopy. Older
CT scans could not differentiate between the cru-
cial anatomical layers and the mesorectal fat in
the lower pelvis and therefore did not help the
visualization of the margins of the tumor [15,
16]. Ultrasound, which was often used, discrimi-
nates between the bowel layers and helps to diag-
nose the earlier T stages, but performs poorly in
the identification of the mesorectal fascia [17,
18]. Furthermore, ultrasound is not reproducible
and does not provide the surgeon with a roadmap
for surgery in anything other than pT1 cases, nor
does it help to identify patients that require pre-
operative treatment. The introduction of MRI as
the principal local staging imaging technique
made it possible to identify the mesorectal fascia
and the relation of the tumor to this fascia.
Patients at risk for an irradical resection can be
identified, and treatment plans could be adjusted.
I. Martijnse et al.
[19, 20] In the MERCURY study, MRI could pre-
dict extramural tumor spread to within 0.5 mm
[21]. Even the current multislice CT does not
have the spatial resolution that is needed in low
rectal cancer staging [22, 23]. Even though some
question the use of MRI in low rectal cancer [24],
most physicians agree that MRI is superior to
define the surgical planes for resection both in
mid and low rectal cancer [25–27]. In modern
rectal cancer surgery, it is essential that the sur-
geon knows whether the tumor infiltrates through
the muscularis propria in the anal canal to avoid
an intersphincteric resection, which would lead
to an involved or threatened circumferential
margin. In locally advanced rectal cancer in the
lower rectum, MRI imaging to evaluate the rela-
tion of the tumor to the levator muscles is equally
important for the surgical planning, and the com-
parison of MRI before and after neoadjuvant
treatment may lead to different surgical options
[28]. A recent manuscript demonstrated that MRI
was able to predict long-term outcome in low
rectal tumors, proving its validity in staging in
rectal cancer [29].
27.3 Is Selective Use of Preoperative
Radio(−Chemo)Therapy
Effective in Patients with Low
Rectal Cancer?
In the Dutch TME study, preoperative short
course radiotherapy did not seem effective in
reducing local recurrence rates in patients under-
going APE. Preoperative radiotherapy did not
compensate for positive CRM, which were found
in 30% of low rectal cancer patients [30].
However, the latest update did show that patients
with negative margins after APE responded well
to preoperative short course irradiation [14].
Similar findings apply to the MRC CR07 study
which showed higher positive CRM rates after
APE than AR and subsequent worse outcome
[31]. Reassuring are the recent findings from a
Swedish population-based study, which also sug-
gested an effect of preoperative radiotherapy on
lower rectal cancers and APE patients [32].
Better local staging helps to identify patients
at risk for CRM. Long-course preoperative
27 Will Extralevator Abdominoperineal Excision Become the New Gold Standard?
Fig. 27.1 Cylindrical
extralevator specimen from
William Ernest Miles and
two important steps in the left
lateral semiprone perineal
phase: above, wide approach
with cutting of the coccyx;
below, everted specimen
and dissection of the ventral
side [41]
radio(−chemo)therapy may downstage and
downsize the tumor, which in combination with
a better delineation of the tumor in the lower pel-
vis facilitates a better surgical resection [33–40].
Most national guidelines have therefore included
(radio-)chemotherapy in the preoperative treat-
ment plan of rectal cancer. In a recent Dutch
audit, the number of CRM + margins in 2009 and
2010 was reduced to 14% for tumors between 0
and 5 cm from the anal verge (paper submitted).
Therefore, selective use of preoperative treat-
ment can influence T stage and circumferential
resection margins which are the most important
prognostic variables in low rectal cancer and sub-
sequently result in improved outcome.
27.4 How to Decide on Which
Surgical Procedure to Perform?
Being well informed after local imaging and pos-
sibly after downstaging the tumor, the surgical
resection remains the most important prognostic
factor with at least a 1 mm margin. Currently there
is a debate on which surgical technique is the best,
263
comparable to the discussion in the 1930s. In
those days, Miles was a proponent of a one-stage
abdominoperineal resection. Starting with the
abdominal phase, the pelvic colon was mobilized
and a stoma created. After closure of the abdo-
men, the patient was turned into a right-sided
semiprone position. A generous incision was
made encircling the anus and extending up to the
sacrococcygeal joint. The coccyx was then
transected and the levator muscle cut near its lat-
eral insertion. This access allowed eversion of the
rectosigmoid and dissection of the remaining con-
nections between the internal genital organs and
the rectum (Fig. 27.1). The ischiorectal fat was
removed en bloc with the specimen. Dealing
mostly with advanced cases, he had noticed tumor
deposits in the ischiorectal fat and, as we know
now, mistook these for lymph nodes [41]. Gabriel
was a proponent of the perineal first approach.
This approach also included a wide resection dur-
ing the perineal phase as was custom in those days
for a perineal-only approach [42]. The patient was
placed in prone position and turned for the abdom-
inal phase [43, 44]. However, despite the efforts
of these pioneers of wide perineal dissection, the
264
Lloyd-Davies method of operating patients with
the legs in stirrups in supine position which
allowed a simultaneous perineal and abdominal
access by two teams became the most popular
technique and was used worldwide [45].
In those days, every procedure started as an
exploratory laparotomy with no preoperative infor-
mation on local tumor infiltration or metastatic dis-
ease in contrast to the modern colorectal surgeon.
The resection is now based on the anatomical rela-
tionship of the tumor to its surroundings. The basis
for a successful resection is a detailed understand-
ing of the basic pelvic anatomy, not only to achieve
a radical resection, but also to avoid unnecessary
damage to the patient [46, 47].
In TME surgery, the plane of dissection fol-
lows the mesorectal fascia, which envelopes the
mesorectum and terminates at the pelvic floor,
where visceral and parietal fascia blend and con-
tinue in the intersphincteric plane in close contact
with the internal anal sphincter. For low rectal
cancer, an intersphincteric resection is only safe
in early stage rectal cancer. Due to the reduction
in mesorectal fat at the height of the levators and
its disappearance in the sphincter area, smaller
degrees of tumor spread will result in increased
numbers of positive margins (Fig. 27.2). Fortu-
nately, the levator muscles act like a bowl in
which the distal rectum and mesorectum com-
fortably rest. Therefore, distal tumors extending
into and beyond the mesorectal fascia or inter-
sphincteric plane can be removed en bloc with
the external sphincter-levator muscle complex
via an extralevator approach [48, 49].
27.5 What Are the Advantages
and Limitations of Performing
an Extralevator APE
in the Supine Position?
Performing APE in the classical supine position is
preferred by several surgeons since it avoids the
unpopular and time-consuming turning of the
patient during the operation. Furthermore, the onco-
logical advantage of the supine position is that the
tumor can be assessed from both the abdominal and
perineal incision. Especially in locally advanced
I. Martijnse et al.
Fig. 27.2 Illustrating that at different levels of the rectum,
small extensions of tumor into the mesorectum have different
consequences for the resection. The red arrow indicates the
extralevator route, necessary to avoid breaching of the plane
between distal mesorectum and parietal fascia
tumors with fixation to pelvic structures and where
the pelvic floor muscles are often infiltrated by
tumor, this bimodal approach can be very useful.
A disadvantage of this technique would be the
limited surgical space and reportedly difficult expo-
sure of the anatomical structures. However, with
the correct positioning of the patient and placing
the legs in movable stirrups with individual drap-
ing, a wide range of movement and good exposure
of the perineum is obtainable. Lloyd-Davies origi-
nally described the position [45]. This is also the
position when APE surgery is compared to AR.
The perineal phase is commenced after finishing
the abdominal dissection. One reason for explain-
ing the inferior results is that the dissection along
the mesorectal fascia is carried too far down, that is,
up to the level where mesorectal and parietal fascia
blend. The protecting levator muscles are dissected
from the distal mesorectum exposing the tumor
resulting in typical waist formation at the tumor
site with consequently a higher chance on positive
margins. Waist formation was clearly illustrated by
Salerno by comparing the pathology specimens
and the preoperative MRI. Tumors near the
27 Will Extralevator Abdominoperineal Excision Become the New Gold Standard?
Fig. 27.3 Illustrating how digital hooking of the levator
may lead to waist formation of the specimen [51]
junction of the mesorectal and visceral fascia were
at highest risk for an incomplete resection [25, 50].
The perineal dissection technique, as demonstrated
in Fig. 27.3, further leads to waist formation. Many
surgeons were taught to hook their finger behind
the levator and then transect the levator from poste-
rior to anterior. However, by hooking the finger as
shown, the levator is incised too medially and is
bluntly mobilized from the tumor leading to tumor
exposure and positive margins [51].
These pitfalls can be avoided. Several authors
have shown that they can avoid a high positive
CRM rate and demonstrate that quality of sur-
gery, or rather the lack of quality, does not need
to be a prognostic variable [52–56].
27.6 How Should Surgery
in the Supine Position
Be Performed?
Surgery can commence with either the abdomi-
nal or the perineal phase; however, it is advised
to start with the perineal phase first when there is
265
no suspicion of intra-abdominal metastases. It is
important to realize that this phase is the most
important one. Good visualization, focused and
standardized dissection, and knowledge of the
pelvic anatomy are essential to achieve radical
surgery.
The legs are lifted and the perineal stage
commences. An incision is made around the
anus at the transition of anal to perineal skin.
The external sphincter is covered by the deep
perineal fascia, which is a continuation of the
fascia covering the levator ani muscles. On the
lateral sides, this fascia can easily be followed
until the lateral attachment of the levator ani to
the arcuate line. At this lateral level, the levator
ani can be cut, exposing the mesorectum
(Fig. 27.4). Dorsally, the anococcygeal ligament
must be transected. At this point, a U-shaped
incision is used to transect the levator ani mus-
cle. Dissection of the anterior aspect of the
external sphincter must not be started until this
point of the procedure is reached. The interfas-
cial presacral space can be opened up as far as
the level of S3. The perineal body in male and
female is the central tendinous anchor of the
anterior perineal muscles. Posterior of the
perineal body, the urogenital diaphragm muscles
and the anterior levator muscles blend with the
extension of the mesorectal fascia and outer lon-
gitudinal layer of the muscularis propria of the
rectum and constitute the anterior part of the
anal sphincter. This segment lacks an inter-
sphincteric dissection plane. Dissecting from
the deep anterior levator ani muscles toward the
more superficial perineal body, first the pub-
orectalis is cut at the level of the prostate or cer-
vix where Denonvilliers’ fascia is identified and
removed with the specimen (Fig. 27.4). The dis-
section continues by transecting the muscle
attachments to the longitudinal layer of the mus-
cularis propria. Pushing the anteriorly fixed rec-
tal specimen down facilitates this dissection.
This results in tension on these muscle bundles
and avoids a false route leading into the rectum.
Unlike laterodorsally, there is no true dissection
plane on the anterior side. The anterior part of
the external sphincter is tightly connected to the
perineal body and the urogenital diaphragm by
266
Fig. 27.4 Perineal phase in supine position
intertwining muscular bundles anchoring the
anus in the perineum. At this point, the abdomi-
nal phase can commence.
Mobilization of the rectosigmoid and lympho-
vascular pedicle occurs according to the princi-
ples of TME. During dissection, the mesorectal
fascia is left intact and care is taken to avoid dam-
age to the hypogastric nerve. On the anterior side
when the peritoneal flap is opened and
Denonvillier’s fascia is followed until the vesi-
cles, sufficient dissection has been performed.
On the posterior side, the correct plane is easy to
find. The final phase is a sharp dissection of the
remaining attachments through the abdominal
phase and removal of the specimen.
When the surgeon does decide to start with the
abdominal phase prior to perineal dissection, the
dissection must be limited. To avoid coning in
toward the tumor, dissection should stop above
the levator muscles after which the perineal phase
I. Martijnse et al.
can start. The focus on the perineal dissection
and its standardization by beginning perineal dis-
section laterally and dorsally leaving the levator
muscle on the specimen and then transecting the
anterior attachments in the described technique
helps to avoid iatrogenic tumor perforations and
involved margins.
27.7 What Are the Advantages
and Pitfalls of Performing
an Extralevator APE
in the Prone Position?
Extralevator excision in the prone position is
becoming increasingly popular. It is believed
that this technique is easier to learn and that in
this position superior exposure of the anatomy
can be achieved. Furthermore, it has been
hypothesized that the blood loss is less due to the
27 Will Extralevator Abdominoperineal Excision Become the New Gold Standard?
higher position of the venous plexus. However,
there is very limited evidence to support either
the prone or the supine approach. They both have
their advantages and disadvantages, and the
experience of the surgeon on either technique
will determine the outcome. Standardization of
technique is considered to be the most important
factor for radical surgery.
The main limitation of this technique is that a
bimodal approach is not possible. In advanced
tumors, it is impossible to assess and dissect from
both the abdominal and the perineal phase.
27.8 How Should Surgery
in the Prone Position
Be Performed?
Surgery always commences with the abdominal
phase with either a conventional laparotomy or a
laparoscopic approach. Inspection of the abdo-
men is performed, and the sigmoid and the rec-
tum are mobilized along the TME planes. Once
the hypogastric nerves and the vesicles have been
identified on the anterior side, dissection from the
abdominal phase must be stopped. The incisions
are sutured and the patient is turned into prone
position. Care must be taken in positioning the
patient to avoid pressure ulcers.
Normal surgical preparation with disinfection
and covering with sterile drapes is performed.
A rhombus-like incision is made around the anal
skin and extended proximally above the sacro-
coccygeal joint (Fig. 27.5). With diathermy, dis-
section is performed on the lateral sides, and
limited dissection is performed on the anterior
(perineal body) and the posterior side. Posteriorly,
dissection is performed behind the os coccygis in
order to remove this “en bloc” with the rectal
specimen to create extra space. Lateral dissection
takes place along the levator ani muscle until the
mesorectum is reached. On the posterior side, the
dissection plane is relatively easy to find, and this
is followed until the mesorectum is encountered.
The specimen is then everted from the perineal
wound. Care must be taken to avoid tearing the
specimen by pulling with too much force. This
creates more space and a better view on the chal-
267
lenging anterior side where the specimen remains
attached. By rolling the specimen from side to
side and applying gentle traction on the speci-
men, the dissection continues along the correct
plane. From the perineal body onward, the con-
necting muscles are divided. The most challeng-
ing point during the dissection is the 2 cm after
cutting these connecting muscles before reaching
the prostate. This is where the ureter is in very
close proximity to the plane of dissection, and
care must be taken to avoid taking a false route.
The hypogastric nerves are identified and spared.
In front of the prostate, the plane of the fascia of
Denonvillier should be followed until the vesicles
are reached. The specimen can now be removed.
Excision of the ischiorectal fat is only neces-
sary in exceptional cases, for example, when
tumor infiltrates through the external sphincter-
levator muscle funnel or when the tumor has per-
forated or fistulated. Furthermore, when the anal
skin is involved, a more radical excision should
be considered. More ischioanal fat should then be
removed to achieve radical excision of the tumor,
but the surgical technique remains the same.
27.9 Which Surgical Technique
Should Be Performed?
Recently the Cleveland Clinic published a man-
uscript comparing the supine and prone posi-
tion. The type of surgery chosen was based on
the preference of the surgeon, which resulted in
two comparable groups with similar patient
characteristics. CRM involvement rates were
14.6% and 9%, and the iatrogenic rectal perfo-
ration rates were 2.4% and 4.6% for supine APE
and prone APE, respectively, and no difference
in oncological outcome was noticed [54].
Recently a paper from a Dutch referral center
for advanced rectal cancer showed that stan-
dardization of the supine APE technique resulted
in a perforation rate of 0.7% and CRM + (<1 mm)
of 14%, keeping in mind that two-thirds of their
patients had T4 tumors [56]. Excellent results
have also been demonstrated with the prone
APE technique [48, 57].
268
Fig. 27.5 Perineal phase in the prone position
An increased number of radical resections are
achieved by the en bloc removal of the distal rec-
tum and levator muscles, therefore highlighting
the need of an extralevator excision more than
the positioning of the patient. A recent review
of more extended perineal resections showed
that the rate of inadvertent bowel perforation
and the rate of CRM involvement for extended
I. Martijnse et al.
vs. standard APE were 4.1% vs. 10.4% (relative
risk reduction 60.6%, p = 0.004) and 9.6% vs.
15.4% (relative risk reduction 37.7%, p = 0.022),
respectively. The local recurrence rate was 6.6%
vs. 11.9% (relative risk reduction 44.5%, p < 0.001)
for the two groups [58].
These results set a new standard for APE.
Colorectal surgeons have to know their own results
27 Will Extralevator Abdominoperineal Excision Become the New Gold Standard? 269

Table 27.1 Three-point grading system for assessment of the plane of mesorectal dissection in TME/anterior resection
specimens for rectal cancer
Grade Short description Long description
Mesorectal plane Good surgery Intact smooth mesorectal surface with only minor irregularities. Any
defects must be no deeper than 5 mm. No coning of the specimen
distally. Smooth CRM on slicing
Intramesorectal plane Moderate surgery Moderate bulk to mesorectum but irregularity of the mesorectal
surface. Moderate distal coning. Muscularis propria not visible with
the exception of levator insertion. Moderate irregularity of CRM
Muscularis propria plane Poor surgery Little bulk to mesorectum with defects down onto the muscularis
propria and/or very irregular CRM. Includes infraperitoneal
perforations

and should strive that the quality of surgery is no
longer a prognostic factor.
Secondary endpoints such as nerve preserva-
tion and other postoperative complications will
eventually make the difference besides the ability
to teach and implement the principle of extraleva-
tor resection.
27.10 What Role Do Pathologists Play
in the Treatment of Rectal
Cancer Surgery?
Pathologists have played an essential role in the
improvement in rectal cancer outcomes. Besides
tissue diagnosis and staging, the pathologist plays
a central role in the multidisciplinary approach.
They give feedback on preoperative radiology
and the quality of surgery. Furthermore, an evalu-
ation of the effectiveness of the administered
neoadjuvant therapy can be made. This facilitates
internal auditing as well as a continued education
and improvement of all members of the MDT.
The involvement of the CRM has proven to be
the most important prognostic factor for local
recurrence within the pelvis. Pathologic feedback
during the era of TME has resulted in a significant
increase of radical resections [59–61].
A three-point grading system of the macro-
scopic specimen was developed for the MRC
CLASSIC and CR07 trials and has been shown to
predict CRM involvement [31]. The recom-
mended mesorectal grading system is described
in Table 27.1.
This grading system reports the plane of
dissection besides the CRM status and perfora-
tion rates. It helps to improve the quality of the
specimen produced by giving an objective feed-
back to the surgeon.
Within the Dutch TME and the UK CR07
trial, 57% and 52% of the anterior resection spec-
imens were graded as being in the mesorectal
plane, 19% and 34% were intramesorectal, and
24% and 13% were muscularis propria, respec-
tively [31, 62]. The CR07 trial showed that
through pathological feedback, CRM involvement
rates fell to as low as 8%.
For abdominoperineal excision, an addi-
tional grading system for the quality of the dis-
section around the sphincters has been
developed. Besides grading the mesorectum,
the plane of dissection around the anal sphinc-
ters should also be graded as shown in
Table 27.2. The levator ani muscle is left
attached to the mesorectum during extralevator
excision that creates a more cylindrical speci-
men. The extra tissue around the tumor results
in an increased radical resection rate and less
perforations of the tumor (see Fig. 27.6). The
assessment of the plane of APE surgery is based
on similar principles like the anterior resec-
tions. Any defects must be no deeper than
5 mm, and there should be no waisting of the
specimen. The APE specimens should receive
two grades, namely one grade for the sphincter
and another for the mesorectum.
In order for the pathologist to evaluate and audit
the quality of the MDT, their reports must be stan-
dardized. The specimen should be examined and
graded accordingly before fixation and slicing.
Photographs of the specimen provide a permanent
record of the surgical quality. However, the macro-
270 I. Martijnse et al.

Table 27.2 Sphincter/levator grading according to the plane of surgery as assessed at the time of pathological dissec-
tion noting the presence and extent of any defects below the mesorectum in the sphincter/levator muscle complex
Grade Short description Long description
Extralevator plane Good surgery The specimen has a cylindrical shape due to the presence of levator
muscle removed en bloc with the mesorectum and sphincters. Any
defects must be no deeper than 5 mm. No waisting of the
specimen. Smooth CRM on slicing
Sphincteric plane Moderate surgery The specimen is waisting, and the CRM in this region is formed by
the surface of the sphincter muscles which have been removed intact
Intramuscular/submucosal Poor surgery The specimen is waisted and includes deviations into the sphincter
plane/perforation muscle complex, submucosa, and complete perforations

a b c

Fig. 27.6 Three APE specimens including an extralevator APE (a), a standard APE with classic surgical waist (b), and
a standard APE with a large anterior perforation (c)

scopic evaluation of this assessment of the quality 27.11 Is a New Standard

of surgery is rarely performed. The grading system
is essential to improve surgery and to evaluate the
preoperative radiology and the effectiveness of
(neo)adjuvant treatment in relation to the predicted
circumferential tumour margin.
The identification of the importance and
frequency of CRM involvement, the importance
of planes of surgery, and the identification of the
major issues involved in APE for low rectal can-
cer enables surgeons to evaluate the quality of
surgical dissection and radiologists to audit the
accuracy of preoperative staging. It can be con-
cluded that surgery has developed throughout the
years by looking at the grades in previous studies,
but there is still room for improvement.
for Abdominoperineal
Excision Necessary?
A recent update of the Dutch Surgical Colorectal
Audit of 2009 and 2010, covering more than 90%
of APE surgery in the Netherlands, demonstrated
that 14% of patients had a positive CRM (<1 mm)
which was significantly higher than after AR
(11%) (data presented at ECCO Stockholm).
This percentage of margin involvement has
significantly improved when compared to the
30% of positive CRM in APE patients in the
Dutch TME study, which accrued patients
between 1995 and 2000 [62]. From these recent
figures, it may be concluded that the awareness of
27 Will Extralevator Abdominoperineal Excision Become the New Gold Standard?
a poor outcome has led to a decrease in margin
involvement and iatrogenic perforations, both
important indicators of surgical quality.
Besides the increased awareness for radical
surgery, preoperative planning with MRI, MDT
meetings, and the selective use of neoadjuvant
treatment is common practice.
With improved imaging, the area at risk has
been made visible which has resulted in patient
tailored treatment protocols. When evaluating all
these changes in the modern treatment of low
rectal cancer, the question whether a drastic
change in surgical technique is necessary could
be fighting a ghost from the past. Unfortunately,
the excellent recent reviews of How and Stelzner
still do not give a clear answer since most studies
are a little bit dated and without the present stan-
dard of staging, neoadjuvant treatment, and feed-
back from the pathologist [6, 58].
Several papers support the more conventional
approach, among them Messenger who states
that a meticulous executed conventional tech-
nique, taking care not to breach the interface
between tumor and levators also yields excellent
results [55].
Even more, the number of patients requiring
APE has diminished over the years, resulting in
the selection of more advanced tumors that
undergo an APE compared to AR. Most impor-
tantly, extralevator excision whether in supine or
prone position is not the debate; the real issue is
how to identify those patients who require preop-
erative treatment and subsequently a more
extended resection [7].
No rectal cancer patient should be allowed to
go to surgery without being discussed in a MDT
where preoperative treatment, MRI TNM stage,
but also the exact anatomical landmarks which
dictate type and extent of surgery, have been dis-
cussed. The extralevator resection principle
should be part of the standard surgical armamen-
tarium. Finally, the role of the pathologist is to
give continuous feedback on the decisions made
during that MDT and how well the procedure
was executed. In the end, tumor perforations and
involved radial margins should become very rare
and cease to be a prognostic factor.
271
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 Which Patients Do Benefit from
Extended Resections in Case of 28
Locally Advanced Rectal Cancer?

Ralph L. Dudink, Miranda Kusters, and Harm Rutten

Contents 28.1 Case Presentation

28.1 Case Presentation .......................................... 275
A male patient, 69 years of age, consulted his
28.2 What Is the Role of Neo-adjuvant
(Chemo-)radiation in the Treatment
general physician for rectal bleeding and an altered
of Primary Unresectable Patients? .............. 276 defecation pattern. At digital rectal examination,
a fixed tumour was found, and, subsequently, the
28.3 Which Extended Resections
Are Necessary to Achieve patient was referred for further evaluation.
a Radical Resection? ..................................... 278 At the start of a complete workup, the colonos-
28.4 Abdominosacral Resection ........................... 278 copy confirms the suspected malignancy of the
rectum at 7 and 8 cm in length, covering the com-
28.5 Results ............................................................ 280
plete circumference. Pathology examination of
28.6 Results After Pelvic Exenteration ................ 281 the biopsies taken reveals an adenocarcinoma.
28.7 Is an Extra Intra-operative Boost A chest and abdominal CT scan do not show
of Irradiation Effective to Reduce signs of distant metastasis. An MRI of the pelvis
the Chance of Local Recurrence? ................ 283 demonstrates a large tumour of 10 cm invading
28.8 Is There a Role for the Use the mesorectal fascia and infiltrating into the
of the Cellsaver in Locally prostate and bladder (see Fig. 28.1).
Advanced and Locally
This patient with a T4 tumour infiltrating
Recurrent Rectal Cancer Surgery? ............. 284
through the mesorectal fascia into the surround-
28.9 Which Patients Do Benefit ing structures requires an extended resection out-
from Extended Resections
in Case of Advanced Cancer? ...................... 285 side the involved mesorectal fascia. The subject
of this chapter are those patients in whom the nor-
References ................................................................. 287
mal anatomical relations are disturbed by tumour
growth. In those patients, often deemed unresect-
able for cure at presentation, a tailored multidisci-
plinary approach is necessary. Several key topics
regarding such treatment will be discussed.
First, the question will be raised if the expec-
tations from neo-adjuvant chemoradiotherapy are
different in these patients when compared to less
locally advanced cases. Another topic will be if
R.L. Dudink • M. Kusters • H. Rutten (*)
extended resections including the sacrum or the
Department of Colorectal Surgery, Catharina Hospital,
Eindhoven, The Netherlands pelvic organs are worthwhile in offering the
e-mail: harm.rutten@cze.nl patient a chance for cure. The third question will

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 275

DOI 10.1007/978-3-642-25005-7_28, © Springer-Verlag Berlin Heidelberg 2012
276
a b
Fig. 28.1 (a) Sagittal T2-weighted MRI slice showing a T4
locally advanced rectal carcinoma which invades the blad-
der (black arrowhead) and the prostate (grey arrowhead).
deal with the usefulness of an intra-operative
radiation boost to further increase the therapeutic
ratio of the radiotherapy component. And last,
some thoughts about the use of the cellsaver to
deal with the blood loss, which may be excessive
in these extended procedures, and its effect on
oncological outcome.
28.2 What Is the Role of Neo-
adjuvant (Chemo-)radiation
in the Treatment of Primary
Unresectable Patients?
To improve downstaging and downsizing of the
tumour, neo-adjuvant treatment became the stan-
dard of treatment in locally advanced rectal cancer.
Several studies have shown that neo-adjuvant long-
course treatment schemes can effectively downstage
and downsize tumours, which subsequently results
in a better oncological outcome [1–3]. However,
there is no uniform definition of which scheme
should be used. The addition of a 5-FU-based radi-
ation sensitizer resulted in increased downstaging,
compared to radiotherapy alone [1, 4, 5]. Since the
introduction of 5-FU agents, bolus injections have
been replaced by continuous 5-FU administration
[6–9]. Several studies, including two randomized
R.L. Dudink et al.
(b) Transverse T2-weighted MRI slice showing the same
tumour, which invades the bladder (black arrowhead). The
mesorectal fascia is invaded as well (white arrowhead)
multicentre studies, have shown that the addition
of oxaliplatin enhanced the downstaging effect of
the 5-FU-based neo-adjuvant treatment scheme
[10–16]. However, this increased downstaging
did not always result in a better oncological
outcome [15, 16].
Nonetheless, the question is not: does neo-adju-
vant CRT work, but does intensified CRT work?
The Catharina Hospital Eindhoven is a national
referral centre for primary unresectable T4 tumours.
During the period of 1994–2010, a total of 504
consecutive patients without metastatic disease
received four different neo-adjuvant treatment
schemes. In the early years, long-course radio-
therapy was the standard of treatment (RTH).
However, in 1998, the EORTC 22921 study intro-
duced neo-adjuvant chemoradiation, consisting
of a bolus injection of 350 mg/m2 5-FU and leu-
covorin 20 mg/m2 (5-FU bolus) [1]. In 2003, the
CORE study commenced. It introduced two new
principles: (1) continuous administration of 5-FU
in the form of 825 mg/m2 capecitabine twice daily
and (2) the addition of a second radiation sensi-
tizer in the form of 50 mg/m2 oxaliplatin once
weekly (CORE) [17]. In 2005, however, Dutch
guidelines changed and long-course radiotherapy
with capecitabine twice daily only became the
standard of treatment (CAP). Therefore, selection
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 277

1.0 Multivariable cox regression 0.10

Multivariable cox regression local
Cancer specific survival curve
recurrence rate

0.08
0.9

Local recurrence rate

Cum survival

0.06
Radicality of resection
0.8 R0
R1
0.04
Type of neo-adjuvant
0.7 treatment
RTH 0.02
5FUBolus
CAP
CORE 0.00
0.6

0 12 24 36 46 60 72 84 96 0 20 40 60 80
Months Months

Fig. 28.2 The left figure shows cancer-specific survival for the different neo-adjuvant treatment schemes after multi-
variate Cox regression analysis. The right figure shows the importance of radical resection

of the different neo-adjuvant treatment schemes ratios were 3.78, 2.73, 1.34 and 1.00 (p = 0.001)
was based on hospital policy rather than tumour and for downstaging 0.31, 0.44, 0.30 and 1.00
characteristics. All patients received 45–50.5 Gy (p < 0.0001). Toxicity rates between the CAP and
preoperative radiotherapy in 25 fractions and the CORE regimens did not differ significantly.
minimum waiting period was 8 weeks. In multivariate Cox regression analysis, the
The RTH, 5-FU bolus, CAP and CORE neo- CORE regimen remained significantly better for
adjuvant treatment schemes were administered to cancer-specific survival [18] (Fig. 28.2).
106, 137, 106 and 155 patients, respectively. R1 In previous papers, it has been shown that nega-
resections (tumour cells at the resection margin) tive circumferential resection margins remain of
occurred in 24.5%, 13.1%, 9.4% and 6.5% and paramount importance [19, 20]. Radical resec-
CRM+ (defined as tumour within 1 mm of the tion is a strong prognostic outcome parameter
circumferential resection margin) in 31.1%, [21–23]. Downstaging and downsizing before
21.9%, 14.2% and 8.4% after the different preop- surgery are essential to avoid positive resec-
erative treatments. No response to neo-adjuvant tion margins. Furthermore, pathologic complete
treatment was found in 57%, 44%, 49% and 27%, response (ypCR) is an important prognostic fac-
respectively. Pathologic complete response rates tor. Pathologic complete response rates vary in
(pCR) were 4.7%, 13.1%, 7.5% and 14.2%. In literature, ranging from 0% to 40% for combined
these challenging patients, intensification of the capecitabine and oxaliplatin regimens [13]. Any
neo-adjuvant treatment did lead to a more pro- response to neo-adjuvant treatment may also be an
nounced effect on downstaging. This could also important factor [3, 24–27].
be turned into a better oncological outcome. The interim results of two recent studies show
After multivariate regression analysis for R1, contradictory results [28, 29]. The NSABP04
CRM+ and any downstaging, the different neo- found no increase in pathologic complete response
adjuvant treatment schemes had a highly significant and an increase in toxicity when oxaliplatin was
impact on oncological outcome. Odds ratios for added. The CAO/ARO/AIO04, however, did find
having R1 resection for the RTH, 5-FU bolus, an increased pathologic complete response rate,
CAP and CORE group were 3.74, 1.94, 1.14 and without higher toxicity. The ACCORD study
1.00 (p = 0.003). For CRM+ resection, the odds showed an increase in radicality of resection and
278
tumour response but could not translate this into
better oncological outcome [16]. However, the
Italian randomized STAR-01 phase III trial did
find a significant reduction of distant metastases
when oxaliplatin was added [15]. For a definitive
answer, the long-term results of these trials should
be awaited. However, these trials were multi-
institutional and the definition of locally advanced
did not refer to unresectable T4 patients. In pri-
mary unresectable patients, intensified RCT may
lead to better downstaging and hence increase the
chance for a radical resection [18].
28.3 Which Extended Resections
Are Necessary to Achieve
a Radical Resection?
The main goal in curative surgery for both locally
advanced and locally recurrent rectal cancer is
achieving a radical resection. Radicality of the
resection is the most important factor which
influences local control and oncological outcome
in general.
Only a thorough preoperative staging can
provide the road map for a potential surgical
intervention. A CT thorax/abdomen is neces-
sary to exclude distant metastatic disease, as
most patients with distant metastases will be no
candidate for an extended resection (maybe with
the exception of those with limited resectable
metastases). An MRI scan of the pelvis is manda-
tory, as delineation of tumour infiltration into the
soft perirectal tissues is a prerequisite for surgi-
cal planning. Furthermore, the MRI is the best
modality for local restaging to evaluate response
to neo-adjuvant treatment, which may lead to
less extended surgery. A PET scan may be help-
ful, especially in locally recurrent cases to dif-
ferentiate between benign and malignant lesions.
Preoperative discussion in a multidisciplinary
team with experience in the treatment of locally
advanced and locally recurrent rectal cancer is
essential to reach optimal treatment plans.
Tumours which invade the sacrum or the sacral
neural roots at the level of S2 or higher or tumours
which extend more than a few centimetres beyond
the infrapiriform foramen will often be considered
R.L. Dudink et al.
truly unresectable. Intraperitoneally metastasized
tumours have always been an exclusion criterion
for curative surgery for a long time, but nowa-
days, there are curative options with HIPEC
(hyperthermic intraperitoneal chemotherapy).
The location of the tumour influences the
radicality of the resection and the consequent
local recurrence rate. In both primary and locally
recurrent rectal cancer, it has been shown that the
more dorsally the tumour is located, the higher
the irradical resection rate and local (re)recur-
rence rate is [30–34]. In these patients, often the
only chance for a radical resection is a sacral
resection.
Central and anterior tumours might require
resection of the bladder and the prostate or semi-
nal vesicles in males and the vagina and uterus in
females. Lateral and dorsolateral tumours are
sometimes fixed to the pelvic sidewalls and can
cause major bleeding during surgery.
28.4 Abdominosacral Resection
A locally advanced dorsal rectal carcinoma and
especially the dorsal recurrent rectal carcinomas
constitute a specific problem. When the dorsal
resection margin is threatened or involved, it is
not possible to achieve a radical resection with-
out an en bloc resection of the pelvic floor mus-
cles, os coccyx or partial resection of the sacrum
(see Fig. 28.3).
The sacral approach in prone position was
originally described more than 100 years ago [35].
The combined abdominal and sacral approach
was known as abdominosacral extirpation of the
rectum [35]. In its posterior approach, a much
wider resection is possible. The anterior approach
follows the rules of TME. Oncological outcome,
as described in literature, is disappointing. Five-
year overall survival rates vary between 15% and
30%, and local control rate varies between 15%
and 40% [36–38].
Indications for abdominosacral resection
(ASR) typically include invasion of the sacrum or
coccyx, tumour growth into the pelvic floor mus-
cles or lateral pelvic sidewalls and the need for a
wider dorsal resection in order to achieve a radical
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer?
a b
Fig. 28.3 (a) Sagittal T2-weighted MRI slice showing a pri-
mary locally advanced rectal carcinoma which invades the
sacrum and spinal canal (black arrowheads). (b) Transverse
a b
Fig. 28.4 (a) Sagittal view of a wide field en bloc resec-
tion, indicated by the dotted line, of tumours with primar-
ily latero-dorsal spread (Reproduced with permission [3])
(b) Posterior line of transection (Reproduced with permis-
resection margin (Fig. 28.4) [39]. Double J-ureter
catheters can be helpful to identify and subse-
quently avoid damage to the ureters. An ASR
starts with the abdominal phase. If the tumour
growth only extends dorsally without threatening
the ventral plane, TME rules can be followed, e.g.
the ventral dissection plane will be guided by
Denonvilliers’ fascia. If the tumour invades ven-
tral structures, e.g. the prostate in the male or the
uterus in the female, a more extended resection in
the ventral plane is also necessary. The resection of
the mid sacrum S2–S4 can be best done in prone
position, as the venous plexus collapses in prone
position and blood loss will be much less. Distal
279
T2-weighted MRI slice showing the same tumour. The
mesorectal fascia is clearly visible (black arrowheads) and is
invaded by the tumour (white arrowhead)
c
sion [3]). (c) The dotted line shows the horseshoe-shaped
circumferential margin at risk for irradical resection
(Reproduced with permission [3])
sacral resections can also be performed in litho-
tomy position. It is very helpful to identify the
level of sacral transection by full thickness cut
through the sacrum with the osteotome (chisel)
during the abdominal phase. The level of transec-
tion should be distal to the dura mater, which proj-
ects as far as mid S2 [36, 39].
Before the patient is turned in prone position,
the abdominal phase can be completed by closure
of the abdomen and placement of the stoma.
A midline incision is made across the sacrum
from L5 to the perineum. The incision is contin-
ued around the anus or scar after abdomino-
perineal extirpation (APE). The gluteus muscles
280 R.L. Dudink et al.

insertion from the sacrum, the sacrospinous and Table 28.1 Operative details of patients undergoing
sacrotuberous ligaments are transected near the sacral resection for T4 primary rectal cancer (n = 25) or
locally recurrent rectal cancer (n = 70).
sacrum. The levator ani muscles are in direct view
after this step and can be transected near their lat- T4-LARC LRRC
eral insertion at the obturator internus. The osteot- No. of patients No. of patients
Level of transection
omy performed during the abdominal phase may
S2 1 10
now be palpated. The sacral resection is com-
S3 5 33
pleted by a cut with the osteotome in the dorsal
S4 1 15
cortical wall in a V shape, in order to avoid dam- More distally 18 12
age to the sacral roots. The surgical specimen can Bladder resection
now be removed en bloc. An omentoplasty, which Total with ileal 20 9
has been mobilized during the abdominal phase conduit
can be used to fill the presacral space before clo- Partial 17 1
sure. In most cases, when no skin is lost, wound Urinary bladder flap 3 2
closure is primary. However, in case of a large right
defect, a myocutaneous rectus abdominis flap Urinary bladder flap 10 2
left
(VRAM) is rotated in the perineal wound [39].
Uterus extirpation
Other authors have advocated the use of (bio-) Without adnexes 0 1
meshes to create a new pelvic floor [40–42]. In With adnexes 40 16
our experience, prosthetic material was never nec- Vagina
essary for closure of the perineo-sacral defect. Posterior wall w/o 26 14
reconstruction
With reconstruction 10 5
28.5 Results Prostate
Capsule 29 6
From 1994 until 2010, we identified a group of Prostatectomy 3 6
369 patients who underwent surgery for T4 pri- Seminal vesicles
mary rectal cancer and 301 patients who under- Right only 13 0
Left only 8 0
went surgery for locally recurrent rectal cancer.
Both 20 3
For the analysis of the results, patients with peri-
Reconstruction
toneal carcinomatosis or distant metastasis were
VRAM w/o skin 11 4
excluded, resulting in a total of 336 patients with
VRAM with 14 7
T4-LARC (188 male, 147 female; mean age abdominal skin
60 years) and 212 patients with LRRC (126 male,
86 female; mean age 62 years) who were treated
with curative intent. achieved in 18 patients (72%), and R1 resection
Twenty-five patients with T4-LARC under- occurred in 7 patients (28%).
went sacral resection. Sacral resection was per- Post-operative complications typically incl-
formed by transection at either S2 (n = 1), S3 uded wound healing problems, superficial and
(n = 5), S4 (n = 1) or more distally (n = 18). All deep wound infections with or without wound
patients had preoperative long course of radio- dehiscence and abscesses (see Table 28.2).
therapy (23%) or radiochemotherapy (77%). Five-year cancer-specific survival is 68%.
Operative details are summarized in Table 28.1. Overall survival is 56%. Twenty-one percent of
Mean blood loss was 5,225 ml (200–18,000). patients develop local recurrence within 5 years
Packing of the small pelvis because of excessive of follow-up. Five-year metastasis-free survival
bleeding was performed in two patients (8%). is 69%, and relapse-free survival is 61%.
Intra-operative radiotherapy was administered in Seventy patients with LRRC underwent sacral
all but three patients. A radical resection was resection. In these patients, preoperative treatment
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 281

Table 28.2 Post-operative complications in patients sacral resection (p = 0.191). There is no significant
undergoing sacral resection for T4 primary rectal cancer difference in the level of resection. Five-year
(n = 25) or locally recurrent rectal cancer (n = 70)
overall survival rates are 29% and 40%, respec-
T4-LARC LRRC tively (p = 0.217). Five-year local recurrence rates
No. of patients No. of patients are 46% and 43%, respectively (p = 0.379).
Wound infection 1 8
Metastasis-free survival rates are 47% and 50%,
Abdominal 1 8
infection/presacral
respectively (p = 0.442). Relapse-free survival
abscess rates are 24% and 39%, respectively (p = 0.025).
Abdominal 0 1 Ferenschild et al. report local control rates of
bleeding 88% for locally advanced rectal cancer and only
Wound dehiscence 2 1 10% for patients with recurrent rectal cancer,
Persisting ileus 1 3 with radicality of resection and lymph node posi-
Enterocutaneous 0 1 tivity being the only significant outcome factors
fistula
[36]. Three- and five-year overall survival rates
Abdominal sepsis 0 3
were reported at 46% and 30%, respectively [36].
Urinary leakage 0 1
Ureter obstruction 0 1
Typically, reported 5-year survival rates vary
Urinary retention 0 15 between rates of 18% and 37% [36]. Radicality
Urinary tract 0 2 of resection remains the most important prognos-
infection tic variable [36, 39, 43].
Severe pneumonia 4 1
DVT/pulmonary 0 1
embolism 28.6 Results After Pelvic
CVA 0 1 Exenteration
Death 0 1

In the T4 locally advanced rectal cancer patients,

consisted of no treatment (15%), reirradiation with
or without RCT 65% and full course of radiation
with or without RCT in 20%. Twenty-five patients
had a presacral recurrence (36%), 11 patients had
a posterolateral recurrence (16%), 7 had an anas-
tomotic recurrence (10%), 1 had a perineal recur-
rence and the remaining patients had a recurrence
located anteriorly. Sacral resection was performed
by transection at either S2 (n = 10), S3 (n = 33), S4
(n = 15) or more distally (n = 12).
Mean operation time was 420 min (240–660),
mean blood loss was 6,868 ml (500–20,000).
Packing of the small pelvis because of excessive
bleeding was performed in 15 patients (21%).
Intra-operative radiotherapy was administered in
all but four patients. A radical resection was
achieved in 31 patients (44%), R1 and R2 rates
were 28 (40%) and 11 (16%), respectively.
The post-operative complications are summa-
rized in Table 28.2.
Five-year cancer-specific survival rate for
patients who underwent a sacral resection is 34%
compared to 48% in patients who did not undergo
treated at our institute, 20 complete bladder
resections with ileal conduit, 17 partial bladder
resections and 13 urinary bladder flap procedures
were performed.
Forty patients underwent excision of the uterus
and adnexes as part of the en bloc resection of a T4
tumour. Twenty-six patients underwent resection
of the posterior vaginal wall without reconstruc-
tion, a further ten resections required subsequent
reconstruction. The prostate capsule was resected
in 29 patients and radical prostatectomy was per-
formed three times. Seminal vesicles were either
resected on the right side (n = 13), left side (n = 8)
or bilaterally (n = 20). Reconstruction of the
perineum or vagina using a vertical rectus abdo-
minis myocutaneous flap (VRAM) with or with-
out abdominal skin was performed in 11 and 14
patients, respectively.
Mean blood loss was 3,261 ml (50–25,000).
Intra-operative radiotherapy was administered in
328 of 336 patients. Radical resection was achieved
in 282 patients (84%), and R1 resection occurred
in 52 patients (16%). Packing of the small pelvic
282 R.L. Dudink et al.

Table 28.3 Post-operative complications in patients prostatectomy. Furthermore, the right seminal
with T4 primary rectal cancer (n = 336) or locally recur- vesicle was resected in 3 patients, the left semi-
rent rectal cancer (n = 212)
nal vesicle was resected in 5 patients and both
T4-LARC LRRC were resected in 27 patients. Mean operation
No. of patients No. of patients time was 380 min (170–660), and mean blood
Wound infection 29 19
loss was 6,607 ml (420–34,000). Intra-operative
Abdominal infection/ 26 23
presacral abscess
radiotherapy was administered in all but 13
Abdominal bleeding 6 3 patients. A radical resection was achieved in 124
Wound dehiscence 8 1 patients (59%), and R1 and R2 rates were 63
Persisting ileus 2 4 (30%) and 25 (11%), respectively. Packing of the
Enterocutaneous 2 1 small pelvic because of excessive bleeding was
fistula performed in 36 (17%) of patients. A hemostatic
Abdominal sepsis 6 6 balloon was placed in two patients (1%). Post-
Anastomotic leakage 10 3 operative complications are summarized in
Urinary leakage 1 3 Table 28.3.
Ureter obstruction 0 1 Five-year cancer-specific survival is 43%, and
Urinary retention 5 29
10-year cancer-specific survival for these patients
Urinary tract 4 4
infection
with locally recurrent rectal cancer is 34%.
Urosepsis 1 1 Overall survival rates are 36% and 20%, respec-
Severe pneumonia 10 3 tively. Local recurrence rates after 5 and 10 years
DVT/pulmonary 1 3 are 43% and 51%, respectively. Five-year metas-
embolism tasis-free survival is 49% and 44% after 10-year
CVA 1 1 follow-up. Relapse-free survival rates after 5-year
Death 2 2 and 10-year follow-up are 34% and 24%, respec-
tively. Radicality of resection is the most impor-
tant prognostic variable, in which there is no
because of excessive bleeding was performed in significant difference between R1 and R2 resec-
20 (6%) patients. A hemostatic balloon was placed tions (see Fig. 28.5).
in three patients (1%). Post-operative complica- A recent study, describing pelvic exentera-
tions are summarized in Table 28.3. tion for locally advanced and recurrent rectal
In these patients, 5-year cancer-specific sur- cancer, confirms that radicality of resection was
vival is 66% and overall survival is 53%. Local the only significant outcome factor in multivari-
recurrence and metastasis-free survival rates at ate analysis. An excellent 2-year overall sur-
5-year follow-up are 19% and 67%. Relapse-free vival rate of 80% for primary and 75% for
survival is 58%. recurrent tumours was reported. Nine percent
In the locally recurrent rectal cancer patients developed local recurrence [44]. Ferenschild
group, 26 underwent total bladder resection with et al. report 5-year local control rates for pri-
ileal conduit, four partial bladder resections were mary and recurrent rectal cancer at 89% and
performed and urinary bladder flap was per- 38%, respectively [45]. Five-year overall sur-
formed on either the right side (n = 7) or left side vival rates were reported at 66% and 8%, respec-
(n = 10). Extirpation of the uterus was performed tively. Completeness of resection was identified
either with (n = 38) or without extirpation of the as one of the most important prognostic factors
adnexa (n = 2). Partial extirpation of the vagina [45]. Harris et al. report a 3-year local recur-
was performed in 33 patients, 11 patients under- rence rate of 13% [40]. Surprisingly, there was
went extirpation of the vagina with subsequent no significant association between local recur-
vertical rectus abdominis muscle reconstruction. rence and circumferential margin involvement.
Resection of the prostate capsule was performed The authors report 5-year overall survival rates
in 12 patients and 16 patients underwent total of 48% and 33% for radical and irradical
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 283

Fig. 28.5 Local recurrence Local recurrence

rates according to radicality of
resection in recurrent rectal 1.0
cancer

0.8

Local recurrence rate

0.6

0.4

0.2

0.0

0 20 40 60 80 100
Months
Radicality of resection

R0 R0-censored
R1 R1-censored
R2 R2-censored

resected patients, respectively [40]. Wiig et al.
also emphasized the importance of a complete
resection in salvage surgery for recurrent rectal
cancer. A 5-year survival for R0 patients at 53%
compared to only 19% for R1 patients [46] was
noticed. None of the R2 resected patients sur-
vived for 4 years (Fig. 28.5).
28.7 Is an Extra Intra-operative
Boost of Irradiation Effective
to Reduce the Chance of Local
Recurrence?
Intra-operative radiotherapy (IORT) is an entity
which is only practiced in a few specialized cen-
tres. It is administered as a boost of 10–15 Gy
after preoperative external beam radiotherapy
(EBRT) and is feasible without increased toxicity
[47–49]. The theory behind IORT is that it
reduced local recurrence rates by sterilizing
microscopic residual tumour particles in a specific
area. IORT is only applied on locally advanced
rectal cancer (cT3+/T4) and in recurrent rectal
cancer, as there is risk for remaining tumour
cells.
Historical studies suggest that IORT might
improve local control and survival [47, 50, 51].
Some studies suggest that it can only improve
local recurrence rates [52, 53], but some authors
find no benefit [54, 55], and some have even
abandoned IORT [56].
The only way to quantify the effect is by
analyzing the sites of local recurrence between
centres with a different policy in IORT applica-
tion. Most institutions using IORT-containing
284
multimodality treatment regimens deliver the boost
to the presacral space because this is the area con-
sidered most at risk [51] and because other areas
are difficult to cover with the applicator [57]. In
two studies reporting on patterns of local recur-
rence after IORT, 59–67% of the local relapse
showed to develop outside the presacral IORT
radiation field [51, 57].
In our institution, the delivery of the boost is
to the area mostly considered at risk on the
basis of radiological and intra-operative
findings. In a previous study, we questioned
whether this approach leads to less outfield
local recurrences than the mentioned 59–67%
in centres where IORT is only applied to the
presacral area.
From 1994 and 2006, 290 primary locally
advanced patients received intra-operative irradi-
ation. After 5 years 34 of the 290 patients devel-
oped local recurrence (13.2%). The subsites of
the local recurrences were identified on MRI or
CT scan. Relating the patterns of local recurrence
to the IORT-target, 47% of the local recurrences
developed outside the IORT-field [30]. This is
less than in the few studies reporting on this sub-
ject, in which the boost of IORT was given only
on the presacral area.
Consequently, it might be suggested that an
IORT-boost specifically to the area at risk is more
effective in the prevention of local recurrence,
possibly because the area that causes tumour spill
is sterilized. Also very suggestive that there is
effect of IORT is that 62% of the patients with an
irradical resection in this study [30] do not
develop local recurrence.
Delivery of IORT to any specific area is tech-
nically very feasible. Normally, it can be deliv-
ered through an abdominal access. However, the
ventral area can be irradiated more adequately
through the perineal wound. The only situation
when IORT cannot be delivered is when there is
major blood loss during the operation and pack-
ing is necessary.
IORT equipment is expensive and the logis-
tics are complex. Furthermore, non-metastasized
locally advanced rectal carcinoma and local
recurrence are not very common. Therefore, for
optimal treatment of these advanced cancers,
R.L. Dudink et al.
surgery in high-volume referral centres special-
ized in multimodality treatment is essential.
Thus, we recommend the application of IORT
in locally advanced rectal cancer, and data sug-
gest that a boost to the area considered most at
risk is most effective in preventing local recur-
rences from developing.
28.8 Is There a Role for
the Use of the Cellsaver
in Locally Advanced and
Locally Recurrent Rectal
Cancer Surgery?
As mentioned before, blood loss may be consid-
erable in locally advanced and recurrent rectal
cancer because dissections planes often need to
be extra-anatomically. Hence, allogeneic blood
transfusion is necessary in many cases.
Preservation techniques for the patient’s own
blood, or intra-operative cell salvage, has become
widely accepted and utilized in many braches of
surgery when substantial blood loss can occur.
However, autologous blood transfusion has not
been adopted widely in cancer surgery due to the
fear of reintroducing viable tumour cells shed
from the surgical site into the circulation. Based
on this theoretical risk, the American Medical
Association Council on Scientific Affairs recom-
mended against autologous blood transfusion in
cancer surgery in 1986 [58].
On the basis of these concerns, one could
readily choose for allogeneic blood transfusion.
However, fresh autologous blood is superior to
allogeneic blood in a number of areas. In the past,
a couple of studies suggested a relationship
between perioperative blood transfusion and a
higher risk of recurrence of colorectal cancer
[59]. It is hypothesized that allogeneic blood
transfusion has an immunosuppressive effect due
to transfused allogeneic passenger leukocytes
[59–61]. Furthermore, a dose-dependent relation-
ship is suggested [59]. Allogeneic blood transfu-
sion is also associated with a higher risk of
post-operative bacterial infections [61, 62].
Furthermore, autologous blood has a higher
2,3-diphosphoglycerate (2,3-DPG) concentration
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer?
Table 28.4 Five-year oncological outcome for the use of the cellsaver
Cancer-specific survival (%) Metastasis-free survival (%)
Cellsaver No cellsaver p-value Cellsaver No cellsaver p-value
All 74 57 0.001 70
patients
Q1 78 69 0.363 59
Q2 87 62 0.054 81
Q3 71 50 0.012 70
Q4 63 38 0.027 66
and thus lower oxygen binding affinity, resulting
in better tissue oxygenation [63]. Experimental
studies have demonstrated that transfusion with
stored allogeneic blood results in less tissue oxy-
gen consumption when compared to fresh autolo-
gous blood [64].
Given these advantages, the cellsaver was
used to collect, filter, wash and return the patient’s
erythrocytes in order to maintain the circulating
red cell volume. After collection, the heparinized
blood is being centrifugated, washed with a 0.9%
saline solution and concentrated to hematocrit
levels of 60–65%. The intra-operative red blood
cell salvage (ICS) device was used with a leuco-
cyte depletion filter, which was replaced after
every two processed bowls. In case of contamina-
tion by faeces or pus, ICS blood was not returned
to the patient. If blood loss was excessive, plasma
volume was replaced by moderate use of fresh
frozen plasma.
From 1994 until August 2010, data on 546
patients who have been treated for locally
advanced (n = 444) or recurrent (n = 102) rectal
cancer was collected prospectively. Four quartiles
representing the volume of blood loss were cre-
ated: Q1 less than or equal to 1,250 ml (n = 153),
Q2 1,251 ml up to 2,500 ml (n = 140), Q3 2,501 ml
up to 5,000 ml (n = 138), Q4 5,001 ml or more
(n = 115).
In these patients, mean blood loss was 3,697 ml,
3,110 ml for locally advanced rectal cancer
patients and 6,209 ml for recurrent rectal cancer
patients. Autologous blood was returned in 315
patients (58%). Cancer-specific 5-year survival
for all patients and per quartile blood loss volume
was higher when the cellsaver was used, compared
to those without cellsaving (see Table 28.4). There
285
Local recurrence rate (%)
Cellsaver No cellsaver p-value
61 0.036 12 22 0.007
72 0.743 9 13 0.227
66 0.337 5 17 0.047
57 0.085 13 30 0.014
35 0.005 22 42 0.151
seems to be a survival benefit in patients with the
highest blood loss. The metastasis-free and local
recurrence-free survival rates show that the intro-
duction of the cellsaver did not compromise onco-
logical outcome and is safe to use in these kinds of
patients (see Table 28.4 and Fig. 28.6).
The use of the cellsaver during oncological
procedures remains controversial. However,
approximately 20–45% of patients with colorec-
tal cancer develop metastases, which suggests
that tumour cell dissemination is an early event in
colorectal cancer. One study detected circulating
tumour cells in 41% of colorectal cancer patients
in the preoperative stage [65]. Furthermore, it is
suggested that surgical manipulation enhances
the dissemination of malignant cells [65, 66].
However, it has been estimated that only 0.01–
0.000001% of circulating tumour cells have the
potential to form metastatic lesions [58]. The
most widely used technique to remove tumour
cells from the patient’s blood is the leucocyte
depletion filter. Several studies were not able to
detect viable tumour cells after filtering the blood
[67–69]. One study evaluated the effect of the use
of the cellsaver on local recurrence after radical
retropubic prostatectomy for prostate cancer.
There was no statistical significant difference
found for local recurrence rate [70].
28.9 Which Patients Do Benefit from
Extended Resections in Case
of Advanced Cancer?
So, are extended resections including the sacrum
or the pelvic organs worthwhile in offering the
patient a chance for cure? It depends on different
286 R.L. Dudink et al.

Fig. 28.6 (a) Five-year a Cancer specific survival

cancer-specific survival for Locally advanced rectal cancer
locally advanced rectal cancer,
stratified for the use of the 1.0
cellsaver (p = 0.043).
(b) Five-year cancer-specific
survival for locally recurrent
rectal cancer, stratified for the use 0.8
of the cellsaver (p = 0.061)

Cum survival 0.6

0.4

Cellsaver used
0.2
No
Yes
No−censored
Yes−censored
0.0

0 10 20 30 40 50 60
Months

b Cancer specific survival

Locally recurrent rectal cancer

1.0

0.8
Cum survival

0.6

0.4

Cellsaver used
0.2
No
Yes
No−censored
Yes−censored
0.0

0 10 20 30 40 50 60
Months
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer?
important factors in the tailored treatment of
patients presenting with extended tumour growth.
Achieving a radical resection should be the pri-
mary goal when treating these patients, as sup-
ported by numerous authors [36, 37, 39, 40,
42–46, 71–75]. Radical resection offers the only
chance of cure. In case of a tumour invading sur-
rounding structures or organs, en bloc resection
is necessary to avoid tumour dissemination or
positive margins [40]. In these patients, multivis-
ceral resection offers the only possibility for cure
[40]. Lateral lymph node involvement, fixation to
the bony pelvis and sciatic nerve involvement are
poor outcome parameters and challenge the sur-
geon [71, 76].
Therefore, to achieve a radical resection,
proper patient selection is of paramount impor-
tance [36, 37, 40, 42, 44, 71, 72, 74, 75, 77].
Hence, accurate preoperative staging, including
CT thorax/abdomen, MRI of the small pelvis and
possibly PET, is required to evaluate if curative
surgery is feasible. Contraindications for resec-
tion are distant metastasis, extensive sidewall
involvement, sacral invasion above S2, encase-
ment of external iliac vessels, extensions of
tumour through the sciatic notch and poor perfor-
mance status [42, 71].
Because of the complexity of extended sur-
gery, these procedures should be undertaken in
specialized centres committed to the multimodal-
ity treatment of these patients. Therefore, central-
ization should be advocated [43, 44, 72].
Only in very few patients, there may be a place
for these extended procedures in a palliative set-
ting. Only if other measures have failed and life
expectancy is still moderate, an extended resec-
tion to alleviate the symptoms of progressive
local disease, which may have led to uncontrol-
lable tenesmus, severe pelvic pain or other qual-
ity-of-life-limiting symptoms, may be considered.
Especially in metastasized patients, who respond
well to palliative chemotherapy, the response of
the metastases may last longer than the postpone-
ment of local progression of the primary to severe
symptoms [37, 42].
287
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 Can Standard Surgical Procedure
Reliably Be Avoided in Major 29
Responders After Radio(chemo)
therapy?

Claudio Coco and Gianluca Rizzo

Contents Abbreviations

29.1 Introduction ................................................... 291 cCR Clinical complete response

CT Chemotherapy
29.2 Role of Total Mesorectal
Excision After Pathological
DFS Disease-free survival
Complete Response ....................................... 292 DWI Diffusion-weighted imaging
LE Local excision
29.3 Wait and See Policy ....................................... 293
MRI Magnetic resonance imaging
29.4 Definition and Value OS Overall survival
of Clinical Complete Response .................... 295
pCR Pathological complete response
29.5 Role of Local Excision After PET Positron emission tomography
Major Clinical Response
RCT Radiochemotherapy
to Neoadjuvant Treatment ........................... 296
TEM Transanal endoscopic microsurgery
References ................................................................. 300 TME Total mesorectal excision

29.1 Introduction

Based on the results of large randomized con-

trolled trials, the management of locally advanced
rectal cancer actually consists of neoadjuvant
radio(chemo)therapy (RCT) followed by radical
surgical rectal resection with total mesorectal
excision (TME). This approach has shown its
efficacy in reducing local recurrence rate, by
downstaging both the tumor and associated
C. Coco (*) • G. Rizzo lymph nodes and in increasing the likelihood of
Department of General Surgery, sphincter preservation [28, 55]. The degree of
Catholic University of Sacred Heart, tumor downstaging varies between patients and
Rome, Italy
can range from no response at all to complete
Complesso Integrato Columbus, sterilization of all tumor cells. This last condition
U.O.C. Chirurgia Generale 2,
is called pathological complete response (pCR).
Via Moscati 31-33, Rome 00168, Italy
e-mail: coco_claudio@rm.unicatt.it; During the last 10 years, there has been an
gianluca.rizzo1979@libero.it increasing proportion of patients who achieved a

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 291

DOI 10.1007/978-3-642-25005-7_29, © Springer-Verlag Berlin Heidelberg 2012
292 C. Coco and G. Rizzo

pCR. As it is well known from many studies survival, overall survival, and cancer-specific
[3, 5, 15, 16, 19, 25, 27, 35, 36, 40, 41, 49, 55, survival were 98.8%, 84.7%, 91.6%, and 95.6%,
61], the rate of pCR after neoadjuvant RCT in respectively. Yeo and the Korean Radiation
rectal cancer ranges between 8% and 35% Oncology Group in 2010 reported clinical data of
(Table 29.1). Pathological complete response has 304 ypT0N0 rectal cancer patients following pre-
a very important prognostic value and is associ- operative RCT and curative radical resections
ated with very good results in terms of local con- between 1993 and 2007 [63]. After a median
trol, disease-free survival (DFS), and overall follow-up of 43 months, 5-year DFS was 88.5%
survival (OS) [9, 14, 20, 52, 57, 58] (Table 29.2). and OS was 94.8%. In a recent pooled analysis
These good results have been confirmed in a large published in Lancet Oncology [37], Maas et al.
multicenter study published in 2008 by Capirci identified 27 articles, based on 17 different data-
and the Gastro-Intestinal Working Group of the sets, for long-term outcome of patients with and
Italian Association of Radiation Oncology. This without pCR after RCT and TME. Four hundred
study collected 566 patients with pCR (pT0N0) eighty-four of 3,105 (15.6%) included patients
after neoadjuvant therapy and surgery with TME had a pCR. After a median follow-up for all
for locally advanced rectal cancer with no evi- patients of 48 months, 5-year crude DFS was
dence of metastases at the time of diagnosis [12]. 83.3% for patients with pCR (with a disease
After a median follow-up of 45.6 months, locore- recurrence occurred in 61 patients) and 65.6% for
gional recurrence occurred in 7 patients (1.2%) those without pCR (p < 0.0001). The adjusted
and distant metastases in 49 patients (8.9%). hazard ratio for pCR for failure was 0.54 (95%
Overall, 5-year rates of local control, disease-free confidence interval: 0.40–0.73), indicating that
patients with pCR had a significantly increased
probability of disease-free survival. Even after
Table 29.1 Rate of pCR after RCT for extraperitoneal
rectal cancer adjustment for other relevant prognostic factors,
pCR still had a significant impact.
Authors Patients % pCR
Luna-Pérez et al. [36] 120 25
Hiotis et al. [25] 488 10
Mehta et al. [40, 41] 62 35 29.2 Role of Total Mesorectal
Sauer et al. [55] 405 8 Excision After Pathological
Wiltshire et al. [61] 135 21 Complete Response
Bosset et al. [5] 572 13
Gambacorta et al. [19] 102 27
Hughes et al. [27] 143 18 Total mesorectal excision was introduced by
Pucciarelli et al. [49] 235 24 Heald and colleagues [24] in 1982, and this tech-
Coco et al. [15, 16] 272 21 nique is based on the concept that an adequate en
Beddy et al. [3] 126 21 bloc clearance of the rectal mesentery, including
Lindebjerg et al. [35] 135 19 its blood supply and lymphatic drainage, would

Table 29.2 Oncologic outcome in patients who obtained pCR after RCT
Median FU
Authors Patients pCR (%) (months) 5-year LC 5-year DFS 5-year OS
Theodoropoulos et al. [58] 88 16 (18) 33 100 100 100
Garcia-Aguilar et al. [20] 168 21 (13) 37 100 95 95
Rödel et al. [52] 344 40 (12) 41 100 86 NS
Chan et al. [14] 120 32 (27) – 100 97 97
Stipa et al. [57] 200 60 (30) 39 96 NS 90
Bujko et al. [9] 131 22 (17) 48 95 91 NS
FU follow-up, LC local control, DFS disease-free survival, OS overall survival, NS not stated
29 Can Standard Surgical Procedure Reliably Be Avoided in Major Responders After Radio(chemo)therapy? 293
minimize possible disease relapse. Early experi-
ence by Heald et al. (on 100 cases) documented
very good results in terms of local recurrence rate
also without the benefit of adjuvant RT [24].
Actually, TME is considered the gold standard of
treatment for extraperitoneal rectal cancers in
Europe and in the USA.
While generally the value of TME is out of
doubt, there is much more concern about its role
in pathological complete responders patients. It
raises the question of what can be the contribu-
tion of a TME in improving results in this specific
group of patients and if it is reasonable to imag-
ine to improve the prognosis by removing a
healed organ.
On the other hand, what is definitely known is
that TME is associated with a significant postop-
erative morbidity and mortality rate, respectively
between 20% and 35% and between 1% and 4%
[48, 51]. The most frequent postoperative com-
plication after TME is anastomotic leakage. Leak
rates following TME are reported in the range of
15–20% compared with a 5% or less after colonic
and intraperitoneal rectal anastomoses [48].
The anterior resection syndrome, including
dysfunction as incontinence, urgency, incomplete
rectal evacuation, inability to defer defecation,
and clustering of bowel movements, is consid-
ered a consequence of TME and low rectal anas-
tomoses. Loss of the physiological rectal reservoir
and alteration of anus-rectal physiology are
responsible for compromised anorectal function.
In 2007, our institution published functional gas-
trointestinal results [15, 16] of 100 patients
treated with neoadjuvant long-term RCT and
anterior resection with TME, from 1996 to 2003.
After 1 year from surgery, sensation of incom-
plete evacuation was reported in 58% of cases,
necessity to return to the bathroom <15 min in
37%, and inability to evacuate completely
<15 min in 35%; urgency was referred in 31% of
cases. Incontinence to flatus was reported in 46%
of cases, soiling in 19%, and incontinence to
solid stools in 5% with 14% of patients needed of
wearing pad. In 29% of cases, these functional
gastrointestinal disorders affected normal social
and physical lifestyle. These poor functional
results after TME are also present after short-
term RT: sensation of incomplete evacuation is
reported in a range varying from 35% to 69% and
urgency between 16% and 42%; incontinence to
flatus, soiling, and incontinence to solid stools
are reported, respectively, in a range varying from
25% to 68%, from 20% to 50%, and from 7% to
14%, with almost 25% of cases which need to
wear a pad [7, 18, 38].
There are evidences in literature that TME
compromises urinary function (from 10% to
70%) and sexual function (from 13% to 70%)
too, even if nerve-sparing techniques or laparo-
scopic approach are employed. About urinary
functional outcome, the Dutch Colorectal Cancer
Study Group [47] on 306 patients reported a rate
of 39% of urinary incontinence with 57% of the
patients wore pads because of urinary inconti-
nence. Moreover, 70% of patients needed to uri-
nate again within 2 h, 53% referred urgency, and
47% complained an incomplete bladder empty-
ing. Concerning sexual disorders after TME,
Sartori et al. [54] reported a reduced sexual desire
and impaired spontaneous erectile function in
almost half the cases, respectively in 47.1% and
41.1%; about one-quarter (23.5%) of patients
still had not the possibility of penetration.
Keeping in mind all these considerations about
the possible complications after a TME, there is
more than a suspect that this operation in pCR
patients (Fig. 29.1) could be an overtreatment. At
the same time, the real problem nowadays is how
can we identify patients with a pCR before a
standard surgical resection and how reliable is
our diagnosis of clinical complete response
(cCR).
29.3 Wait and See Policy
Long-term results of “wait and see” approach
have been firstly reported by Habr-Gama and
colleagues in 2004 [22] on selected group of
patients with radiological and clinical evidence
of CR after neoadjuvant RCT. Two hundred
sixty-five patients with distal resectable rec-
tal cancer were treated with preoperative RCT
(RT at a dose of 50.4 Gy in 1.8 Gy fractions
for six consecutive weeks plus concomitant CT
294
Fig. 29.1 Clinical complete response after radiochemo-
therapy for rectal cancer: no macroscopic evidence of
disease is visible on specimen after total mesorectal
excision
consisted of fluorouracil, 425 mg/m2/day, and
folinic acid, 20 mg/m2/day, on the first 3 days and
last 3 days of RT) from 1991 to 2002. Patients
were assessed at 8 weeks after completion of
RCT, and patients without any abnormality dur-
ing tumor response assessment were considered
to have cCR; these patients were referred to
monthly follow-up visits for repeat physical and
digital rectal examination, proctoscopy, biopsies
(when feasible), and serum CEA levels (abdomi-
nal and pelvic scans and chest radiographs were
repeated every 6 months during the first year).
Patients with sustained complete tumor regres-
sion for at least 12 months were considered stage
0, cCR, and were included in observation group.
Seventy-one patients (26.8%) were deemed to
have achieved cCR; all other patients proceeded
to surgery (resection group). After a median
follow-up of almost 5 years (57.3 months, range
12–156 months), OS and DFS was 88% and
83% in the resection group and 100% and 92%
in the observation group, respectively; only two
patients (2.8%) in the observation group had
C. Coco and G. Rizzo
an endoluminal relapse, both of whom were
successfully treated; three patients (4.2%) devel-
oped metastatic disease. This series was updated
in 2005 and in 2006 extending to 360 patients
treated and 99 patients included in the observa-
tion group because classified as having achieved
cCR (MRI was included as staging tool) [23].
Local recurrence has occurred in three additional
patients (five in total, 5%) in the observation
group, all amenable to salvage surgery, and none
of whom have developed further recurrence.
Few other studies have assessed nonoperative
observational treatment after RCT. Other units
from the same city as Habr-Gama have reported
contrasting results. In the experience published
by Rossi et al. [53], in 1998, 16 patients with low
infiltrative rectal tumors (with initial indications
for abdominoperineal resection) were selected
prospectively to be treated with RCT (5,040 cGy
RT dose and CT during the first 3 and last 3 days
of RT, using 425 mg/m2/day of 5-fluorouracil and
20 mg/m2/day of folinic acid) as an attempt to
preserve sphincter function. Six patients (37.5%)
achieved a cCR and were followed in close sur-
veillance by monthly proctoscopy. Five of six
(83.3%) patients failed locally after 1–10 months,
and only a single patient maintained local control
at 34 months. Nakagawa et al. [43] reported on
51 patients with locally advanced extraperitoneal
rectal cancer treated with RCT (external beam
radiation plus 5-fluorouracil plus folinic acid).
Ten (19.2%) patients showed cCR. Eight of ten
(80%) recurred locally within 3.7–8.8 months,
and six succeeded in achieving salvage surgery.
Only two patients survived without cancer at 37
and 58 months. In a recent report from UK by
Hughes et al. [26], 10 of 58 patients unfit for sur-
gery were identified as having had a cCR at clini-
cal reassessment 6–8 weeks after RCT. The
reasons for not proceeding with surgery in these
ten patients were patient choice in three patients
and comorbidity in seven patients. Six of these
ten patients (60%) subsequently developed
intrapelvic recurrent disease with a median time
to local progression of 20 months. Local relapse
preceded the development of metastatic disease
or occurred simultaneously. No patients under-
went salvage resection.
29 Can Standard Surgical Procedure Reliably Be Avoided in Major Responders After Radio(chemo)therapy? 295

The excitement born by Habr-Gama’s results
and the necessity of a systematic prospective trial
induced the Royal Marsden Hospital (Sutton,
Surrey, UK) and Pelican Cancer Foundation
(Basingstoke, Hampshire, UK) to start a pilot
study investigating a nonoperative approach for
complete responders patients [45].
29.4 Definition and Value
of Clinical Complete Response
At present, the criticisms existing about the
“wait and see” approach are mainly due to the
difficulties in identifying with certainty pCR
patients. We must assume that what appears to
be a cCR is equal to a pCR, but this is not true
in many times and we still not have nowadays a
uniform accepted definition of cCR.
Several studies have investigated how cCR
is correlated with pCR. In Table 29.3 are
reported some who evaluated the ratio between
cCR and pCR [25, 29, 46, 56, 64]. The ratio
varies between 25% and 77%. This large vari-
ability depends on the fact that the definition of
clinical complete response as “no evidence of
disease” is often vague and not homogeneous.
The largest, published in 2002, was a retro-
spective review of the clinical and pathologic
characteristics of 488 patients, from the Memorial
Sloan-Kettering prospective colorectal database,
who received preoperative chemoradiation fol-
lowed by resection for primary rectal cancer [25].
Definition of cCR was based on the absence of
detectable tumor on preoperative digital rectal
examination and proctoscopy; pCR was defined
as the absence of cancer cells in the resected
specimen. A cCR was achieved in 93 patients
(19%) and pCR rate among all patients was 10%.
The pathologic complete response rate among
clinical complete responders was 25% with 75%
of cCR patients which had persistent foci of
tumor that were not detectable on preoperative
examination. Moreover, 55 patients (59.1%)
preoperatively defined as cCR were affected by a
pT ³2 cancer and 16 (17.2%) had positive nodes
at pathological staging. On the contrary, 27 of
395 patients clinically classified as not com-
plete responders were ypT0N0 at pathological
examination.
In the study of Kim and colleagues in 2001
[29], all patients underwent sigmoidoscopy and a
digital rectal examination to evaluate clinical
response after RCT and endorectal ultrasound
was done after RCT in 12 of the 26 patients. In
the study of Onaitis et al. [46], clinical restaging
after treatment consisted of proctoscopic exami-
nation and often computed tomography scan. In
Schell’s experience [56], digital rectal examina-
tion, endoscopy, computed tomography scan, and
endorectal magnetic resonance or endorectal
ultrasound were utilized to define cCR.
In last years, new diagnostic techniques con-
curred to refine the definition of cCR. Diffusion-
weighted imaging (DWI) has shown promising
results in the assessment of treatment response to
neoadjuvant therapy. A recent multicenter com-
parative study [30, 31] evaluated the accuracy of
DWI in addiction to standard rectal MRI for
selection of complete responders (only for ypT0)
after RCT. A total of 120 patients with locally
advanced rectal cancer from three university hos-
pitals (Maastricht University Medical Center,
Catholic University of Sacred Heart in Rome,
and University Hospital of Leuven) underwent
RCT followed by a restaging MRI, consisting of
standard T2W-MRI and DWI. Three independent
readers first scored the standard MRI only for the
likelihood of a CR, after which DWI images were

Table 29.3 Ratio between Authors Patients cCR (%) Ratio pCR/cCR (%)
cCR and pCR
Kim et al. [29] 95 22/95 (23%) 17/22 (77%)
Onaitis et al. [46] 141 30/141 (21%) 18/30 (60%)
Hiotis et al. [25] 488 93/488 (19%) 23/93 (25%)
Schell et al. [56] 74 11/74 (15%) 8/11 (73%)
Zmora et al. [64] 109 47/109 (43%) 15/47 (33%)
296
added and the scoring was repeated. Histology
was the standard reference. A pCR occurred in 25
patients (20.8%). The accuracy for three readers
improved from 76%, 68%, and 58%, using only
MRI, to 80%, 80%, and 78%, respectively, after
addiction of DWI (p-value: 0.39, 0.02, and 0.002).
Positive predictive value increased, after adding
DWI, from a range of 0–56% to 62–81%, and
negative predictive value increased from 79–85%
to 88–90%. In this study, authors did not evaluate
lymph nodes. Standard MRI accuracy for lymph
node post-RCT is high and, in our institution, is
reported as 86.8% on the basis of morphologic
criteria [1]. The only study [30, 31] specifically
focused on DWI for staging of rectal cancer
nodes after RCT already showed good results for
standard MRI only (negative predictive value:
94–95%) and reported no clear benefit after addi-
tion of DWI (negative predictive value:
92–93%).
Positron emission tomography (PET) demon-
strated high accuracy defining the response to
RCT. Nearly the same multicenter study group
has recently developed predictive models for
pathologic complete response based on clinical
data (including age, gender, clinical tumor and
nodal stage, and tumor location and tumor length
based on MRI or endoscopy if MRI was unavail-
able) and on PET-based data (maximal tumor
diameter, gross tumor volume, and maximal and
mean SUV values within the gross tumor vol-
ume) [60]. Sequential PET-CT data in combina-
tion with clinical variables seem to significantly
increase the performance of prediction models
for pathologic complete response with an accu-
racy of 86 ± 5%.
Further complicating the situation is the fact
that there is not a standard interval of time from
the end of RCT when the diagnosis of cCR should
be done. This can vary from 4 weeks up to
1 year.
In 2010, a questionnaire was sent to members
of the Association of Coloproctology of Great
Britain and Ireland regarding investigations, clin-
ical management, pathological assessment, and
oncological outcome in rectal cancer patients
with a complete response to neoadjuvant RCT
[62]. A total of 122 consultants responded: most
C. Coco and G. Rizzo
surgeons (58%) would not consider conservative
management of patients with a complete response
and even more (69%) expressed that they would
never discuss nonoperative management in
patients with rectal cancer who are fit for curative
surgery.
In conclusion, cCR is an evolving concept,
but, at the current time, even using the latest avail-
able imaging diagnostic techniques, we have
always a 15–20% of error in identifying pCR. In
these patients with a major clinical response, we
are in a dilemma. Should we wait and see or
should we perform a TME? The first option seems
too little but at the same time the second one
seems too much.
29.5 Role of Local Excision After
Major Clinical Response
to Neoadjuvant Treatment
Historically, local excision was considered in
rectal cancer patients as an alternative to radical
resection if patients were unfit for major surgery
or refused a permanent stoma. When used alone,
local excision of rectal tumors was associated
with a high recurrence rate, but the key for an
appropriate use of local excision for rectal cancer
is the patient selection [2]. So, during the last
25 years, local excision as curative procedure
was accepted only for highly selected rectal can-
cer patients who presented with a T1 (sm1 or
sm2) nonmucinous adenocarcinoma, with small
size (less than 4 cm), exophytic, mobile, moder-
ately or well differentiated histology, and without
vascular, lymphatic, or perineural invasion [2].
Traditional local excision (Fig. 29.2), usually
performed using transanal surgical techniques
(Parks, Mason, Francillon, etc.), is performed
under general or regional anesthesia; the tumor
should be removed with a 1-cm margin of normal
mucosa around the tumor; the resection should
be a full-thickness excision, and the perirectal fat
should be seen clearly. Tumor fragmentation
should be avoided. The excised specimen should
be oriented and pinned before fixation. Short-
term postoperative complications (including uri-
nary retention, bleeding, and pelvic sepsis) are
29 Can Standard Surgical Procedure Reliably Be Avoided in Major Responders After Radio(chemo)therapy? 297
Fig. 29.2 Transanal
endoscopic microsurgery
equipment
infrequent, and most patients are discharged from
the hospital within 48 h of the operation. The
introduction of transanal endoscopic microsur-
gery (TEM) by Buess in 1983 [6] was an impor-
tant technical advance in the local excision of
rectal cancer. For the TEM technique (Fig. 29.2),
a large operating proctoscope with a stereoscopic
telescope is used, specially designed instruments
are introduced through the proctoscope, and the
rectum is insufflated with CO2, which maintains
exposure. This method, compared with the tradi-
tional transanal approach using Park’s retractor,
permits good exposure of the operative field with
stereoscopic magnified endoscopic vision that
allows extremely precise dissection and permits
a complete full-thickness excision to be per-
formed with an appropriate margin (ablation with
1 cm of surrounding free margin and with the
largest amount of adjacent perirectal fat) [10].
Moreover, TEM enables extension of local exci-
sion to tumors located in the mid-upper rectum
that are not amenable to removal by standard
transanal techniques [10]. TEM is technically
difficult and requires a significant investment
in equipment and training for competent per-
formance [2].
Local excision of rectal cancers after RCT,
especially using TEM, is increasingly being
described in the literature. The first docu-
mentation was in 1990 in a study conducted
in Comprehensive Rectal Cancer Center of
Philadelphia [39]. Fourteen patients, unable to
tolerate radical surgery or with completely disap-
peared tumor after irradiation, were treated with
preoperative RT (for a total dose of 45 Gy) and
full-thickness local excision by transanal, trans-
sphincteric, and transsacral techniques. Follow-up
observation ranged from 24 to 48 months with a
median of 31 months. Local recurrence devel-
oped in three patients (21%), and 3-year actuarial
local recurrence rate was 23%. Actuarial Kaplan-
Meier survival at 3 years was 61%. The Italian
Lezoche’s group has the largest number of pub-
lications on the subject. In 2002, this group of
study evaluated the results of preoperative high-
dose RT (50.4 Gy) and TEM in 35 patients with
pre-RT T2N0 rectal cancer [32]. The tumors were
responsive (50% or more reduction of the diam-
eter) to preoperative RT in 82.8% of cases. Low
responsiveness or unresponsive patients were
submitted to radical surgery with TME. After a
median follow-up of 38 months, only one local
298
Table 29.4 Rate of lymph
node metastasis in relation Authors
to pathological tumor stage
after RCT Read et al. [50]
Bujko et al. [8]
Guillem et al. [21]
Mignanelli et al. [42]
recurrence (2.85%) was noted and the probabil-
ity of surviving at 96 months was 83%. A larger
publication [33] from the same group included
data from a 15-year experience of the technique
on 151 patients with N0 rectal cancer (88 T2 and
63 T3) who underwent to TEM after preoperative
high-dose RT. The definitive histology was 34
(22.5%) pT0, 23 (15.2%) pT1, 68 (45.0%) pT2,
and 25 (16.3%) pT3. No pT0 patients did not go
to radical surgery with TME. For the patients
with pre-RT T2, the probability of local failure
was 6% and 5% for T3 patients. The probability
of metastasis was 3% for pre-RCT T2 patients
and 4% for T3 staging. The rectal cancer-specific
survival rate at the end of the follow-up period
was 90% for pT2 and 77% for pT3 patients. In
2008 results were published from a randomized
study [34] that was performed to compare the
oncologic results obtained by TEM and those
by laparoscopic TME resection in the treatment
of T2N0, G1–2 rectal cancer after neoadjuvant
therapy (high-dose 50,4 Gy RT combined with
continuous infusion of 5-flurouracil). The study
enrolled 70 patients: of these, 35 were random-
ized to TEM and 35 to TME. At pathological
exam, there were 11 (32%) pT0 in TEM group
and 10 (29%) in TME group. After a median
follow-up of 84 months, two local recurrences
(5.7%) were observed after TEM and one (2.8%)
after TME. Distant metastases (2.8%) occurred
in one case each after TEM and TME. The prob-
ability of survival for rectal cancer was the same
(94%) for TEM and TME.
As nodal positivity is an accepted adverse
prognostic factor after RCT, the majority of stud-
ies have assessed the value of TEM after RCT
primarily in patients who were node negative
before treatment on the assumption that they
would remain so after RCT. Only two studies
[11, 44] investigated the role of TEM after RCT
C. Coco and G. Rizzo
Nodal metastases (%)
Patients pCR ypT1 ypT2 ypT3 ypT4
644 2 4 23 47 48
316 5 8 26 55 64
180 3 7 20 36 36
242 3 11 29 37 ns
in node-positive patients. In the first [11], 47
patients underwent by traditional local excision
for a relatively small (median diameter: 4 cm),
low (median distance from anal verge: 4 cm) rec-
tal cancer. After long-term RCT (RT doses of 45,
50.4, or 52.5 Gy with concurrent 5-fluorouracil-
based CT), 49% of patients obtained a pCR, and
in 36%, only a microscopic disease was observed.
At a median follow-up of 63 months, five patients
(10.6%) developed local recurrence. None of the
LE patients who developed local recurrence have
died of rectal cancer. Thirteen patients (27.7%)
were pre-RCT N1; of these, 3 (23.1%) developed
a local recurrence versus 2 (5.9%) of the 34
patients with pre-RCT N0 disease; this difference
was relevant but not statistically significant
(Fisher exact test, p = 0.1213), probably due to
the small number of N1 patients observed. In
contrast, the second study [44] did not find that
nodal positivity before RCT was associated with
increased rates of local recurrence but, after a
median follow-up of 64 months, the rate of local
recurrence was high in both groups: 15% in node-
negative and 18% in node-positive patients. The
major criticism of this technique remains the
impossibility to radically remove all the mesorec-
tal fat and, consequently, we have no direct path-
ological information about mesorectal lymph
nodes status. Even when a tumor that has under-
gone significant pT downstaging after RCT is
resected with clear margins, lymph node may
still be involved [8, 21, 42, 50] (Table 29.4).
The main reason for performing local excision
(in cCR patients) instead of radical surgery with
TME is to preserve the anatomical and functional
integrity of the rectum, avoiding a permanent
colostomy and some of the bowel, bladder, and
sexual dysfunction secondary to radical surgery
and improving quality of life. Although it seems
reasonable, few studies have assessed this con-
29 Can Standard Surgical Procedure Reliably Be Avoided in Major Responders After Radio(chemo)therapy? 299
cept formally. Cataldo PA and colleagues [13]
prospectively evaluated functional outcome on
39 patients who underwent TEM (without pre- or
postsurgical RCT) by a completed preoperative
and postoperative (6 weeks) survey including
fecal incontinence severity index, fecal inconti-
nence quality of life, number of bowel move-
ments per 24 h, and ability to defer defecation.
There was no change in any of these parameters
when preoperative and postoperative data were
compared. To date, no published data exist about
quality of life after TEM for rectal cancer previ-
ously treated with RCT. In our institution from
2000 to 2008, 21 patients underwent TEM after
RCT for rectal cancer and no needed further radi-
cal surgery. After 1 year, all patients were asked
by a questionnaire on evacuation and continence.
No patients referred more than three daily bowel
movements, sensation of incomplete evacuation,
necessity to return in bathroom, or inability to
completely evacuate within 15 min. Only one
patient (4.8%) refers urgency. If compared with
an historical series of 100 patients who under-
went radical surgery with TME [15, 16], these
symptoms were statistically less frequent. The
median evacuation score was 24.5 (score varied
from 0 to 28; the highest value corresponds to
better function), significantly lower than patients
who underwent TME (16.1; p-value: 0.004).
Continence score in TEM patients results to be
significantly lower than TME series (18.6 vs.
13.7; p < 0.001; score varied from 0 to 20; the
highest value corresponds to better function):
only two patients (9.5%) referred incontinence to
flatus after TEM; no patients reported soiling,
incontinence to solid stools, necessity of a pad, or
lifestyle limitations after RCT and TEM.
Local excision after neoadjuvant treatment
of rectal cancer can be seen under two different
points of view. It can be considered as a minimal
treatment of residual disease or it can be consid-
ered just a diagnostic tool. If we consider local
excision and especially TEM, not as a therapeu-
tic choice but as the most effective diagnostic
tools we have today to confirm a pathological
complete response after neoadjuvant RCT, we
have probably in our hands the most safe way to
avoid unnecessary radical resections. The full-
Table 29.5 Rate of lymph node metastasis in ypT0
patients
Authors # ypT0 # pN+ % N+
Crane et al. (2003) [17] 84 1 1.2
Read et al. [50] 42 1 2.3
Bedrosian et al. [4] 45 4 8.8
Pucciarelli et al. [49] 56 1 1.8
Tulchinsky et al. [59] 17 1 5.8
Coco et al. [15] 56 1 1.8
Maas et al. [37] 509 26 5.1
Total 809 35 4.3
thickness excision of the rectal wall disk pre-
viously containing the rectal cancer can assess
indeed the pathologic response of the primary
tumor (ypT) with an accuracy of nearly 99%.
This result in assessing pathological response
of T can be reached with a very low morbidity
rate and with good functional results. We still
have the problem to have no direct pathologi-
cal information about mesorectal lymph nodes,
but we can have data on this aspect in a round-
about way. In 2007, our group have published
an analysis of 272 consecutive rectal cancer
[15] submitted to neoadjuvant RCT and surgery
with TME, to prospectively evaluate the correla-
tion between pathological response of primary
tumor and mesorectal lymph node involvement.
A pCR was recorded in 56 patients (20.6%),
and lymph node metastases were found in 72
patients (26.5%). When a pCR of primary tumor
(pT0, TRG1) occurred, the rate of lymph node
involvement has been less than 2% (1.8% in our
series). Despite at univariate analysis also clini-
cal pretreatment N-stage was statistically corre-
lated with the risk of pathological lymph node
metastasis, at multivariate analysis, the best
predictors of pathologic lymph node involve-
ment were only ypT stage (p = 0.0013) and TRG
(p = 0.0011). Table 29.5 reports a collective
review of recent papers [4, 15–17, 37, 49, 59]
published on this topic. If we sum all the series,
we can see that on 809 pT0 patients, only 35
(4.3%) had a lymph node involvement. So we
can consider local excision after a major clini-
cal response as the best diagnostic tool to patho-
logically confirm the complete response of the
primary tumor after RCT and to estimate with
300
a very high accuracy (near 96%) the mesorectal
nodal involvement. If pathological examination
of surgical specimen after TEM reveals the pres-
ence of residual neoplastic diseases, patients
should be advised to undergo a standard surgical
resection with total mesorectal excision because
of the higher risk of lymph node involvement.
Conclusions
Pathological complete response after RCT is
increasingly reported and identifies a group of
patients with favorable prognosis in which
major surgery is probably useless. On the
other hand, a radical resection with TME has a
high rate of short- and long-term morbidity.
Major clinical response is an evolving concept
not easy to define and not truly reliable in pre-
dicting pCR. “Wait and see” policy appears
today still controversial, and reported results
are contrasting.
If a major or complete clinical response
after a neoadjuvant treatment occurs, full-
thickness local excision, rather by TEM,
should be considered as the best diagnostic
tool we have today to confirm the tumor
response. The accuracy of the pathological
definition of tumor response after a local exci-
sion is near 99% and, in ypT0 patients, is pos-
sible to predict the absence of lymph node
involvement with an accuracy of nearly 96%.
Clinical trials to confirm validity of an organ-
sparing approach after local excision diagno-
sis of ypT0 are required.
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 Part VII
Q&As on Pathology
 What Is the Correct Procedure
for Handling the Surgical Specimen? 30
Nigel Scott

Contents 30.1 Introduction

30.1 Introduction .............................................. 305
In spite of recent developments in the preoperative
30.2 Specimen Dissection and Sampling ........ 306
30.2.1 Specimen Dissection and Macroscopic
imaging of rectal cancer using endoluminal ultra-
Assessment................................................... 306 sound, CT scans, magnetic resonance imaging
30.2.2 Sampling for Microscopic Examination ...... 307 (MRI) and PET-CT, pathological examination of
30.3 Microscopic Examination and Key the operative specimen remains a key part of the
Features in the Pathology Report ........... 308 management of the rectal cancer patient. The
30.3.1 Histological Typing and Grading ................. 309 pathologist’s report allows the patient to be placed
30.3.2 Direct Tumour Spread and pT Stage............ 309
in a prognostic category, indicates the likelihood
30.3.3 Circumferential Resection Margin
Involvement.................................................. 310 of tumour recurrence and determines the need for
30.3.4 Mesorectal Grade ......................................... 311 post-operative adjuvant therapy. A good macro-
30.3.5 APR Grading................................................ 311 scopic description, especially when supplemented
30.3.6 Local Peritoneal Involvement ...................... 312
by high-quality digital images, facilitates audit of
30.3.7 Vascular Invasion ......................................... 312
30.3.8 Lymph Node Metastasis and pN Stage ........ 314 the quality of radiology and surgery. Following
30.3.9 Examination of the Specimen After neoadjuvant treatment, pathological examination
Neoadjuvant Radiotherapy........................... 315 provides an immediate indication of how sensi-
References ............................................................... 316 tive the tumour is to radio- and chemotherapy.
Finally, the accurate recording of a minimum
standardised pathological data set is vital to
stratification and interpretation of clinical trials,
comparison of outcomes between different cen-
tres and health-care systems, evaluation of the
impact of population-based interventions such as
bowel cancer screening and the conduct of epide-
miological studies.
In this chapter, I intend to outline what I con-
sider the most important elements of rectal can-
cer reporting. I do not intend to cover biopsy
N. Scott reporting or evaluation of polypectomy and
Department of Histopathology, local excision specimens but will describe in
Leeds Teaching Hospitals NHS Trust,
St James University Hospital,
some detail the examination of rectal cancer
Leeds, UK after radical surgery. Inevitably, this is written
e-mail: nigel.scott@leedsth.nhs.uk from the perspective of a UK pathologist trained

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 305

DOI 10.1007/978-3-642-25005-7_30, © Springer-Verlag Berlin Heidelberg 2012
306
under the guidance of the Royal College of
Pathologists. Since 1998, the Royal College of
Pathologists minimum data set has provided a
detailed, evidence-based set of instructions for
colorectal cancer reporting, widely available on
the college website [54]. This was last revised in
2007 and is now the standard against which all
UK pathology reports are judged. The introduc-
tion of a reporting proforma to accompany or
replace free text reports has also had a major
impact on the completeness of pathological
reporting in the UK as demonstrated by numer-
ous audits [7]. Proformas are increasingly help-
ful in the construction of large population
databases by cancer registries, and we would
strongly encourage their use.
30.2 Specimen Dissection
and Sampling
30.2.1 Specimen Dissection
and Macroscopic Assessment
Ideally, the resection specimen should be received
fresh and unopened. Digital pictures are taken of
the front and back to demonstrate the quality of
mesorectal excision and any significant perito-
neal pathology, e.g., tumour perforation. The rec-
tum is opened from both ends along the anterior
margin to within 5–10 mm of the tumour. It may
not always be possible to see the tumour clearly,
especially after chemoradiotherapy, but if the
bowel is cut a few millimetres at a time and a
finger inserted into the lumen to palpate the
tumour edge, it is usually possible to avoid cut-
ting into the lesion. The opened rectum is then
pinned to a cork board and immersed in formalin
for 48–72 h. If the tumour is more than 1 or 2 cm
long, a formalin-soaked paper wick can be
threaded through the lumen to facilitate fixation.
Prior to dissection, the specimen is examined
macroscopically and its external appearance
described. This includes the type of operation per-
formed, e.g., abdominoperineal excision or ante-
rior resection; length of bowel resected; location
of tumour with respect to distal resection margin
and peritoneal reflection; any peritoneal abnor-
malities, e.g., tumour perforation; coincidental
N. Scott
polyps, ulcers or colitis; and an assessment of the
completeness of mesorectal excision. The latter
is particularly important when trying to gauge
the quality of surgery and in recent studies has
been shown to be an important prognostic factor
for both loco-regional recurrence and survival.
Mesorectal grading is described in more detail
below. Additionally, in the case of APR speci-
mens, distance from tumour to dentate line is
recorded. Although not widely used at present, a
new grading system has recently been proposed
to reflect the extent of surgical dissection at the
level of the anal canal and ano-rectal junction.
This has not yet entered general practice in the
UK but is described briefly in section 30.3.5 for
completeness.
Tumour dimensions may be difficult to mea-
sure accurately when the tumour-bearing bowel
is left unopened; however, tumour size is not an
important prognostic factor. Moreover, length
and width can usually be estimated adequately
from the tumour slices after dissection.
The mesorectal surface (circumferential resec-
tion margin, CRM) is painted with India ink
(or an appropriate alternative), and the tumour-
bearing segment is sliced in the transverse plane
at 3–5-mm intervals. Slices through the tumour
and surrounding mesorectum are laid out in order
on a white board, with proximal and distal ends
identified, and photographs taken (Fig. 30.1). It is
at this stage that tumour dimensions and macro-
scopic type can be recorded. Slices where tumour
invades closest to the CRM (either by direct
spread or within lymph nodes or vessels) are pho-
tographed individually (Fig. 30.2).
Following a systematic examination of the
tumour slices, the maximum distance of tumour
invasion outside muscularis propria is recorded
as well as the closest point of approach to the
inked circumferential margin. The location of
cancer in the bowel wall is described as involving
anterior, left, right and posterior quadrants or
with reference to a clock face (as viewed from
below), e.g., ‘tumour located between 2 and 7
o’clock’. It should also be recorded where the
CRM is threatened, e.g., ‘tumour invades to
within 2 mm of the CRM at 3 o’clock’.
The mesorectum proximal and distal to the
luminal cancer is sliced in a similar way to look
30 What Is the Correct Procedure for Handling the Surgical Specimen?
Fig. 30.1 Digital image of slices through tumour and mesorectum for presentation at a multidisciplinary team meeting
Fig. 30.2 Slice through tumour and mesorectum show-
ing direct tumour spread to the CRM at 12 o’clock and
satellite tumour deposits within 1 mm of the CRM at
3 o’clock
for lymph nodes and other mesorectal tumour
deposits, but these slices are not routinely photo-
graphed unless the CRM is threatened.
307
Anterior
Proximal
30.2.2 Sampling for Microscopic
Examination
The distal resection margin of the specimen is
examined histologically only if macroscopic
tumour lies within 3 cm. Previous audits indicate
this margin is rarely invaded (<1% of all resec-
tions). The only exception to this rule is where on
histology the carcinoma shows a highly infiltrative
growth pattern, extensive lymphatic channel
invasion or is of signet ring cell type.
At least four blocks of tumour are sampled to
determine tumour type, grade and direct spread
(pT stage). These blocks must include the perito-
neum if tumour extends above the peritoneal
reflection, the area of deepest invasion through
the bowel wall and closest point to the circumfer-
ential margin. Ideally, one or more large (whole
mount) sections including the whole circumfer-
ence of the rectum and surrounding mesorectum
should be processed for histology. These large
sections are particularly useful for correlation
with MRI images at the multidisciplinary team
308
Fig. 30.3 Whole mount H&E stained section showing
pT3 tumour well clear of the inked CRM
(MDT) meeting (Fig. 30.3). Sections through the
tumour are usually taken at right angles to the
bowel wall to demonstrate mural penetration;
however, a recent study suggests that one or more
additional blocks cut tangentially across the outer
surface of muscularis propria may increase the
detection of vascular invasion [44].
At least two blocks of tissue should be sam-
pled where tumour invades close to the perito-
neum. Peritoneal involvement may be suspected
macroscopically from areas of serosal pallor,
retraction or puckering but, in a minority of cases,
may only be detected microscopically. Conversely,
peritumoural fibrosis and inflammation can often
simulate peritoneal invasion, and microscopic
examination is always necessary to correctly
classify the lesion.
Where direct tumour spread or macroscopic
tumour nodules lie within 3 mm of the circumfer-
ential margin, these areas should be sampled for
histology. CRM involvement (CRMI) is defined
as tumour invasion 1 mm or less from the
mesorectal surgical margin. It is important to
note this is not the same as the TNM classification
of an R1 or R2 resection where tumour is actually
present, microscopically or macroscopically, at
the margin, i.e., 0 mm clearance. It is also impor-
tant to note that the peritoneal surface is NOT a
surgical margin, and tumour involving the serosal
surface should not be confused with CRM
involvement or an R1 resection.
N. Scott
The distance between tumour and CRM is
measured using the vernier scale on the micro-
scope or an ocular micrometer. In the case of
involved lymph nodes adjacent to the CRM, the
measurement is made from the edge of the intra-
nodal tumour deposit rather than the lymph node
capsule.
Once blocks have been taken from the primary
tumour, peritoneum and CRM, a careful search
for lymph nodes (and other tumour deposits) is
made by inspection and manual palpation of the
perirectal fat. The vascular pedicle containing the
inferior mesenteric and superior rectal artery
should be identified first and sliced at 2–3-mm
intervals from its cranial tip to identify the lymph
node closest to the high vascular tie. This is the
C2 lymph node as defined in the Dukes staging
system and, although not included in recent edi-
tions of the TNM classification, is nevertheless a
marker of poor prognosis if involved. Most lymph
nodes will be found in the posterior and lateral
quadrants of the mesorectum at the level of the
tumour and immediately above [11]. Nodes are
rarely found in the anterior mesorectum. Tumour
deposits may occasionally be found in the distal
mesorectal fat in which case they are usually
associated with extensive proximal lymphatic
metastasis and a high likelihood of tumour recur-
rence [40].
30.3 Microscopic Examination
and Key Features in the
Pathology Report
Microscopic examination of tissue samples will,
in many instances, confirm the macroscopic
assessments described above. In a proportion of
cases, however, conclusions from the macro-
scopic assessment may have to be modified as a
result of histology, e.g., tumour involvement of
peritoneum versus subperitoneal fibrosis. Finally,
a number of important pathological features can
only be diagnosed by looking down the micro-
scope, e.g., tumour grade, small vessel invasion,
small lymph node metastases, etc. The accurate
assessment of these parameters relies upon ade-
quate sampling of the gross specimen. It cannot
30 What Is the Correct Procedure for Handling the Surgical Specimen?
be emphasised too much that good histology will
never compensate for inadequate macroscopic
examination and an intelligent purposeful
approach to selection of tissue blocks. It may take
30–45 minutes for the proper dissection of a rec-
tal cancer excision specimen, but the extra effort
taken will be more than paid back by the quality
of the report.
The list of pathological prognostic factors
which could be included in a report is large. Core
data items of key importance to the correct man-
agement of patients, quality control of diagnosis
and surgery and prediction of disease recurrence
are more limited however, and include tumour
site, tumour size, relationship to anal canal and
peritoneal reflection, distance to nearest longitu-
dinal resection margin, mesorectal grade, tumour
type, tumour grade, presence of vascular invasion,
pT stage, pN stage, total number of lymph nodes
harvested, pR stage and CRM involvement.
While some of these features have already
been mentioned in the preceding section, a more
detailed description is given below including evi-
dence from clinical and pathological studies
which supports their inclusion as important data
items in the pathologist’s report.
30.3.1 Histological Typing and Grading
Four blocks of tumour are sufficient to type and
grade most rectal carcinomas. Typing is per-
formed according to the fourth edition of the
WHO Classification of Tumours of the Digestive
System [13]. Over 90% are adenocarcinomas and
most are either well or moderately well differen-
tiated. Rarer types of carcinoma encountered in
the rectum include signet ring cell carcinoma,
adenosquamous carcinoma, squamous cell carci-
noma, neuroendocrine carcinoma and undiffer-
entiated carcinoma. Mucinous adenocarcinomas
are defined as tumours in which over 50% of the
tumour volume is made up of extracellular mucin
pools and can be either low or high grade. This
type is more commonly seen in the colon.
Tumour grade reflects how well differentiated
the carcinoma is i.e., the degree to which it
resembles normal rectal (glandular) epithelium.
309
Grade is mainly determined by the extent of gland
formation. In the WHO grading system, tumours
are divided into low- and high-grade categories,
the latter corresponding to poorly differentiated
carcinomas in a three-tier system. In the UK, the
Royal College of Pathologists has proposed that
colorectal adenocarcinomas are graded accord-
ing to the dominant pattern of differentiation,
whereas WHO advises that grade is based on the
least differentiated component [13, 54]. Both
have been shown to correlate with tumour stage
and prognosis.
30.3.2 Direct Tumour Spread
and pT Stage
All pathological reports on rectal cancer must
describe the maximum extent of direct tumour
spread through the bowel wall and provide
the correct TNM stage. Use of Dukes stage is
optional. In the UK, carcinoma is only diagnosed
when neoplastic cells invade through muscularis
mucosae into submucosa. Neoplastic glandular
proliferations confined to the mucosa are, by
common convention, regarded as dysplasia. The
only exception to this rule occurs following neo-
adjuvant therapy where, very occasionally, small
islands of adenocarcinoma are left behind in the
mucosa after extensive tumour regression in the
remainder of the specimen. In this circumstance,
the TNM category pTis can be used. While
intramucosal adenocarcinoma clearly exists, it
is doubtful whether this stage of carcinogenesis
can be consistently recognised using morpho-
logical criteria alone (except where the tumour is
poorly differentiated and invades as single cells),
and the risk of lymph node metastasis in such
early disease is widely regarded as negligible if
it exists at all [16]. pT stage is described in the
seventh edition of the TNM system as: pT0 – no
evidence of primary tumour, pTis – carcinoma in
situ: intraepithelial or invasion of lamina propria,
pT1 – adenocarcinoma confined to the submu-
cosa, pT2 – invasion of muscularis propria, pT3
invasion through muscularis propria into perirec-
tal fat, pT4a – tumour perforation of the visceral
peritoneum and pT4b – direct tumour invasion
310
into other organs or structures [43]. The latter
includes invasion of the levator ani muscle in
advanced low rectal cancers. Other organs com-
monly invaded by aggressive rectal tumours and
included in en bloc excisions or pelvic exentera-
tions include the urinary bladder, seminal vesi-
cles, prostate gland, vagina and uterus. Invasion
of these structures should always be confirmed
by microscopic examination. Occasionally, only
fibro-inflammatory changes are seen in the adhe-
sion between a rectal cancer and excised uterus
or bladder. The prognosis in these patients is bet-
ter than if carcinoma were present, and unless
there is convincing evidence of previous tumour
perforation at this site, the final pT stage should
be pT1–3 rather than pT4. Rectal perforation is
seen in 10–20% of operations and may be either
spontaneous or iatrogenic. Surgical perforation
is particularly likely to occur during an APR
procedure. In an analysis of the Dutch TME-
radiotherapy trial, perforation was documented
in 13.7% of APR specimens and 2.5% of ante-
rior resections, although not all of these occurred
through the tumour and therefore, would not all
qualify as pT4 [27]. Both iatrogenic and spontane-
ous perforations are associated with an increased
risk of tumour recurrence however, and must be
documented in the pathology report.
In addition to pT stage, it is now common
practice in the UK to measure the maximum
extent of direct tumour spread outside the muscu-
laris propria in millimetres. This is usually per-
formed at the time of macroscopic examination
and then confirmed microscopically. Where the
muscularis propria is destroyed by carcinoma, an
estimate is made by extrapolating the line of the
muscle wall from adjacent bowel. Several studies
show that advanced pT3 tumours which have
invaded further outside the bowel wall have a
higher risk of local recurrence and poorer survival
than more superficially invasive lesions [9, 21].
This is found to be true for both node-positive and
node-negative groups. In 2007, the Mercury study
group found that MRI scans were highly accurate
in measuring this parameter preoperatively [20].
Subsequently, this has led to the proposition that
patients could be selected for preoperative radio-
therapy on the basis of MRI determination of
extent of extramural spread, vascular invasion
N. Scott
and threatened CRM [46]. Routinely measuring
extramural invasion is therefore, not only a record
of a valuable prognostic factor but can be used to
audit the quality of magnetic resonance imaging.
30.3.3 Circumferential Resection
Margin Involvement
In 1986 Quirke and colleagues from Leeds, UK,
described the results of the first systematic exam-
ination of the circumferential or radial resection
margin of the rectum [29]. In this seminal paper
they showed a strong relationship between CRM
involvement (CRMI) and local recurrence in the
pelvis. Eleven out of 13 patients (85%) with CRMI
eventually developed a loco-regional recurrence
compared with 3% of those with clear margins.
Prior to this publication most pathologists’ atten-
tion had been concentrated on the distal mural
resection margin. Subsequent studies from Leeds
and elsewhere, including large population-based
series and data from randomised controlled trials,
confirmed the prognostic significance of tumour
at the CRM, defined as carcinoma 1 mm or less
from the resection line, the most recent publica-
tions reporting local recurrence in approximately
20% of CRM-positive cancers compared with
10% if the margin was uninvolved. As well as
being one of the best pathological predictors of
local recurrence, CRM positivity is also predic-
tive of distant metastasis, disease-free survival
and overall survival. In a series of 141 patients
undergoing curative surgery for rectal cancer in
Leeds between 1985 and 1990, CRMI was the
strongest independent prognostic factor together
with lymph node status [2]. Reported series
where preoperative radiotherapy or chemoradio-
therapy has been used likewise show CRMI to be
an important prognostic factor, even after neoad-
juvant therapy [25].
An analysis of the relationship between sur-
vival, recurrence rates and tumour distance from
the CRM has generally supported the validity of
the 1 mm definition with the exception of a single
study from the Dutch TME-radiotherapy trial
which suggested that a 2-mm cut-off was more
effective in defining a poor prognostic group [24, 28].
It is clear, however, that within the group of
30 What Is the Correct Procedure for Handling the Surgical Specimen?
tumours 1 mm or less from the surgical margin,
those which are actually present at the specimen
edge i.e., 0 mm (TNM category R1), have a par-
ticularly high risk of recurrence. For this reason,
it has been suggested that the TNM residual
tumour classification be expanded to accommo-
date CRMI and include two categories of R1:
‘R1-dir’ where distance from carcinoma to the
edge is 0 mm and ‘R1 < 1 mm’ where clearance is
>0 mm but <1 mm [55].
A national audit conducted in the UK between
1999 and 2002, including data from 39 differ-
ent surgical units, found the CRM to be involved
in between 0% and 33% of surgical resections;
overall rate 12.5% [47]. In the Dutch TME-
radiotherapy trial and recently reported MRC
CRO-7 trial in which total mesorectal excision
was the normal practice, the margin was found
to be involved in 18.3% and 12% of unirradiated
patients respectively [24, 28, 35]. Not surpris-
ingly, CRMI was more common in advanced-
stage tumours. In addition, margin involvement
is more common when the tumour is situated low
down in the rectum and an APR is performed
and when the tumour is located anteriorly. Short-
course radiotherapy with immediate surgery has
no impact on CRMI, but chemoradiotherapy and
delayed surgery cause tumour regression; conse-
quently the CRM is less often positive [8].
The CRM can be involved by direct tumour
spread, vascular invasion, perineural spread or
lymph node metastasis. CRMI due to nodal dis-
ease is uncommon according to a recent publica-
tion from the Mercury group where it occurred in
<2% of all cancers and accounted for one in ten
of all positive margins [39]. When assessing
lymph nodes close to the circumferential margin,
it is important for the pathologist to be aware that
the distance measured is that from the edge of the
intranodal tumour deposit rather than the distance
from the lymph node capsule. Two studies have
looked at the relationship between mode of CRMI
and local recurrence. Both have reported that
recurrence rates in patients with CRMI due to
nodal involvement are identical to those with a
negative margin [6, 24, 28]. Until this is corrobo-
rated by larger studies however, tumour within a
lymph node <1 mm from the CRM is still
classified as CRMI.
311
30.3.4 Mesorectal Grade
The mesorectum is an anatomically defined enve-
lope of fat surrounding the rectum and separated
from surrounding structures by a thin mesorectal
fascia. It contains the main vascular supply and
lymphatic drainage of the rectum; consequently
most rectal tumours and involved lymph nodes
will be contained within it. Since it is now widely
believed that many local recurrences can be pre-
vented by careful removal of the mesorectum,
the pathologist should pay particular attention to the
quality of mesorectal excision i.e., whether the
mesorectum is removed intact or not. Quirke has
described a grading system which categorises
the rectal cancer specimen according to whether
the surgeon has dissected outside the mesorectal
fascia (mesorectal plane excision) or cut into the
mesorectum, leaving mesorectal fat behind in the
pelvis: intra-mesorectal and muscularis propria
plane excision [31]. Examples of complete and
incomplete TME are shown in Fig. 30.4. This
mesorectal grading system has been evaluated
in the Dutch and MRC CRO-7 trials of short-
course radiotherapy [24, 28, 32]. In both studies,
mesorectal grade was found to be an indepen-
dent predictor of local recurrence. In the Dutch
study, there was in addition a significant asso-
ciation between plane of surgery and survival in
patients with an uninvolved CRM. Trial data and
single-centre series indicate that deep defects in
the mesorectum exposing muscularis propria are
seen in 13–32% of operations, and that incom-
plete mesorectal excisions are more common
after abdominoperineal resection and where the
CRM is positive [14, 15, 24, 28, 32]. It is impor-
tant in the case of APR specimens however, not
to confuse normal anatomical thinning of the
mesorectum as one approaches the pelvic floor
(ano-rectal junction) with ‘coning’ by the surgeon
who may inadvertently cut into distal mesorectal
fat as he dissects deep into the pelvis.
30.3.5 APR Grading
There is currently some variation between sur-
geons in how an abdominoperineal resection is
performed [52]. While some operators dissect
312
a
b in a more systematic audit of a difficult surgical
Fig. 30.4 (a) Abdominoperineal resection specimen
with ‘mesorectal plane excision’: mesorectum is
bulky with smooth surface and no obvious defects. (b)
Abdominoperineal resection specimen with ‘muscularis
propria plane excision’: mesorectum is irregular with tat-
tered surface and multiple defects exposing muscular wall
down and around the mesorectal fascia to the pel-
vic floor and ano-rectal junction, others perform
a wider perineal resection, excising the levator
muscle which is then left covering the distal part
of the surgical specimen (extralevator abdomi-
noperineal excision). For the pathologist the first
procedure results in an APR specimen with an
hourglass appearance and narrow waist at the
inferior limit of the mesorectum. If the tumour
occupies this area, even very superficial inva-
sion through the muscularis propria or internal
anal sphincer will result in a positive CRM. If,
however, an extralevator excision is performed,
the specimen has a cylindrical shape and CRMI
is reduced. To compliment mesorectal grading
and facilitate the audit of surgery for low rectal
cancer, Nagtegaal et al. proposed that APR speci-
mens should be classified by the pathologist as the
N. Scott
following: (1) intramuscular/submucosal plane
where perforation has occurred or the surgeon has
dissected into muscularis propria, (2) sphincteric
plane where the surgeon has dissected around the
sphincter muscle tube or (3) extralevator plane
where the levator muscle is removed en bloc and
the specimen has a cylindrical appearance [27].
It remains to be seen whether this classification
will have the same prognostic significance as
mesorectal grading, but it will undoubtedly assist
procedure.
30.3.6 Local Peritoneal Involvement
Rectal tumours located at or above the level of
the anterior peritoneal reflection may ulcerate the
peritoneal surface and are classified as TNM
stage pT4a. Few studies have specifically
addressed this pathological feature which occurs
in 5–27% of resected cancers, but there is grow-
ing evidence that microscopic peritoneal involve-
ment is not only associated with an increased risk
of loco-regional failure but is also predictive of
overall survival [36]. In a recent publication,
Mitchard et al. suggested that between 27% and
50% of local recurrences might be attributable to
peritoneal seeding [22]. Peritoneal involvement
in the UK and USA is diagnosed according to
descriptions provided by Shepherd et al. where
tumour cells must be seen at the peritoneal sur-
face associated with inflammation or mesothelial
ulceration [37]. We have found the Shepherd
classification to be highly reproducible between
experienced GI pathologists (kappa values rang-
ing between 0.74 and 0.89) and would strongly
recommend its use. In our study of over 100 cases
of pT3/pT4 colorectal cancer, at least 3 out of 4
pathologists agreed on the presence of LPI in
more than 90% of examinations [17].
30.3.7 Vascular Invasion
Multiple studies have shown that vascular inva-
sion is a significant prognostic factor in rectal
cancer and is correlated with haematogenous
30 What Is the Correct Procedure for Handling the Surgical Specimen? 313

Fig. 30.5 (a) H&E stained

section (×200) of extramural a
vein invasion: this lesion
might easily be missed as
vessel wall is difficult to
identify and lumen is
obliterated by carcinoma.
(b) Elastin Van Gieson
stained section (×200) of
same area as (a): vein wall is
highlighted by black staining
elastic fibres

metastasis to the liver [23, 45]. In a minority of
specimens, invasion of large veins can be recog-
nised macroscopically in tumour slices, but in
most cases the diagnosis is made microscopi-
cally. The frequency with which vascular
involvement is seen varies according to tumour
stage and grade and the method of detection.
Reported rates vary between less than 20% and
60% or more. Increasing the number of tumour
blocks examined and taking sections parallel
rather than perpendicular to the bowel wall may
increase the rate with which invasion is seen.
Routine use of an elastin stain to highlight the
vein wall has been evaluated in several studies
and not only increases detection rate but
improves reproducibility of diagnosis between
different pathologists [1, 50]. Elastin stains are
particularly helpful where a small vein is com-
pletely occluded by the invading tumour and its
wall partially destroyed (Fig. 30.5). Even with-
out these techniques however, extramural venous
invasion (EMVI) should be seen in over 25% of
314
cases and must always be reported. A recent
large population-based study showed that the
5-year survival of patients with stage II disease
(Dukes stage B) and EMVI was significantly
worse than that seen in patients with a single
metastatic lymph node [23]. EMVI therefore,
helps to identify a group of patients with ‘high-
risk’ Dukes B cancers who may benefit from
adjuvant chemotherapy.
30.3.8 Lymph Node Metastasis
and pN Stage
Rectal adenocarcinomas are metastatic to regional
lymph nodes contained within the surgical speci-
men (mesorectal, superior rectal artery and inferior
mesenteric artery nodes) in 35–50% of patients.
Lateral pelvic lymph nodes (also regarded as
regional nodes in the TNM classification) may
be involved by tumour in as many as 10–25% of
patients with pT3/pT4 cancers lying distal to the
peritoneal reflection, but it is unusual in European
and North American surgical practice for the sur-
geon to perform a lateral pelvic lymph node dis-
section, and these nodes are rarely seen by the
Western pathologist.
It is essential that time and effort are spent on
finding as many lymph nodes as possible in the
resection specimen. The total number of lymph
nodes found and the number containing metasta-
ses should always be reported. Although pNX is
applied only to cases where no lymph nodes at all
can be found, the UICC guidelines advise that in
most cases 12 or more nodes should be identified.
Evidence from several studies indicates that the
frequency of lymph node positivity increases
with the number of lymph nodes found and that
patients staged as node negative (TNM stage II)
on the basis of a small lymph node harvest (the
exact figure varies between studies) have a
significantly worse survival outcome than those
where larger numbers of negative nodes are found
[23, 48]. While there are other potential explana-
tions for this relationship, it seems very likely
that failure to sample an adequate number of
nodes in the surgical specimen risks understaging
the patient’s disease. The pathologist needs to be
aware that it cannot be taken for granted that
N. Scott
nodes containing metastases will be large and
easily found; 45–50% of involved nodes are
<5 mm in diameter [3]!
Most pathologists will identify nodes by a
combination of thin slices through the mesorec-
tal and mesocolic fat, visual inspection and
palpation. Fat clearance techniques and lymph
node enhancement solutions e.g., GEWF, can
enhance the lymph node yield but have not yet
been widely adopted, presumably owing to cost,
the greater time required and perceived difficulty
of incorporating such techniques into a busy cut-
up schedule. There is also little evidence that
these methods increase the frequency with which
patients are classified as having nodal metasta-
ses (pN1/pN2) despite substantially improving
overall lymph node yield. Similarly, while there
are one or two studies suggesting that more posi-
tive nodes can be found by cassetting individual
lymph nodes separately, processing the entire
node for microscopic examination, serial slicing
larger nodes and examining smaller nodes at three
or more levels, the evidence is still insufficient
to make clear recommendations on this subject
[49]. For the time being most pathologists will
embed only a fraction of larger nodes and exam-
ine a single section at a single level.
Macroscopic (and microscopic) tumour nod-
ules may occasionally be found in the mesorectal
fat unassociated with residual lymph node struc-
tures. These have been variously called satellite
tumour deposits and mesorectal microfoci [12,
33]. In some cases there is convincing evidence
that these deposits have arisen as a result of
perineural or vascular spread; in other instances,
it is surmised that they represent lymph nodes
outgrown by metastatic tumour deposits. While
these lesions are clearly associated with more
advanced cancers and reduced survival, incorpo-
rating them into the TNM staging system has
caused considerable controversy. Older iterations
have regarded them as lymph node deposits
if 3 mm in size (fifth edition) or, alternatively,
when they possess the rounded outline of a node,
irrespective of size (sixth edition) [41, 42]. The
current seventh edition removes these
qualifications and places them in a distinct cate-
gory of lymph node metastasis i.e., pN1c [43]. In
the UK, the Royal College of Pathologists has
30 What Is the Correct Procedure for Handling the Surgical Specimen?
advised retaining the fifth edition of the TNM
system for routine reporting, but it is question-
able whether all pathologists are able or willing
to apply these rules consistently. A recently pub-
lished pathological review of colorectal cancers
from the UK and Sweden showed that reporting
of these lesions was most reproducible using cri-
teria described in the fifth edition and that the
result of successive changes to the classification
has been to increase the proportion of pN1/pN2
cases in these particular series from 34% using
the fifth edition to 43% using the seventh [26].
30.3.9 Examination of the Specimen
After Neoadjuvant Radiotherapy
Over the past 10–15 years it has become common-
place for surgery to be performed after a period of
preoperative radiotherapy with or without con-
comitant chemotherapy. This usually takes the
form of either short-course radiotherapy adminis-
tered over 5 days followed by resection a week
later or chemoradiotherapy given over several
weeks with a delay of 6–8 weeks before surgery.
After short-course radiotherapy and early surgery
the pathologist will see acute radiation proctitis in
the peritumoural mucosa but little or no evidence
of tumour regression. Results from the Dutch
TME-radiotherapy trial found a modest increase in
the frequency of poorly differentiated mucinous
tumours following this regimen but no evidence of
downstaging [19]. In contrast, chemoradiotherapy
with delayed surgery will produce complete
tumour disappearance (ypT0 ypN0) in 10–20% of
cases and lesser degrees of regression in many of
the others. In these specimens it may be difficult to
identify the tumour macroscopically or reliably
differentiate residual carcinoma from post-radio-
therapy fibrosis. While there is some correlation
between macroscopic appearances and degree of
regression, in up to a third of cases where there is a
good clinical response i.e., minor mucosal abnor-
mality or ulcer scar, residual malignant cells can
still be demonstrated microscopically [5]. In these
cases it is important that the pathologist performs a
sufficiently thorough examination to confirm com-
plete tumour regression which has been shown
to have a very good prognosis [51, 53]. Where
315
complete regression has not occurred, the patholo-
gist needs to sample the remaining cancer widely
enough to allow accurate assessment of lesser
degrees of tumour response and provide reliable
staging. In our experience regression can vary quite
markedly between different parts of the same
tumour, a fact which may be missed if only limited
sampling is performed. While there is no univer-
sally agreed protocol for sampling tumours follow-
ing neoadjuvant treatment, Quirke has suggested
that where no residual tumour is visible macro-
scopically, the whole tumour site should be sliced
at 5–8-mm intervals and processed for microscopy
[30]. If tumour cells are still not seen after com-
pletely embedding the lesion, each block is to be
examined at three levels. Where macroscopic
tumour persists, at least four blocks should be sam-
pled including one large (whole mount) block.
It is also widely recognised that identification
of lymph nodes is more difficult following preop-
erative radiotherapy and lymph node harvests are
significantly reduced. It is our experience, how-
ever, that it is still possible to find more than 12
nodes in most cases if a careful examination is
performed. Interestingly, a recent study suggests
that the relationship between low lymph node
numbers and poorer survival in stage II cancers
described for patients treated by surgery alone
does not hold true after radiotherapy [34]. This
needs to be validated however.
Reporting of T and N stage CRMI, histologi-
cal type and grade, peritoneal involvement and
vascular invasion is identical to that for the
untreated specimen except that the prefix ‘y’ is
used to denote that staging has been performed
after preoperative radiotherapy, e.g., ypT2 ypN1.
Tumour regression grade (TRG) should also be
reported, although its exact role in patient man-
agement is still debated. There is good evidence
that TRGs are prognostic, but it is not clear if
they offer any additional information that is not
provided by TNM stage and CRM status. Despite
this many oncologists will request tumour regres-
sion grading as a measure of the tumour’s radio
and chemosensitivity and the likelihood of
response to future chemotherapy. The most com-
monly employed TRG is that developed by
Mandard et al. for oesophageal cancer [18].
Dworak described a similar system for colorectal
316
Table 30.1 Tumour regression grading: comparison of three commonly used classifications
Mandard et al. [18] TRG 1 TRG 2
No residual Rare residual
cancer cancer cells
Royal College of TRG 1 TRG 2
Pathologists [54]
No residual Minimal residual
tumour cells, tumour. Occasional
mucus lakes microscopic tumour
only foci identified with
difficulty
Beddy et al. [4] TRG 1
No cancer cells, single cells or
small groups of cancer cells
cancer, and more recently, Beddy et al. and the
Royal College of Pathologists have proposed a
simpler classification with three grades instead of
five [4, 10]. These have the advantage of being
more reproducible but still retaining prognostic
significance. Three of these TRG classifications
are described and compared in Table 30.1.
Regressed primary tumours and lymph
node metastases may leave behind areas of
inflammation, fibrosis, calcification and pools of
mucin. These are not to be regarded as evidence
of residual tumour unless tumour cells are actu-
ally seen and do not count towards ypT stage,
ypN stage or CRM involvement. It may be neces-
sary however, to examine multiple levels through
an area of mucin accumulation before one can be
sure that no malignant cells are present, and very
occasionally immunohistochemistry is required
to distinguish between tumour cells and mac-
rophages. In a series of 108 patients undergo-
ing long-course chemoradiation at the Memorial
Sloan-Kettering Cancer Centre, acellular mucin
pools were found in 15% of irradiated cancers
[38]. Follow-up confirmed that the presence of
these pools had no significant impact on survival.
Conclusion
The effective management of rectal cancer
cannot be achieved without the collaboration
of pathologists, radiologists, surgeons and
oncologists cooperating in a multidisciplinary
team. It is only by working together and regular
N. Scott
TRG 3 TRG 4 TRG 5
Fibrosis Residual cancer Absence of
outgrowing outgrowing regressive changes
residual cancer fibrosis
TRG 3
No marked regression
TRG 2 TRG 3
Residual cancer Fibrosis outgrown by cancer or no
outgrown by fibrosis with extensive residual
fibrosis cancer
meetings that we understand which pieces of
information are important for clinical decision
making and where the uncertainties lie. The
recent emphasis on quality control of diag-
nosis and treatment and the introduction of
national guidelines with explicit recommenda-
tions for surgical and pathological audit have
created a new role for pathologists who must
now describe and record features which not
only have a prognostic function, and guide the
selection of adjuvant treatments, but are also a
measure of the quality of surgery performed.
If the pathologist is to achieve these aims
there must be a standardised, evidence-based
approach to examining the rectal cancer speci-
men and an agreed minimum data set which is
collected on every case. In this chapter, I have
set out to describe what I believe to be the most
important elements of rectal cancer reporting
and the evidence, as it currently stands, for
their inclusion in the pathologist’s report.
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 What Is the Prognostic
Value of (y)pT and (y)pN? 31
Nadine Ectors

Contents 31.1 Introduction

31.1 Introduction ................................................... 319
Based on scientific evidence gathered over a couple
31.2 ‘pT’: Pathologic Classification of Primary
Tumour Extent .............................................. 320
of decades, total mesorectal excision (TME) has
been introduced as the standard surgical tech-
31.3 ‘pN’: Pathologic Classification of Lymph
nique in rectal cancer and neoadjuvant chemo-
Node Involvement.......................................... 321
radiation (CRT) has become standard practice
31.4 SLN: Sentinel Lymph Nodes ........................ 322 for advanced rectal cancers. Both therapeuti-
31.5 Isolated Tumour Cells (ITC) and cal approaches, TME and CRT, have generated
Micrometastasis............................................. 323 specific issues related to pathological assessment
31.6 In Between ‘T’ and ‘N’ and Close to ‘V’: of rectal resection specimens (see Part VII). The
Tumour Deposits ........................................... 323 macroscopic and microscopic pathologic assess-
31.7 CRT: y(pT) and y(pN) .................................. 324 ment of the resection specimen provides the
opportunity to achieve the most accurate esti-
References ................................................................. 325
mation of prognosis. In general, rectal cancer is
slow-growing and spreads in a mostly predictable
and gradual fashion. This mode of direct spread
is the basis of anatomical staging. The anatomic
extent of rectal cancer being, still, by far the most
important prognostic factor.
Dr. Cuthbert E. Dukes (1890–1977), a patholo-
gist at St. Mark’s Hospital in London, proposed
in 1929 a classification of rectal cancer based on
findings from pathological examination of the
resected bowel. The classification reflected the
extent of spread of the cancer in view of its prog-
nostic significance. This classification has been
N. Ectors subjected to some revisions and adaptations caus-
Department of Imaging and Pathology, ing some confusion and misinterpretations [30].
University Leuven,
Anyhow, the Dukes’ classification was cited in
Leuven, Belgium
terms of ‘American chaos versus British order’
Activity Center Biobanking, University Hospitals
[31]. The TNM staging system of the American
Leuven, Campus Gasthuisberg, Herestraat 49, 3000
Leuven, Belgium Joint Committee on Cancer (AJCC) and the
e-mail: nadine.ectors@uzleuven.be Union for International Cancer Control (UICC)

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 319

DOI 10.1007/978-3-642-25005-7_31, © Springer-Verlag Berlin Heidelberg 2012
320 N. Ectors

Table 31.1 TNM classification of malignant tumours (seventh edition) – digestive system tumours: colon and
rectum
T Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ: intraepithelial or invasion of lamina propria
T1 Tumour invades submucosa
T2 Tumour invades muscularis propria
T3 Tumour invades subserosa or into non-peritonealized pericolic or perirectal tissue
T4 Tumour directly invades other organs or structures and/or perforates visceral peritoneum
T4a Tumour perforates visceral peritoneum
T4b Tumour directly invades other organs or structures
N Regional lymph nodesa
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1–3 regional lymph nodes
N1a Metastasis in one regional lymph node
N1b Metastasis in 2–3 regional lymph nodes
N1c Tumour deposit(s), i.e. satellitesb in the subserosa, or in non-peritonealized pericolic or perirectal soft
tissue without regional lymph node metastasis
N2 Metastasis in four or more regional lymph nodes
N2a Metastasis in 4–6 regional lymph nodes
N2b Metastasis in seven or more regional lymph nodes
M Distant metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to one organ (liver, lung, ovary, non-regional lymph node(s))
M1b Metastasis in more than one organ or the peritoneum
Changes in TNM7 compared to TNM6
a
Regional lymph nodes of the rectum: superior, middle and inferior rectal (haemorrhoidal), inferior mesenteric, internal
iliac, mesorectal (paraproctal), lateral sacral, presacral and sacral promontory (Gerota). Metastasis in nodes other than
those listed above (e.g., external iliac or common iliac nodes) is classified as distant metastasis
b
Tumour deposits (satellites), i.e. macroscopic or microscopic nests or nodules, in the pericolorectal adipose tissue’s
lymph drainage area of a primary carcinoma without histological evidence of residual lymph node in the nodule, may
represent discontinuous spread, venous invasion with extravascular spread (V1/2) or a totally replaced lymph node
(N1/2). If such deposits are observed with lesions that would otherwise be classified as T1 or T2, then the T classification
is not changed, but the nodule(s) is recorded as N1c. If a nodule is considered by the pathologist to a be a totally replaced
lymph node (generally having a smooth contour), it should be recorded as a positive lymph node and not as a satellite,
and each nodule should be counted separately as a lymph node in the final pN determination

(first publication in 1940) is nowadays the most
universal cancer staging system. The T (tumour), N
(node) and M (metastasis) staging system classifies
tumours according to the anatomic extent. Tumour
staging according to the TNM system is currently
accepted as the strongest prognostic parameter for
different types of cancers, including rectal cancers.
Staging provides clinically applicable prognostic
information for individual patient management
as well as standardization allowing interpreta-
tion and comparison of evidence-based data at a
much broader scale. The TNM classification has
been modified over the years, up to the seventh
edition, attempting to follow the pace of progress
and evidence-based developments in oncology
(Table 31.1) [39, 40].
31.2 ‘pT’: Pathologic Classification
of Primary Tumour Extent
Tumour extent is classified as Tis, T1, T2, T3 and
T4. Changes and discussions relate to sub-
classification.
31 What Is the Prognostic Value of (y)pT and (y)pN?
Unlike other organs, for colorectal carcino-
mas, ‘carcinoma in situ’ (pTis: Carcinoma in situ:
intraepithelial or invasion of lamina propria)
includes lesions limited to the epithelium with an
intact basement membrane as well as invasive
lesions extending into the mucosal lamina pro-
pria up to but not through the muscularis muco-
sae (intramucosal carcinoma). The underlying
argument being that the lamina propria of the rec-
tum contains extremely few lymphatics. However,
the direct link between the number of lymphatic
vessels and the associated risk of lymph node
metastasis has been questioned recently [34].
In pT1 tumours (invasion through the mus-
cularis mucosae into the submucosa but not
into the muscularis propria), the frequency of
lymph node metastasis relates to the depth of
invasion, i.e. the superficial (2%), middle (8%)
and deep (23%) thirds of the submucosa [12,
34]. This sub-classification is especially useful
for the assessment of local excisions of early
lesions.
Tumour extension into the muscularis propria
(pT2), into the subserosa or the non-peritoneal-
ized pericolic or perirectal tissue (pT3) and into
other organs or structures and/or perforating vis-
ceral peritoneum (pT4) has been subject to split-
ting and lumping manoeuvres in, e.g. the TNM
and Japanese staging systems. For example, the
sub-classification of pT3 was included in the
third edition of the TNM supplement (2003) and
is included in the Japanese classification [44].
Data confirming the impact of pT3 sub-
classification on prognosis of patients with rectal
cancer exist; however, it did not find wide accep-
tance probably because of discussions on the
basis and validity of the cut-off values for sub-
classification and the lack of standardized meth-
ods of assessment [25]. More recently, TNM7
introduced differentiation between pT4a and
pT4b, which was previously also addressed in the
third edition of the TNM supplement (2003) [44].
Multivariate analysis having demonstrated that
involvement of the serosa by tumour (pT4b) is an
important independent prognostic factor imply-
ing an increased risk of distant metastasis and a
shorter median survival time [17]. Whether the
risk incurred in pT4a differs significantly from
pT4b and how they relate has been questioned
321
recently [25]. According to the SEER analyses,
prognosis for patients with pT4a is (10–20%
5-year survival) better than prognosis for pT4b,
independently of the N category [10].
For rectal cancer, invasion of the external
sphincter is classified as pT3, while invasion into
the levator ani muscle(s) is classified as pT4 [43].
31.3 ‘pN’: Pathologic Classification
of Lymph Node Involvement
Invasion in regional lymph nodes is classified as
N0, N1 and N2. The risk of metastasis to regional
lymph nodes correlates with the T category and
other parameters (e.g. grade).
The number of positive lymph nodes affects
prognosis for most TN categories of rectal can-
cer. The categories pN1 (1–3 positive regional
LN) and pN2 (³4 positive regional LN) remained
unchanged in TNM7. However, both were sub-
classified in a and b based on numbers of involved
lymph nodes (Table 31.1). Patients staged pN1a
(1 positive regional LN) were shown to have a
3–10% better 5-year relative and observed sur-
vival compared to pN1b (2–3 positive regional
LN), while pN2a (4–6 positive regional LN) have
a 5–20% better 5-year survival than pN2b (³7
positive regional LN) [10]. Nevertheless, some
authors persist arguing on the basis and validity
of the cut-off values for sub-classification.
A high-quality, i.e. complete ‘total mesorectal
excision’ (TME), specimen includes the primary
tumour as well as all regional lymph nodes [1,
24, 33]. The accuracy and predictive value of
stage II (pT3,T4-N0M0) assignment are directly
proportional to the quality of the TME, i.e., the
inclusion of all regional lymph nodes and the
pathological examination of the specimen, i.e.
the retrieval and harvest of all regional lymph
nodes. The minimal acceptable harvest has been
set at 12 lymph nodes [5, 6, 36]. However, ‘lymph
node retrieval in rectal cancer is dependent on
many factors – the role of the tumour, the patient,
the surgeon, the radiotherapist, and the patholo-
gist’, not in the least the pathologist [4, 18].
Although these authors tend to settle for a median
of at least 8 lymph nodes, a number of studies
indicate that examination of increased numbers
322
of lymph nodes is, in itself, associated with an
increased survival advantage (e.g. 18). Moreover,
it has been shown in rectal cancer that lymph
node metastasis are often found in small lymph
nodes (<5 mm diameter) [43].
More recently, the debate has moved away
from the exact number of lymph nodes towards
the lymph node ratio (LNR) as an even better
indicator of prognosis [2, 3, 8, 15, 24, 30]. If the
LNR can be considered as a prognostic factor, it
may have the advantage to be less dependent on
the number of retrieved lymph nodes than stage
[7]. Moreover, in a systemic review, it was pointed
out that marked heterogeneity exists within stage
III patients and LNR may prove useful to stratify
outcome in those patients [2]. Although data look
promising, both publications as well as the SEER
analysis concluded that further evidence is needed
[2, 7, 10]. Independently of the potential of LNR,
it is crucial that the pathology report should
clearly indicate the number of positive lymph
nodes as well as the total number of lymph nodes
examined.
Since the fifth edition of the TNM (1997), the
classification of positive lymph nodes according
to the location along (named) arteries (introduced
as pN3 in TNM4) has been discarded, this in con-
trast to the actual Japanese classification [35]. No
major impact towards patient management is to
be expected.
The regional lymph nodes of the rectum are
superior, middle and inferior rectal (haemor-
rhoidal), inferior mesenteric, internal iliac,
mesorectal (paraproctal), lateral sacral, pre-
sacral and sacral promontory (Gerota). The ‘total
mesorectal excision’ – which ideally should
include all regional lymph nodes – is described
in Japanese literature as a ‘limited resection’.
A Japanese ‘standard resection’ and an ‘extended
resection’ include lateral extensions, i.e. respec-
tively a dissection along the parietal pelvic fascia
and the internal iliac artery and a dissection of the
internal iliac vessels preserving the superior vesi-
cal artery and obturator nerve [1]. Wide pelvic
lymphadenectomies – which do include lymph
nodes along the internal iliac artery – correlate
with increased morbidity and a limited, selective,
improvement of prognosis [45]. Similarly, the
N. Ectors
prognostic significance of apical-node metasta-
sis around the inferior mesenteric artery (IMA)
remains unclear [16]. Therefore, ‘Western’ prac-
tice does not advocate (systematic) extensions of
lymphadenectomies.
Metastasis to non-regional lymph nodes, e.g.
external iliac or common iliac nodes, is classified
as distant metastasis (M1).
31.4 SLN: Sentinel Lymph Nodes
Sentinel lymph node mapping is the standard
nodal staging technique in patients with breast
cancer without gross nodal involvement. This
procedure allows to adapt the extent of the resec-
tion on a case by case basis and thus to avoid
unnecessary extensive surgery, i.e. axillary
lymphadenectomy, to decrease the rate of com-
plications and side effects and to improve quality
of life. The concept is based on the existence and
understanding of an orderly and sequential drain-
age of lymphatic fluid, carrying tumour cells
from the primary tumour through lymphatic ves-
sels and lymph nodes ultimately into the blood
circulation. The procedure consists of preopera-
tive injection and tracing of a marker (blue dye,
radiocolloids) in order to identify and dissect a
sentinel lymph node. The lymph node is sub-
jected to a preoperative extensive pathological
investigation including multiple serial levels with
(in a second time) special/ancillary techniques
(immunohistochemistry, qRT-PCR).
Recently, a number of articles, including sys-
tematic reviews and meta-analysis, have addressed
the issue in rectal cancer [1, 42]. However, the
underlying surgical motive is not applicable in
rectal cancer: involvement of a sentinel lymph
node will not change the extent of the resection
on a case by case basis, i.e. the en bloc resection
of the primary rectal cancer including the regional
lymph nodes; it is the total mesorectal excision,
the cornerstone for locoregional control of rectal
cancer. Moreover, in rectal cancer, sentinel lymph
nodes have been shown not to be representative
of involvement of the locoregional lymph nodes
in an important percentage of patients. Finally,
skip metastasis or aberrant metastasis has been
31 What Is the Prognostic Value of (y)pT and (y)pN?
noted. Therefore, the drainage of lymphatic fluid
in rectal cancer is not sufficiently ‘orderly and
sequential’. Theoretically, mapping of the lym-
phatic drainage of an individual rectal cancer
could be taken into consideration when consider-
ing extended lymphadenectomies. Unfortunately,
specifically, the lateral lymphatic drainage is
extremely variable. In conclusion, sentinel lymph
node mapping in rectal cancer should be consid-
ered as investigational and does not belong to the
routine clinical practice [13, 20].
31.5 Isolated Tumour Cells (ITC)
and Micrometastasis
A micrometastasis is defined, in the TNM staging
system, as a metastasis measuring more than
0.2 mm and less than or equal to 2.0 mm in diam-
eter. Isolated tumour cells (ITC) are defined as
single tumour cells or small clusters of tumour
cells measuring 0.2 mm in diameter or less. The
latter are usually identified by special techniques,
e.g. immunohistochemistry.
According to TNM6 and 7, micrometasta-
sis should be classified as such (abbreviations:
mi or mic) and staged as lymph node positive
(e.g. pN(mi)), owing to their possible malignant
potentiality [37, 39]. In contrast, isolated tumour
cells (ITC) are considered insignificant and thus
should not be taken into account as lymph node
metastasis (pN0). It is explicitly stated that spe-
cial techniques (e.g. multiple tissue levels, immu-
nohistochemistry, qRT-PCR) to detect ITCs are
not recommended for the routine examination of
regional lymph nodes. The pathological report
should clearly mention the number of lymph
nodes involved by micrometastasis and ICTs.
The presence of micrometastasis in colorectal
cancer has been previously investigated, but there
has been no consensus in relation to their prog-
nostic significance, which in part is surely due to
the nature of the studies themselves and other
technical aspects [19]. The prognostic significance
of ITCs is still unproven. Some authors of articles
concerning sentinel lymph node mapping do state
that the main advantage of the sentinel procedure
could well be the improvement of the cancer stag-
323
ing, implying that this additional staging in other-
wise ‘pN0’ patients may improve identification
of potential candidates for adjuvant therapy, how-
ever, up till now without proven benefit [42].
The available data do not provide unequivocal
evidence to support classifying micrometastasis
as positive lymph nodes, let alone to prescribe
adjuvant therapy.
31.6 In Between ‘T’ and ‘N’ and
Close to ‘V’: Tumour Deposits
Tumour deposits are defined, in the TNM staging
system, as irregular discrete tumour deposits in
perirectal fat away from the leading edge of the
tumour and showing no evidence of residual
lymph node tissue, but within the lymphatic
drainage of the primary tumour, are considered
peritumoural deposits nodules. The finding of
tumour deposits (satellites or numerous other
synonyms) has always confronted pathologists
with uncertainty concerning the underlying etio-
pathogenic mechanisms and thus the impossibil-
ity to classify them in a prognostic staging
systems, i.e. as T or N factor or neither of them.
The changes in definitions of tumour deposits
and interpretations in the fifth, sixth and seventh
editions of the TNM classification clearly dem-
onstrate this problem [35, 37, 39]. Unfortunately,
these issues have direct implications concerning
staging and thus treatment of individual patients.
Tumour deposits were first acknowledged
in TNM5 (1997) [35]. The ‘3-mm rule’ stated
that tumour deposits 3 mm or larger in diameter
should be regarded as a positive lymph node.
The implementation of the ‘3 mm rule’ was not
evidence-based, acknowledged post-factum, but
had the advantage of being an ‘objective’ crite-
rium [40]. The next edition of the TNM staging
system (TNM6 2002) introduced controversial
changes [37]. The ‘3 mm rule’ was withdrawn,
and the definitions of lymph nodes as well as
vascular invasion were revised. A tumour nodule
in the pericolic/perirectal adipose tissue without
histological evidence of residual lymph node in
the nodule is classified in the pN category as a
regional lymph node metastasis, as the nodule has
324
the form and smooth contour of a lymph node.
If the nodule has an irregular contour, it should
be classified in the T category and also coded as
V1 (microscopic venous invasion) or V2 if it was
grossly evident, because there is a strong likeli-
hood that it represents venous invasion. This
interpretation elicited major concerns on repro-
ducibility and thus interobserver variability on the
one hand and discussion on biological and clini-
cal underlying evidence on the other hand. These
concerns have been discussed and published in
great length by Philip Quirke and other European
pathologists [11, 26]. The paragraph related to the
tumour deposits, and consequently lymph node
and vascular invasion, has been rewritten, but not
necessarily clarified, in the most recent edition
of the TNM staging system (TNM7 2009) [39]
– tumour deposits (satellites), i.e. macroscopic
or microscopic nests or nodules, in the pericol-
orectal adipose tissue’s lymph drainage area of a
primary carcinoma without histological evidence
of residual lymph node in the nodule, may repre-
sent discontinuous spread, venous invasion with
extravascular spread (V1/2) or a totally replaced
lymph node (N1/2). If such deposits are observed
with lesions that would otherwise be classified as
T1 or T2, then the T classification is not changed,
but the nodule(s) is recorded as N1c. If a nodule
is considered by the pathologist to a be a totally
replaced lymph node (generally having a smooth
contour), it should be recorded as a positive
lymph node and not as a satellite and each nodule
should be counted separately as a lymph node in
the final pN determination. Again, this interpre-
tation elicited major concerns on reproducibility
and thus interobserver variability on the one hand
and discussion on biological and clinical under-
lying evidence on the other hand [21, 27, 40]. In
the meantime, the literature on tumoural deposits
has been thoroughly reviewed concluding that,
indeed, tumoural deposits have an adverse prog-
nostic factor [20]. In a comparative study of two
independent study populations, it was confirmed
that tumoural deposits should be taken into
account in staging patients with colorectal cancer
[22]. However, numerous questions remained to
be addressed as to the definition and reproducibility
and thus interobserver variability before applica-
tion in the TNM classification. Moreover, we still
N. Ectors
do not know if adjuvant therapy in patients sub-
jected to stage migration, following onto these
interpretations, has a true benefit. Therefore, in
a number of European countries, it was decided
that the definitions in TNM5 are the most repro-
ducible and thus should be adhered to, especially
as far as tumoural deposits are concerned [26, 28].
Therefore, it is advisable to indicate the number
of TNM version used (e.g. v5, v6, v7) [41].
As a reminder, the objectives for cancer stag-
ing were defined by the International Union
Against Cancer (UICC) TNM Committee almost
50 years ago in this order: to aid the clinician in
planning treatment, to give some indication of
prognosis, to assist in evaluating the results of
treatment, to facilitate the exchange of informa-
tion between treatment centres and, last but
admittedly not least, to contribute to continuing
investigation of human malignancies [9].
31.7 CRT: y(pT) and y(pN)
Y(pT) and y(pN) refer to a primary tumour and
lymph nodes that have been previously treated by
means of CRT.
Neoadjuvant combined treatment in rectal
cancer is associated with significant tumour
response and downstaging. Minimal residual dis-
ease has been shown to have a better prognosis
than gross residual disease. Thorough pathologi-
cal assessment of rectal resection specimens after
chemoradiation is mandatory (e.g. sampling pro-
tocols, grading systems for tumour response (see
Part VII)) [42] [44].
The College of American Pathologists (CAP)
recommends that (1) tumour regression should
be assessed only in the primary tumour, lymph
node metastases should not be included in the
assessment and (2) acellular pools of mucin in
specimens from patient receiving neoadjuvant
therapy are considered to represent completely
eradicated tumour and are not used to assign pT
stage or counted as positive lymph nodes [43].
The latter statement has received scientific sup-
port from a recent publication addressing
specifically this issue [32].
After neoadjuvant chemoradiation and total
mesorectal excision, lymph node positivity is
31 What Is the Prognostic Value of (y)pT and (y)pN?
associated with significant worse survival time
and time to local recurrence. Neoadjuvant treat-
ment is a well-documented cause of limited
lymph node retrieval (<12) [4, 18]. Lymph node
ratio has been proposed as an alternative prog-
nostic parameter and may possibly show to be a
better independent staging method than absolute
count especially when limited numbers of lymph
nodes have been retrieved [8]. Moreover,
specifically in this setting, the absolute number of
lymph node retrieved may have a less important
impact on prognosis [14].
The consequent application of the TNM7 in
the setting of patients with rectal cancer treated
with neoadjuvant chemoradiation will imply that
a number of patients with tumour regression and
residual tumour foci, interpreted as tumoural
deposits, will be classified in the node positive
group, rightly or wrongly [22].
Conclusions
The TNM classification is a worldwide bench-
mark for reporting the extent of cancer and is
a major prognostic factor in predicting the
outcome of patients and thus a valuable aid
in planning treatment of individual patients.
Mandatory continuous improvement of the
TNM classification should be evidence-based.
The prognostic values of ‘T’ and ‘N’ are facts,
no more, no less. However, the prognostic
values of various subcategories do not always
achieve the same standards of evidence-
based. Communication between the oncology
community and those involved in the TNM
classification in order to create a structured
process for introducing changes is essential
for success.
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 What Is the Prognostic Value
of CRM Involvement? 32
Iris D. Nagtegaal

Contents Last century, the major problem in the treatment

32.1 What Is the CRM? ........................................ 328 of rectal cancer was the very high local recur-
rence rate after surgery. Local recurrence rates of
32.2 What Causes a Positive CRM? .................... 328
30–50% were common and resulted in a very
32.3 Incidence of CRM Involvement ................... 329 poor quality of life and short survival of patients
32.4 The Prognostic Value with rectal cancer. Treatment of these local recur-
of CRM Involvement..................................... 329 rences is difficult and often mutilating. In 1986,
References ................................................................. 330 the landmark paper by Phil Quirke and others [1]
described that involvement of the radial surgical
margin, or circumferential resection margin
(CRM), was the main cause of local recurrence.
This finding, together with the excellent clinical
results by Bill Heald and others with a new surgi-
cal technique [2], total mesorectal excision
(TME), caused a major change in the treatment
and prognosis of rectal cancer patients.
At the same time, there was a shift from post-
operative radiotherapy toward preoperative radio-
therapy. This also strongly improved the prognosis
of rectal cancer patients and decreased the num-
ber of local recurrences. The combination of
TME with short-term preoperative radiotherapy
decreased the frequency of local recurrences even
further [3].
Despite the improvements in outcome for rec-
tal cancer patients, we still need good prognostic
markers. In addition, in order to be able to imple-
ment evidence-based changes in treatment more
quickly, there is an obvious need for surrogate
endpoints. Moreover, changes in organization of
I.D. Nagtegaal health care require careful monitoring of quality
Department of Pathology,
of treatment. Quality indicators are becoming
Radboud University Nijmegen Medical Center,
Nijmegen, The Netherlands increasingly important. With the changes in treat-
e-mail: i.nagtegaal@pathol.umcn.nl ment, the role of the CRM has been doubted.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 327

DOI 10.1007/978-3-642-25005-7_32, © Springer-Verlag Berlin Heidelberg 2012
328
In this chapter, I will demonstrate that the CRM
is a very good prognostic marker, a surrogate
endpoint, as well as a quality indicator.
32.1 What Is the CRM?
The CRM, also known as radial or lateral resec-
tion margin, is the surgical soft tissue margin cre-
ated by careful cleavage of (ideally) the mesorectal
fascia. This cleavage creates a fat envelope that
encompasses the tumor, the mesorectal lymph
nodes, and tumor deposits, resulting in a radical
resection (Fig. 32.1). The CRM should be
reported as the shortest distance from the tumor
to the resection margin. For identification pur-
poses, the margin should be inked during the
pathology workup. A margin of 1 mm or less is
generally considered positive, although a number
of studies show that also patients with a margin
of 2 mm or less are at increased risk [4, 5]. With
an increasing distance from the CRM, the risk of
local recurrence decreases, so it is advisable to
mention the exact margin for each individual
patient in order to determine the risk of this
patient.
The CRM can be determined by the primary
tumor or positive lymph nodes, tumor deposits,
perineural growth, or extramural vascular invasion.
Mesorectal
fascia
Circumferential
resection margin
Tumor
Lymph
node
Fig. 32.1 Histological scan of a rectal carcinoma. The
tumor is growing in the muscularis propria, and the
mesorectal fat column has been remove completely, thus
creating a free circumferential resection margin
I.D. Nagtegaal
Lymph node metastases in the CRM were associ-
ated with a lower than expected local recurrence
rate; however, only 42 of these patients have been
described [4, 6].
32.2 What Causes a Positive CRM?
Both tumor-related and surgery-related factors
determine the risk of a positive CRM [7]. Very
few studies concern the patient-related factors
that contribute to the risk of CRM positivity, and
their results are conflicting.
There is an obvious correlation of CRM + with
TNM stage. Advanced stage increases the risk on
CRM involvement, which has been observed by
many authors [7]. Both increasing depth of tumor
invasion and the presence of tumor deposits and
involved lymph nodes contribute to this correla-
tion. More positive margins are present in tumors
that have an ulcerative growth pattern, and in
tumors that show a stenosing growth pattern.
Bigger tumors more often have a positive CRM.
Histologic factors that are associated with
positive CRM are an infiltrating margin, poor dif-
ferentiation, and vascular invasion. No significant
relationship with tumor budding was observed.
Moreover, poor differentiation in submucosal
transanal biopsies is predictive of CRM involve-
ment (OR 10.8 (95% CI 1.7–67.1)), as is vascular
invasion (OR 16.1 (95% CI 1.9–139.2)) [8]. The
same is true for biopsies with mucinous carcino-
mas [9].
There are more positive margins in tumors
located in the lower rectum than in the middle
and upper rectum. We believe the main cause of
this is the difference in surgical technique applied
and the different local anatomy. Many studies
observed higher CRM + in APR-operated patients
compared to LAR. Perforations are more com-
mon in APR and associated with an increased
CRM+. The mesorectal excision plane is more
often on the muscularis propria, and in the sphinc-
ter area, the plane of resection is often in either
the lumen, submucosa, or in the sphincters.
There is a large variation between surgeons in
the percentage of positive CRM [6], but due to
training, there is a marked improvement to be
32 What Is the Prognostic Value of CRM Involvement?
gained. By judging the quality of the surgery per-
formed by evaluating the completeness of
mesorectal excision, we proved the direct rela-
tion between CRM + and quality of surgery. In
two large randomized multicenter trials [10–12],
we demonstrated that if the mesorectum is
removed as a whole (i.e., the resection margin is
on the mesorectal plane), very few positive mar-
gins are present and local recurrence rates are
very low [10–12]. In contrast, when the plane of
resection is on the muscularis propria, CRM
involvement is common and local recurrence
rates are high. The plane of resection can explain
why, in a few cases (1.1% [6], 2.0% [4]), positive
CRMs are present in TNM stage I tumors.
32.3 Incidence of CRM Involvement
Large differences exist between centers with
regard to the number of CRM + patients, percent-
ages ranging from 1% to 28% in curatively oper-
ated patients. Various factors should be taken into
account when reviewing these percentages. The
percentage of CRM + patients is dependent on
patient selection, performance of preoperative
imaging, preoperative long-course therapy, surgi-
cal technique, and skill of the pathologist.
Frequencies of CRM involvement in single cen-
ter studies should thus be treated with caution.
On the other hand, less variability is present in
the population-based studies, ranging from 8% to
13%. In these studies, there is a difference in
patient selection as well, reflected by differences
in the number of node-positive patients ranging
from 21% to 40%.
Randomized neoadjuvant trials give insight to
mechanisms by which negative CRMs can be
obtained. Short-course 5 × 5 Gy does not influence
the percentage of positive margins, as could be
expected by the lack of downstaging due to this
regimen. When comparing short-course radio-
therapy with long-course chemoradiation, there
is a difference, 13% versus 4% involved margins,
p = 0.017 [13]. In this study, downstaging is
observed as well, 48% versus 32% TNM III
(p = 0.007). The addition of 5FU/folinic acid to
long-term radiotherapy does not decrease the
329
numbers of positive margins, although there was
more downstaging in the radiochemotherapy arm
(p < 0.001) [14]. From the frequencies in the non-
randomized neoadjuvant studies, no conclusions
can be drawn about the efficiency of regimens to
reduce positive margins, due to the variability in
inclusion criteria, treatment schemes, and lack of
pathology quality control.
32.4 The Prognostic Value
of CRM Involvement
High local recurrence rates ranging from 25% to
50% in the past have markedly reduced in recent
years, due to changes in surgical approach com-
bined with neoadjuvant therapy. The recognition
of CRM involvement as one of the main causes of
local recurrence has led to the global introduction
of TME, resulting in fewer positive margins and
less residual disease. Since predictive values
depend strongly on the prevalence of local recur-
rence, the role of CRM was expected to be less
prominent after the introduction of the TME pro-
cedure. However, this does not appear to be the
case owing to the variability of the quality of
TME. Due to the lower local recurrence rates,
both the sensitivity and the positive predictive
value of circumferential margin involvement have
decreased. However, after TME treatment, local
recurrence can be predicted with a high specificity
(92%) and a high negative predictive value (95%),
which are both clinically relevant [15].
A recent review [7] evaluated the prognostic
value of the CRM in a meta-analysis of 17,568
patients, described in the literature between 1985
and 2006. From these analyses, it became very
clear that CRM is an important predictor of local
recurrence. In 4,899 patients treated with surgery,
only a positive resection margin increased the
risk of local recurrence (HR 2.0, 95% CI
1.4–2.9).
The addition of neoadjuvant therapy (varying
from short-course radiotherapy to long-course
radiochemotherapy depending on national guide-
lines and patient selection based on diagnostic
imaging) was expected to compensate for poor
surgical performance and to diminish the role of
330
the CRM. However, when comparing neoadju-
vant studies with non-neoadjuvant studies, a
significant difference in hazard ratio is observed:
6.3 (95% CI 3.7–16.7) versus 2.0 (95% CI 1.4–
2.9). In other words, in contrast to the expecta-
tions, a positive CRM is a more powerful predictor
of local recurrence in patients treated with neoad-
juvant therapy. One could argue that this might
be due to the fact that patients treated with neoad-
juvant therapy are usually patients with locally
advanced tumors. CRM involvement can be seen
as tumor resistance to therapy and indicate a lack
of downstaging. Indeed, when downstaging
occurs, the distance of tumor to the CRM
increases in some but not all studies [14, 16].
However, in patients treated with 5 × 5 Gy, no
downstaging occurs, and still the hazard ratios
are 3.8 and 2.3 (no neoadjuvant therapy, 95% CI
3.3–5.6 and 1.9–3.0) versus 10.0 and 5.3 (5 × 5 Gy,
95% CI 6.7–25.0 and 3.6–10.0). Thus, the effect
of CRM involvement was significantly more pro-
nounced in the patients who were treated with
neoadjuvant therapy, without the downstaging.
To monitor the effects of neoadjuvant treat-
ment on the histology of the tumor, various tumor
regression grading systems (TRG) have been
employed over the years. These pathological
evaluations are based on the relative amount of
tumor cells present and the desmoplastic reac-
tion. The definitions used in the different studies
vary and reproducibility is poor. Despite these
disadvantages, TRG has been suggested as a sur-
rogate and early outcome parameter for neoadju-
vant trials. When comparing the value of CRM
with TRG [7], four independent studies demon-
strate superiority of CRM above TRG in a multi-
variate model.
All studies that included the development of
distant metastases as a separate outcome vari-
able (total n = 2,267) show a significant differ-
ence in prognosis between the CRM + and the
CRM − patients (HR 2.8, 95% CI 1.9–4.3). No dif-
ference is observed between the patients treated
with or without neoadjuvant therapy.
The relation of CRM involvement and patient
survival is not clear from all studies, probably
due to lack of statistical power. However, when
all studies are summarized, there is a clear and
I.D. Nagtegaal
significant relation with CRM, both in the neoad-
juvant setting as well as in the patients treated
with surgery alone (n = 6,148, HR 1.7, 95% CI
1.3–2.3). A recent study investigated the value of
CRM for survival in a multivariate model and
found that CRM is more important than T-stage.
In combination with lymph node status, CRM
status provides a better prognostic model than the
current TNM system [17, 18].
Conclusions
The circumferential margin has been around
for over 25 years. Although the treatment of
rectal cancer has changed significantly over
those years, achieving large improvements in
prognosis, the prognostic value of the CRM is
still there. A positive margin after neoadjuvant
therapy implies a major increase in local recur-
rence risk. In addition, CRM + increases the
risk on development of distant metastases and
decreases overall survival, both in univariate
as in multifactorial analyses.
In addition, a free CRM can be used as a sur-
rogate marker for effectiveness of neoadjuvant
therapy. CRM evaluation, together with grad-
ing of the quality of surgery, is the most impor-
tant quality indicator for surgical treatment.
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conventionally fractionated radiochemotherapy.
Radiother Oncol 72(1):15–24
14. Bosset JF, Calais G, Mineur L et al (2005) Enhanced
tumorocidal effect of chemotherapy with preoperative
radiotherapy for rectal cancer: preliminary results –
EORTC 22921. J Clin Oncol 23(24):5620–5627
15. Wibe A, Rendedal PR, Svensson E et al (2002)
Prognostic significance of the circumferential resec-
tion margin following total mesorectal excision for
rectal cancer. Br J Surg 89(3):327–334
16. Rullier E, Goffre B, Bonnel C, Zerbib F, Caudry M,
Saric J (2001) Preoperative radiochemotherapy and
sphincter-saving resection for T3 carcinomas of the
lower third of the rectum. Ann Surg 234(5):633–640
17. Nagtegaal ID, Gosens MJ, Marijnen CA, Rutten HJ,
van de Velde CJ, van Krieken JH (2007) Combinations
of tumor and treatment parameters are more discrimi-
native for prognosis than the present TNM system in
rectal cancer. J Clin Oncol 25(13):1647–1650
18. Gosens MJ, van Krieken JH, Marijnen CA et al (2007)
Improvement of staging by combining tumor and
treatment parameters: the value for prognostication in
rectal cancer. Clin Gastroenterol Hepatol 5(8):
997–1003
 What Is the Prognostic
Value of TRG? 33
Fabio M. Vecchio

Contents Abbreviations
33.1 Definition and Grades of TRG ..................... 333
CRT Chemoradiotherapy
33.2 Prognostic Significance of TRG ................... 336
CSS Cancer-specific survival
References ................................................................. 337 DFS Disease-free survival
m-RCRG Modified version of rectal cancer
regression grade
RCPath Royal College of Pathologists
RCRG Rectal cancer regression grade
TRG Tumor regression grade
ypTNM TNM staging after neoadjuvant
therapy

33.1 Definition and Grades of TRG

Tumor response to preoperative chemoradiother-

apy (CRT) varies from the total regression of the
tumor with complete absence of tumor cells to
no regression at all. Many studies have demon-
strated that a good response to preoperative CRT
is a favorable prognostic factor. Therefore, an
accurate evaluation of tumor response is useful
for predicting oncologic outcomes and planning
further treatment. The term tumor regression
grade (TRG) was firstly introduced by Mandard
et al. in 1994 [3]. The authors examined 93
resected specimens from patients affected by
esophageal carcinoma treated with preoperative
CRT. They found that TRG was a significant pre-
F.M. Vecchio dictor of disease-free survival (DFS). In their
Department of Pathology,
study, Mandard et al. defined five grades of TRG,
Università Cattolica S.Cuore,
Largo F.Vito, 1, 00168 Rome, Italy ranging from TRG 1 characterized by complete
e-mail: fmvecchio@rm.unicatt.it regression to TRG 5 with no regression at all.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 333

DOI 10.1007/978-3-642-25005-7_33, © Springer-Verlag Berlin Heidelberg 2012
334
Table 33.1 Mandard and Dworak TRG
Mandard TRG Dworak TRG
Definition Score Score Definition
Absence of tumor cells 1 4
Residual cancer cells scattered through the 2 3
fibrosis
Fibrosis outgrowing residual cancer cells 3 2
Residual cancer cells outgrowing fibrosis 4 1
Absence of regressive changes 5 0
Tumor regression was assessed by examining the
residual cancer cells and scoring both cytologi-
cal changes and stromal changes. On the basis of
the combination of these findings, tumor regres-
sion was classified according to the five grades,
reported in Table 33.1.
The main advantage of Mandard’s TRG was that
regression was assessed only by comparing the pro-
portion of residual carcinoma to scarring by a very
simple and reproducible method. In fact, this method
was promptly applied also to rectal cancer treated
with preoperative CRT. In 1997, Dworak et al.
adopted a very similar grading of regression exam-
ining the surgical specimens of 17 patients with rec-
tal carcinoma after CRT [2]. Like Mandard et al.,
they designed five regression grades, but defined
and named them in a different way. Dvorak TRG
varies from grade 0 with no regression to grade 4
with no tumor cells (see Table 33.1, showing the
correspondence between the Mandard and Dworak
TRG systems). In 17 specimens studied by Dworak,
no case of total regression was observed after stan-
dardized pathological workup, i.e., embedding of
the whole suspicious area in paraffin blocks and step
sectioning, if necessary. They pointed out that the
demonstration of residual tumor depended mainly
on the accuracy of the pathological technique.
In 2002, two other different regression grad-
ing systems were proposed by Ruo and by
Wheeler [6, 10]. Ruo et al. analyzed the long-
term prognostic significance of selected clinico-
pathologic factors, including the extent of
pathologic response in 69 patients with locally
advanced rectal cancer. They recorded rectal can-
cer response as percentage histologic response,
ranging from no evidence of treatment effect
(0%) to a complete response with no viable tumor
identified (100%) by a 6-point grading scale:
F.M. Vecchio
No tumor cells (total regression)
Very few (difficult to find) tumor cells in fibrotic
tissue
Dominant fibrotic changes with few tumor cells or
groups (easy to find)
Dominant tumor mass with obvious fibrosis
No regression
No response (%) Grade response 0
1–33 Grade response 1
34–66 Grade response 2
67–95 Grade response 3
96–99 Grade response 3+
100 Grade response 4
In the conclusions of their study, Ruo et al.
found that a marked response to preoperative
radiotherapy ± chemo was clinically associated
with fewer recurrences and good long-term out-
come, but was not an independent predictor of
recurrence-free survival.
Wheeler et al. quantified the histologic regres-
sion of rectal cancer after irradiation in a study on
42 patients. They proposed a 3-point rectal can-
cer regression grade (RCRG).
RCRG 1 was characterized by “good” radio-
responsiveness with sterilization or only micro-
scopic foci of adenocarcinoma remaining. In
RCRG 2, macroscopic disease was present asso-
ciated with marked fibrosis. Finally, RCRG 3
indicated a “poor” response with abundant mac-
roscopic disease and little or no fibrosis. Wheeler
stressed the importance of determining RCRG
by the consideration that as radiotherapy reduced
the number of viable cells present in field of
treatment, it seemed appropriate to use a patho-
logic staging system that measured tumor regres-
sion in addition to the traditional TNM staging
after neoadjuvant therapy (ypTNM). Tumors
with the same ypT stage may have different
TRG because ypTNM staging does not differen-
tiate tumors with quite different responses to
CRT. In these cases, RCRG may aid prediction
of prognosis.
Rodel et al. in 2005 evaluated prognostic
significance of TRG on surgical specimens of
33 What Is the Prognostic Value of TRG?
Table 33.2 Dworak and Rodel TRG
Dworak TRG Rodel TRG
Definition Score Definition
No tumor cells (total 4 Complete regression
regression)
Very few (difficult to 3 Good regression
find) tumor cells in >50% of tumor mass
fibrotic tissue
Dominant fibrotic 2 Moderate regression
changes with few tumor with fibrosis
cells or groups (easy to ³25–50% of tumor
find) mass
Dominant tumor mass 1 Minor regression
with obvious fibrosis with fibrosis <25%
of tumor mass
No regression 0 No regression
Complete pathologic response
Intermediate pathologic response
Poor tumor response
385 patients treated with preoperative CRT [5].
They defined a 5-point TRG derived from Dworak
scale with some modifications (see Table 33.2).
Rodel incorporated Dworak TRG 3 and 2 in TRG
3 and split Dworak TRG 1 in TRG 2 and 1. TRG
0 and 4 remained unmodified. On this basis,
Rodel grouped TRG by a 3-grade system. They
reported that 5-year DFS after CRT and curative
resection was 86% for TRG 4 with no tumor cells
(complete pathologic response), 75% for grouped
TRG 2 + 3 with regression ³25% of tumor mass
(intermediate pathologic response), and 63% for
grouped TRG 0 + 1, with regression <25% of
tumor mass (poor tumor regression).
In 2005, Ryan et al. proposed a modified
Mandard score with a 3-point TRG in which TRG
1 grouped the Mandard TRG 1 and TRG 2, TRG
2 was equivalent to Mandard grade 3, and TRG 3
grouped the Mandard TRG 4 and TRG 5 (see
Table 33.3) [7]. In their study based on 60 patients
with a mean follow-up of 22 months, the Authors
emphasized that TRG 1 and 2 could be consid-
ered a complete pathologic response and that the
modified 3-point TRG had the advantage of bet-
ter reproducibility, with similar prognostic
significance.
Another method of grading the degree of
tumor regression post CRT in rectal cancer was
the system proposed in 2007 by Royal College of
Pathologists (RCPath) included within the 2nd
335
Table 33.3 Mandard TRG and Ryan and Vecchio
modifications
Mandard Ryan Vecchio
score score score
Absence of tumor cells 1 1 1
Residual cancer cells 2 2
scattered through the
fibrosis
Fibrosis outgrowing 3 2
residual cancer cells
Residual cancer cells 4 3 3
outgrowing fibrosis
Absence of regressive 5
changes
edition of dataset guidelines for colorectal can-
cer reporting. The system defined the following
categories:
(A) No residual tumor cells and/or mucus lakes
only
(B) Minimal residual tumors, i.e., only occa-
sional microscopic tumor foci, are identified
with difficulty
(C) No marked regression
In 2009, Bateman et al. proposed a modified
version of Wheeler RCRG (m-RCRG) in which
the key change was the inclusion of a more
detailed definition of each category (Table 33.4)
[1]. In their study performed by reviewing the
rectal excision specimens from 54 patients,
Bateman et al. compared the utility and reproduc-
ibility of three different TRG scoring system: the
Mandard TRG, the modified RCRG, and RCPath
Cancer Dataset method. They concluded that all
three scoring systems were usable in a diagnostic
setting and all with acceptable degrees of interob-
server agreement. The authors favored the use of
m-RCRG for the assessment of rectal cancer
specimens after neoadjuvant therapy because the
m-RCRG system provided the optimum balance
between applicability and the accurate recording
of low, moderate, and high tumor regression.
They also suggested that regression grade scoring
must be entirely based on the microscopic pres-
ence of residual tumor, rather than including mac-
roscopic features suggestive of residual tumor.
Finally, in 2010, Vecchio et al. examined the
relationship between TRG and 10-year outcomes
in 502 patients with locally advanced rectal cancer
treated with preoperative RCT [9]. They proposed
336
Table 33.4 Wheeler RCRG and Bateman m-RCRG
RCRG 1 Sterilization or only microscopic foci of
adenocarcinoma remaining, with marked
fibrosis
m-RCRG 1 The macroscopic features may be varied.
Microscopy reveals no tumor epithelium
or scattered foci of malignant epithelium
comprising <5% of the overall area of
abnormality. Mucin pools may be present
but do not contain malignant epithelium
RCRG 2 Marked fibrosis, but macroscopic disease
present
m-RCRG 2 The macroscopic features may be varied.
Microscopy reveals a combination of
viable tumor epithelium and fibrosis.
Malignant epithelium comprises 5–50%
of the overall area of abnormality
RCRG 3 Little or no fibrosis with abundant
macroscopic disease
m-RCRG 3 The macroscopic and microscopic
features may not be significantly different
to cases in which neoadjuvant therapy has
not been given. Over 50% of the area of
abnormality comprises malignant
epithelium. Some fibrosis may be present
but no more than that commonly seen as
desmoplastic stroma in cases where no
neoadjuvant therapy has been given
a simplification of Mandard score in three grades
(see Table 33.3):
TRG 1: Complete regression with absence of
tumor cells.
TRG 2: Incomplete regression with fibrosis
predominant on cancer cells.
TRG 3: Absent or poor regression with resid-
ual cancer outgrowing fibrosis.
33.2 Prognostic Significance of TRG
Apart from the chosen method, tumor regression
after preoperative RCT has been found to have
prognostic significance [5, 8]. Vecchio et al.
examined the relationship between TRG and out-
come in 144 patients with rectal cancer treated
with preoperative CRT and with a median follow-
up of 72 months. They quantified TRG in five
grades according to Mandard score and com-
bined TRG 1–2 and TRG 3–5. They found that
TRG was a predictor for local failure, metasta-
ses-free survival, DFS, and overall survival. By
F.M. Vecchio
multivariate analysis, only ypN (p < 0.001) and
TRG (p = 0.005) significantly predicted improved
DFS. Moreover, TRG predicted the incidence of
positive nodes (p < 0.0001). Vecchio et al. con-
cluded that, given the ability of TRG to predict
those patients with N+ disease, it might be help-
ful, in combination with other clinicopathologic
factors, in selecting patients for a more conserva-
tive procedure following CRT such as local exci-
sion rather than radical surgery.
Rodel et al. evaluated TRG on surgical speci-
mens of 385 patients with 5-year outcome and
concluded that complete and intermediate patho-
logic response suggested improved DFS after
preoperative CRT. They found that complete
regression of the primary tumor was associated
with better control of disease in lymph nodes
(ypN positive, 10%) and a minor risk to develop
distant metastases (DFS, 86%). Intermediate
tumor regression was associated with intermedi-
ate risk of lymph node involvement (ypN posi-
tive, 32%) and an intermediate prognosis (DFS,
75%). Patients with tumors showing poor tumor
regression also had more advanced ypT catego-
ries, higher incidence of nodal involvement (ypN
positive, 42%), and unfavorable outcome (DFS,
63%). In their study, Rodel et al. did not find any
significant relationship of TRG to specific pre-
treatment characteristics, such as the cT and cN
categories, and hypothesized that tumor regres-
sion after preoperative CRT was a multifaceted
phenomenon that appeared to be associated with
smaller, less aggressive disease and may also cor-
respond to the molecular tumor profiling regulat-
ing treatment response. There is evidence that
positive lymph nodes, after preoperative CRT
indicating an aggressive potential of the malig-
nant cells associated with resistance toward CRT,
suggest an unfavorable prognosis irrespective of
any TRG of the primary tumor [5]. In a recent
paper, Min et al. investigated the clinical impact
of TRG after preoperative CRT for locally
advanced rectal cancer especially in lymph node
negative patients [4]. They studied a group of 178
patients who had cT3–T4 tumors and examined
the prognostic significance of TRG in comparison
with histopathologic staging. They found that
TRG was an independent prognostic factor for
33 What Is the Prognostic Value of TRG?
the cancer-specific survival (CSS) of the ypN0
patients and that TRG had a stronger impact on
the CSS of ypN (−) patients (p = 0.002) than on
that of the ypN (+) patients (p = 0.521).
An accurate prediction of CSS requires both
information on the number of residual cancer
cells (by TRG) and on their location in rectal wall
and perirectal tissue (by ypT stage). Therefore,
TRG determination is the logical complement to
traditional ypTNM staging when considering
patients for further adjuvant therapy. As TRG
defines the amount of residual cancer cells after
preoperative CRT, further investigations are man-
datory in order to define the quality of neoplastic
cells and their behavior, especially in patients
without lymph node metastasis. Identification of
factors indicating a more aggressive phenotype
and/or resistance toward CRT may contribute to
improve the prognostic value of TRG and to
allow tailoring of treatment.
References
10. Wheeler JM, Warren BF, Mortensen NJ et al (2002)
1. Bateman AC, Jaynes E, Bateman AR (2009) Rectal
cancer staging post neoadjuvant therapy – how should
the changes be assessed? Histopathology 54:713–721
2. Dworak O, Keilholz L, Hoffmann A (1997) Pathologic
features of rectal cancer after preoperative radiochemo-
therapy. Int J Colorectal Dis 12:19–23
337
3. Mandard AM, Dalibard F, Mandard JC et al (1994)
Pathologic assessment of tumor regression after pre-
operative chemoradiotherapy of esophageal carci-
noma. Cancer 73:2680–2686
4. Min BS, Kim NK, Pyo JY et al (2011) Clinical impact
of tumor regression grade after preoperative chemora-
diation for locally advanced rectal cancer: subset
analyses in lymph node negative patients. J Korean
Soc Coloproctol 27:31–40
5. Rodel C, Martus P, Papadoupolos T et al (2005)
Prognostic significance of tumor regression grade
after preoperative chemoradiotherapy for rectal can-
cer. J Clin Oncol 23:8688–8696
6. Ruo L, Tickoo S, Klimstra DS et al (2002) Long-term
prognostic significance of extent of rectal cancer
response to preoperative radiation and chemotherapy.
Ann Surg 236:75–81
7. Ryan R, Gibbons D, Hyland JMP et al (2005)
Pathologic response following long-course neoadju-
vant chemoradiotherapy for locally advanced rectal
cancer. Histopathology 47:141–146
8. Vecchio FM, Valentini V, Minsky BD et al (2005) The
relationship of pathologic tumor regression grade
(TRG) and outcomes after preoperative therapy in rec-
tal cancer. Int J Radiat Oncol Biol Phys 62:752–760
9. Vecchio FM, Barba MC, Gambacorta MA et al (2010)
Pathologic tumor regression grade and 10-year out-
comes in 502 patients with rectal cancer treated with
preoperative therapy. Mod Pathol 23(Suppl):171
Quantification of histologic regression of rectal cancer
after irradiation. Dis Colon Rectum 45:1051–1056
 Part VIII
Q&As on Multidisciplinary Team Management
 What Are the Recommendations
to Ensure a Successful 34
Multidisciplinary Team
in Rectal Cancer?*

Sujay Shah, Pawan Mathur,

and Robert Glynne-Jones**

34.7 Health-Care Professionals: The Team ..... 344

Contents 34.7.1 Representation and Attendance ................... 344
34.1 Introduction ................................................ 341 34.7.2 Roles of Individuals ..................................... 344
34.7.3 Is There a Role for Training? ....................... 345
34.2 Do MDTs Improve Clinical 34.7.4 The Meetings ............................................... 345
Outcomes? .................................................. 342 34.7.5 Is Videoconferencing a Good Idea? ............. 345
34.3 What Are the Challenges 34.7.6 The Patients’ Perspective ............................. 347
Facing MDTs? ............................................ 343 34.7.7 The Process .................................................. 347
34.7.8 Data Collection ............................................ 347
34.4 What Are the Primary Functions 34.7.9 Feedback ...................................................... 347
of an MDT?................................................. 343
34.8 What Are the Next Steps? ......................... 348
34.5 What Are the Markers
of a Successful MDT? ................................ 343 34.9 What Is the Future of MDT Working? .... 348

34.6 What Recommendations Can Be References ................................................................. 349

Made for Ensuring a Successful
Multidisciplinary Team Meeting? ............ 344

34.1 Introduction

In the UK, multidisciplinary team discussions

started with the formation of breast cancer teams
nearly 20 years ago and have expanded across all
tumour types over the past decade. It was further
promoted by the 1995 Calman-Hine report – ‘A
policy framework for commissioning cancer ser-
vices’ and the ‘Improving Outcomes Guidance’
S. Shah (IOG). A multidisciplinary team is defined as a
Mount Vernon Cancer Centre, Northwood, ‘group of people of different healthcare disci-
Middlesex, UK
plines, which meets together at a given time
P. Mathur (whether physically in one place, or by video or
Mount Vernon Cancer Centre, Northwood,
Middlesex, UK
**
R. Glynne-Jones (*) This chapter is based on literature searches, analysis of
Mount Vernon Cancer Centre, Northwood, UK national peer review data and results from a national
Middlesex, UK survey of UK MDT members. On Behalf of the Barnet
e-mail: rob.glynnejones@nhs.ne Colorectal Cancer Multidisciplinary Team.

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 341

DOI 10.1007/978-3-642-25005-7_34, © Springer-Verlag Berlin Heidelberg 2012
342
teleconferencing) to discuss a given patient and
who are each able to contribute independently to
the diagnostic and treatment decisions about the
patient’. Multidisciplinary teams were originally
introduced to counter the apparent shortfalls in
cancer care provision in the UK at the time and
aimed to ensure all patients achieved prompt
access to expert advice, up-to-date treatment and
holistic care from relevant professionals with
specialist knowledge and skills. An additional
aspiration was to ensure seamless specialist con-
tinuity of care for all patients as well as the offer
of adequate information and support.
Multidisciplinary team-working has now been
implemented in cancer care systems throughout
much of Europe, the USA and Australia and
forms a core component of guidelines in all can-
cer care services, which is pivotal to many of the
national cancer plans in Europe. There is almost
universal approval for this strategy, which indeed
some consider crucial [1], despite the fact that
there is little evidence for its effectiveness in
improving outcomes [2].
The introduction of multidisciplinary teams
has been based upon the rationale that as the man-
agement of different diseases becomes more com-
plex, it is important to involve the various key
professional groups in clinical decision-making
for individual patients. Hence, a key objective of
multidisciplinary teams is to ensure that patients
are managed by a specialist team. This is particu-
larly relevant in rectal cancer, where preoperative
radiotherapy and chemoradiation are often deliv-
ered according to clinical findings and staging
(particularly in terms of the MRI) and many dif-
ferent surgical options are available with varying
levels of radicality and implications for future
QOL in the patient. Since the cancer itself, surgery
and other adjuvant treatments such as radiotherapy
can impact on physical appearance, physical func-
tioning (bowel, urinary and sexual) and emotional
health, the optimal management will necessarily
take into account both clinical and psychosocial
factors in addition to the prospect of cure. Given
the complexity of these decisions, a multidisci-
plinary approach is essential, if MDTs are to
incorporate modern and changing developments
in all these disciplines into treatment plans [3]. A
large survey of MDT members in the UK in 2009
S. Shah et al.
enabled a set of recommendations to be formu-
lated to define how an effective MDT would work,
which are available online at www.ncat.nhs.uk.
An international survey of 173 colorectal
surgeons (of whom 123 responded) showed that
working in regular MDTs made the use of MRI
for staging more likely and hence significantly
influenced the use of neoadjuvant chemoradia-
tion (RR = 5.67, p = 0.03) for a threatened circum-
ferential margin on MRI [4]. Also, MDT working
improved the quality of pathology reporting
(RR = 4.85, p = 0.01). These changes were not
influenced by caseload. Blazeby [5] provided fur-
ther evidence that multidisciplinary team-work-
ing can make a positive impact on the quality of
clinical decision-making, clinical outcomes for
patients, patients’ experience of care and also the
impact on the working lives of team members.
In this chapter, we will review the evidence for
effective MD team-working and its impact on
outcomes and discuss how the characteristics and
structure of the MDT, the team culture, leaders,
organisation, setting and local environment
influence optimal care for the patient.
34.2 Do MDTs Improve Clinical
Outcomes?
Although MDTs are now in widespread use, pro-
vide relatively seamless coordination of care and
are supported in the literature particularly for rec-
tal cancer [6], there is little evidence to support
their effectiveness. With the overall aim being
improving patient care, very little is known about
the decision-making and the validity of this deci-
sion-making [7]. Few have examined whether
MDT treatment decisions are actually imple-
mented or investigated the reasons why some
decisions changed after the meeting [8]. Indeed,
the data we have suggests that MDT discussions
may even fail to reach a decision in 27–52% of
cases [7].
However, weak study designs, using retrospec-
tive before-and-after studies have typically been
used to evaluate the benefit of multidisciplinary
team-working. The findings are often confounded
by changes over time including increased spe-
cialisation of the cancer workforce, improved
34 What Are the Recommendations to Ensure a Successful Multidisciplinary Team in Rectal Cancer?*
adherence to evidence-based guidelines, better
staging at diagnosis and improved treatments.
In the UK, multidisciplinary team-working is
associated with improved 5-year survival in col-
orectal cancer [9]. The presence of microscopic
tumour cells within 1 ml of the circumferential
surgical resection margin (CRM) in the patho-
logical specimen post surgery is the endpoint
most strongly associated with local recurrence in
rectal cancer and doubles the risk of developing
distant metastases. Improvements in surgical
technique have dramatically altered the risks of a
positive CRM [10]. An increased efficacy for
preoperative CRT followed by surgery after a
delay of 6 weeks to allow downstaging over
SCPRT and immediate surgery has already been
demonstrated in a randomised trial, where the
involvement of the CRM was reduced from 13%
to 4% [11]. In the study by Burton et al., the
authors showed that in one network, 16/66 (26%)
of patients not discussed by the MDT had a posi-
tive CRM (£1 mm). In contrast, those discussed
in an MDT preoperatively achieved a negative
CRM (>1 mm) in 113/116, i.e. 96% of cases.
34.3 What Are the Challenges
Facing MDTs?
There is wide variation in the knowledge, skills
and perspectives of members of multidisciplinary
teams – and in particular the chair or MDT lead.
Multidisciplinary team-working also highlights
the paradox that an evidence base is mandated for
individual clinical decisions, but not for overall
organisational decisions. In addition, there are
substantial constraints in terms of time and
resources for a large and varied number of health-
care professionals (surgeons, physicians, radiation
and medical oncologists, radiologists, patholo-
gists, dieticians, clinical nurse specialists and pal-
liative care specialists) who are required to attend
such additional meetings to discuss cancer care
and multidisciplinary forum. MDT meetings use
resources. For the 174 colorectal MDTs in the
UK, attendance involves over 100,000 person-
hours each year. In addition, preparation time for
radiologists may take 2 h and pathologists 2.4 h
prior to MDT meetings in line with Royal College
343
best practice guidelines [12]. Hence, preparation
costs alone come to around £50 million per annum,
and attendance time will cost a similar amount.
Multidisciplinary teams also require good and
timely communication between primary, second-
ary and tertiary care; good data collection for the
benefit of the individual patient, audit and
research; encouragement of recruitment into clin-
ical trials; assurance that good practice guidelines
are adhered to; optimising the use of resources;
and hopefully improving the working lives of
staff. Hence, MDT meetings pose difficulty for
more rural and remote areas particularly when
specialist centres offer regional services – which
has driven the use of teleconferencing.
34.4 What Are the Primary
Functions of an MDT?
The primary functions of an MDT are generally
agreed to be:
1. To discuss all new and recurrent active col-
orectal cancer patients
2. To act as a specialist forum to discuss complex
cases and make clinical decisions
3. To act as a specialist forum to integrate psy-
chosocial, emotional, sexual and financial
issues that may affect the patients
4. To register patients on relevant cancer regis-
tries and databases
5. To encourage recruitment into relevant and
available clinical trials
6. To improve practical techniques (imaging,
surgical, chemotherapeutic, radiotherapeutic
and pathological) through review and positive
feedback
7. To support clinicians in hard-pressed
circumstances
8. To promote optimal medical management and
care that is both up-to-date and appropriate
34.5 What Are the Markers
of a Successful MDT?
There is no such thing as a perfect MDT.
However, there are several markers that can be
used to gauge the success of MDTs. The
344
‘Improving Outcomes Guidance’ (IOG) defines
the composition of teams and their working
practices (e.g. having protocols for referral and
treatment). The IOGs provide measurable stan-
dards in many settings, and adherence is assessed
using a detailed peer review process. However,
analysis of data collected in the second round of
peer reviews, conducted between 2004 and 2007,
which reviewed 174 colorectal MDTs, showed
that there was considerable variation in MDT
functioning according to the predefined stan-
dards (National Cancer Peer Review Programme
2004–2007) [13]. The reviewers found a highly
committed workforce, despite acknowledged
gaps in the provision of services. Compliance to
the range of expertise in the MDT, i.e. a named
core membership was 88%. MDTS adhered least
well with aspects of team-working that require
additional resources, expertise and time such as
participating in audits, conducting patient expe-
rience surveys and service improvement. This
partly reflects the shortage of some core staff
including oncologists [14]. We also have varia-
tion in the provision of clinical nurse specialists,
who often fail to play as important a role as in
the day to day clinical setting.
Finally, the decisions made by MDTs regard-
ing patient treatments and subsequent treatment
outcomes provide another way of measuring the
level of success of an MDT. However, factors
that affect the quality of clinical decisions made
by multidisciplinary cancer teams (MDTs) are
poorly understood and rarely investigated [7].
34.6 What Recommendations Can
Be Made for Ensuring a
Successful Multidisciplinary
Team Meeting?
In February 2010, the National Cancer Action
Team in the UK published a blueprint for peer
review entitled ‘The Characteristics of an Effective
Multidisciplinary Team (MDT)’ and offered rec-
ommendations regarding membership, attendance,
leadership, team-working and culture, personal
development & training (www.ncin.org.uk/view.
S. Shah et al.
aspx?rid=136) [15]. The recommendations below
are a combination of the views highlighted in this
report as well as additional views.
34.7 Health-Care Professionals:
The Team
34.7.1 Representation and Attendance
It is essential that the there is representation
from members of the all relevant disciplines. In
the case of rectal cancer, this includes surgeons,
oncologists, radiologists, pathologists, clini-
cal nurse specialists and MDT coordinators.
Although attendance should be regular, and
part of the job plan for these individuals, allow-
ances should be made for absences and suit-
able cover available. There should be a regular
attendance register with details of arrival and
departure from meetings. Additionally, indi-
vidual members should strive to be present for
discussion of patients in whose care they have
been involved.
Our own colorectal MDT meets for 2.5 h
weekly. The personnel present includes surgeons,
gastroenterologists, clinical oncologists, several
specialist radiologists (gastrointestinal diagnos-
tic/interventional) with different skills (MRI/CT/
ultrasound), pathologists, clinical nurse special-
ists, stoma nurses, palliative care nurses, doctors
in training and MDT coordinators. Intermittently,
our dietician and anaesthetists also attend. All are
required formally to sign in their attendance.
34.7.2 Roles of Individuals
Specific roles within the team are important, i.e.,
who chairs each meeting, who presents each case
and the function of the MDT coordinator. It is
important to identify who will act on the deci-
sions proposed, who makes the summary and
who informs the GP and the patient. The roles of
the chair and MDT coordinator are vital in ensur-
ing smooth running of the meeting, with careful
attention to each patient’s diagnosis and treat-
ment plans.
34 What Are the Recommendations to Ensure a Successful Multidisciplinary Team in Rectal Cancer?*
All members of the team should be allowed to
raise their views and initiate discussions into the
management of patients. In a study from Lamb
et al. [16], it was felt that ‘most participants (in
the MDT) thought that the discussion was not
balanced equally across groups and sometimes
not open enough’.
A study of colorectal cancer teams in the UK
suggests there is a positive impact of multidisci-
plinary team-working on the working lives of
team members [17, 18]. Providing patient care in
multidisciplinary teams was reported as the pre-
dominant source of job satisfaction by all team
members [18]. An observational study of UK
breast cancer teams also suggests team-working
has a positive impact on the mental health of can-
cer team members [19]. Working in teams may
be beneficial for psychological well-being and to
avoid burnout [20].
34.7.3 Is There a Role for Training?
Educational initiatives should address the
significant shortfalls in training multidisciplinary
team members in the core skills required for effec-
tive team-working, including communication skills,
team-working, handling complaints and leader-
ship. The Pelican MDT Development Programme
originally provided a national initiative which
attempted to improve clinical outcomes in col-
orectal cancer by training all UK MDT colorectal
teams in best clinical practice. The Programme
was intended to be a unique team-based residential
training programme, attended by the whole MDT,
including surgeons, oncologists, radiologists,
pathologists, clinical nurse specialists and MDT
coordinators. The programme focussed on train-
ing individual professional groups in imaging,
different potential treatment modalities (chemo-
therapy, radiotherapy and surgery), optimising the
information obtained from the pathologist and
supportive care. The MDT was encouraged to dis-
cuss and formulate treatment plans, in response to
MDT review of imaging [21] and pathology [22].
Similarly, the programme encouraged reflection
on the clinical roles of the individual key team
members to emphasise a team-based culture within
345
the programme to enhance understanding of how
team members can work together to improve clini-
cal outcomes.
Currently, the National Cancer Action Team
(NCAT) has a training initiative in some networks for
MDT lead to address this issue. There are now plans
to run workshops aimed at MDT chairs and partici-
pants to further improve performances at MDTs.
34.7.4 The Meetings
It is important that meetings take place in a fixed
place and at a fixed time during core hours to
ensure maximal attendance. The environment
should be clean, quiet and of a reasonable size to
accommodate all team members comfortably.
Additionally, suitable equipment should be pres-
ent to view radiological images, histopathologi-
cal slides and any other test results. Access to
relevant databases should be available to ensure
prompt data entry (Figs. 34.1 and 34.2). Ideally,
these should all be set up and running prior to the
start of the meeting.
An important aspect that is often forgotten is
the prompt availability of IT technical support, in
the event of any malfunctioning of equipment.
34.7.5 Is Videoconferencing
a Good Idea?
Effective team-working needs a culture that is
shared within the team, mutual respect and an
understanding of each others’ roles. This is the
oil which lubricates the working of an MDT.
Remote working is necessary with some large
teams to accommodate different hospitals and the
normal working practices of the individuals con-
cerned. However, our experience is that techno-
logical delays, frequent equipment failures and
the loss of normal social interactions of face-to-
face meetings do tend to hinder achieving a
shared team culture.
It is much more difficult to pick up social cues
which facilitate the activity and development of
the functioning team [23]. Often, several people
attempt to speak at once, and then all pause at
346 S. Shah et al.

Figs. 34.1 and 34.2 A regular weekly multidisciplinary team meeting in the UK involving pathologists, surgeons,
radiologists, gastroenterologists, clinical oncologists, colorectal clinical nurse specialists and palliative care nurses

once and finally try to speak again at the same
time, which makes for a very staccato decision-
making process. Interactions appear impersonal,
and the group may not fully function. There is
some evidence that the exchange of information
via virtual teams is less effective than in face-
to-face meetings [24].
However, newer systems, which make use of
wireless Internet connections and virtual servers may
provide a suitable solution to these problems and, in
so doing, make meetings more efficient, particularly
where members have to travel large distances
to attend meetings. There are a number of these
being trialled in various centres across Europe.
34 What Are the Recommendations to Ensure a Successful Multidisciplinary Team in Rectal Cancer?*
34.7.6 The Patients’ Perspective
Evidence for the benefit of multidisciplinary
team-working from the patients’ perspective
may be inferred from the results of NHS patient
surveys. However, patients do not attend, and
their preferences are rarely discussed [7, 8]. The
overall experience of care for cancer patients in
the UK improved between 2000 and 2004
according to analysis of patient experience sur-
veys undertaken by the Picker Institute (Picker
Institute) [25]. Although many factors are likely
to have been responsible (including the impor-
tance given to patient experience in national
policy, stronger leadership at national and local
levels, the provision of funding, the influence of
charities and the power of information obtain-
able from the Internet), those cancers where
team-working was at a more developed stage
(breast, colorectal and lung cancer) showed more
striking improvements than urological cancers
where guidance that included providing care
within multidisciplinary teams was not published
until much later in 2002.
It is important to remember that the patient is
the central figure in the MDT discussion. With this
in mind, it is important to have a good knowledge
of the patient’s comorbid status and their personal
preferences with regard to treatment options.
A study by Blazeby [5] showed that 15.1% of treat-
ment decisions made at upper GI MDT meetings
were not implemented, with the most common rea-
sons for this related to lack of information concern-
ing patients’ wishes or comorbid disease.
34.7.7 The Process
It is recommended that MDTs take place weekly.
It is important that there are clear guidelines on
what patients are suitable for discussion at MDT
meetings, as well as at what stage in their diag-
nostic/treatment journey they should be dis-
cussed. In general, any new patient with a
diagnosis of colorectal cancer, all patients with
a cancer resected and patients with recurrence
or metastatic disease are appropriate for discus-
sion. Following an appropriate cut-off time for
347
inclusion of patients into weekly MDTs, a list
of patients for discussion should be made avail-
able to all those involved in advance of the
meeting. This is particularly important for radi-
ologists and histopathologists for whom pre-
meeting preparation is essential to ensure
efficient discussions at the meeting itself. There
should be a minimum set of criteria that is pre-
sented regarding each patient, ideally by the
individual team member who has made the deci-
sion for inclusion at the meeting. Furthermore,
any relevant imaging/pathological specimen
should be available.
Following the meeting, appropriate steps should
be in place to ensure any recommendations are
carried out, and the patient and their GP are
informed at the earliest opportunity. If appropriate,
onward referral should be made in a timely man-
ner, with all the relevant information enclosed.
34.7.8 Data Collection
A clear database for use in MDTs should be avail-
able, which keeps a record of patient demograph-
ics, clinical information as well as the discussion
regarding the patient at the MDT. This is a manda-
tory requirement for MDTs in the UK and provides
access, both prospectively and retrospectively, to
data that can be used for research and audit. It also
helps identify patients that may be suitable for
ongoing trials. This process also allows for effec-
tive follow-up of patients and their outcomes fol-
lowing treatment (Fig. 34.3).
34.7.9 Feedback
Following meetings, it is important to review pro-
cesses at regular intervals and assess the deci-
sions made retrospectively. This may reinforce
the decisions made and highlight the perfor-
mances of individual MDTs. At the same time,
these may highlight discordance between MDT
recommendations and actual treatment decisions –
in this case, it is important to review the available
data and assess why this discordance arose, and
try and improve on particular areas.
348 S. Shah et al.

Overall compliance by MDT tumour site (local & specialist teams)

77% 77% 75%

73%
70% 69%
70%

60%

50%

40%

30%

20%

10%

0%

ae
st

gy
ng
ta

G
ea

yn
ec

lo
Lu

er
Br

ro
G
or

pp

U
ol

U
C

Fig. 34.3 Overall compliance to quality measures for MDT in peer review assessment

34.8 What Are the Next Steps?
There is evidence that the introduction of multidis-
ciplinary team meetings has led to more rigorous
decision-making processes and has improved out-
comes for patients with cancer as well their experi-
ence of care. Yet, some teams work more effectively
than others. There is also a suggestion that partici-
pation in multidisciplinary teams meetings may
increase team members’ job satisfaction.
Randomised trials are unlikely to be able to
examine the added value in terms of effectiveness
of multidisciplinary teams because they now
form routine clinical practice. However, there is
evidence for a wide variation in the quality of
cancer multidisciplinary teams. Therefore, there
is a need to identify dysfunctional teams and
improve their performance. Hence, reliable mea-
surements of MDT functioning and the opportu-
nity to demonstrate the differences in outcomes
for teams classified as ‘high’ or ‘low’ performers
would be useful.
More formal proformas to standardise all
aspects of multidisciplinary team-working
(such as reporting of diagnostic imaging, sum-
marising patient management decisions and the
communication of these decisions) may improve
the quality and patient-centredness of decision-
making by multidisciplinary teams.
34.9 What Is the Future of MDT
Working?
It is clear from the evidence presented that MDTs
are here to stay and now make up a substantial
amount of time and effort for all concerned;
indeed, a large proportion of peer review out-
comes are based around MDT functionality.
Many MDTs have core members who primarily
work at geographically distance sites, and hence
attending every MDT they are required to is not
possible. Hence, the concept of videoconferenc-
ing has gathered support. Although some research
may show that this style of working may not be
effective, it is here to stay. A natural progression
for MDTs therefore is to embrace current and
developing technology; the majority of mobile
phone companies have ‘health’ sections and all
are producing state-of-the-art communication
portals which facilitate efficient videoconferenc-
ing functionality. Current technology will allow
34 What Are the Recommendations to Ensure a Successful Multidisciplinary Team in Rectal Cancer?*
members to not only log in from their parent sites,
but they will be able to communicate effectively,
see images in higher resolution and include any
information that is part of a patient’s electronic
record. They will even be able to log in from any-
where in the world on a secure line. It may even
be possible to ‘tap’ into another specialist MDT
to get their opinion in real time. The same soft-
ware will automatically create electronic atten-
dance sheets, MDT records and communications
to the GP, patient and other health-care individu-
als. The day of the virtual MDT is here.
Core members of the MDT are clearly
specified, but future MDTs may include individu-
als who are increasingly part of management
decisions such as anaesthetists and perhaps even
patient representatives. Currently, many MDTs
include operative photographs (this in fact makes
up an important aspect of rectal cancer surgery),
but it may be feasible to include photos of patients
so that clinicians may get an idea of whether par-
ticular treatments may be more efficacious or
possible than others (e.g. laparoscopic vs. open
surgery).
Competing Interests All authors declare that they have
no conflict of interest.
Conclusions
Increasingly, in developed countries, cancer
care is being delivered by multidisciplinary
teams. Assessment, training and support both
for the team and the chair and modern facili-
ties including videoconferencing, in addition
to tackling some of the practical barriers to
effective team-working, will require consider-
able future investment and resources.
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 What Is the Appropriate Timetable
for Tailored Follow-up? 35
Lars Påhlman

Contents 35.1 Introduction

35.1 Introduction ................................................ 351
The majority of patients with a newly diagnosed
35.2 Who Shall Be Followed? ............................ 352
rectal cancer will be screened for distant meta-
35.3 Distant Metastases ..................................... 352 static disease. The most common places are the
35.4 Metachronous Bowel Tumours ................. 352 liver and/or the lungs. Subsequently these organs
35.5 Local Recurrence ....................................... 353
should be scanned in the perioperative period.
However, dependent upon tumour stage and
35.6 Imaging Technique..................................... 353 despite a curative resection, one will expect recur-
35.7 Tumour Markers ........................................ 353 rences since occult metastases have not been
References ................................................................. 354 found at the time for surgery. For patients with a
stage I disease, almost no recurrences will appear,
but after stage II, approximately 20% of the
patients will recur, and finally, after a tumour in
stage III as much as 40–50% of the patients will
recur. Due to the anatomy and vascular drainage
from the gastrointestinal tract, the majority of
recurrences will be found in the liver but also in a
minority in the lung since the rectum is also
drained via the caval vein. Other places for distant
recurrences are very rare. Moreover, with good
preoperative staging and correct use of radiother-
apy, local recurrences could be avoided in the
majority of patients, and today, in many centres
the local recurrence rate will not exceed 5%.
The aim in tailoring a follow-up programme
must be to find recurrent disease when still a
potential chance for cure exists. Since curative
treatment often includes major surgery, the
patients must be fit for a second major operation.
Therefore, it is essential to take into account the
L. Påhlman
patients’ co-morbidity and the timing when recur-
Department of Surgical Sciences, Uppsala University,
SE 751 85 Uppsala, Sweden rences do recur but also in which organ a recur-
e-mail: lars.pahlman@surgsci.uu.se rence could appear. In this chapter, a proposal for

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 351

DOI 10.1007/978-3-642-25005-7_35, © Springer-Verlag Berlin Heidelberg 2012
352
tailored follow-up is based upon how to find and
cure the distant metastases, taking care of local
recurrences and screen for metachronous new
primaries in the large bowel.
35.2 Who Shall Be Followed?
The rationale for follow-up and surveillance for
metastatic disease or synchronous tumours
depends upon the health of the patient and the
co-morbidity. If the patients do not tolerate liver
surgery or lung surgery or is too sick to be oper-
ated for a new primary, there is no real rationale
to follow the patient. Therefore, this has to be
taken into account before putting patients in the
follow-up programme.
The second decision making must be based
upon the stage of the disease. Since patients with
stage I disease rarely recur, there is no real ratio-
nale to follow those patients for metastatic dis-
ease. However, they should be scheduled for
surveillance due to metachronous colonic cancer
or precancer lesions to the same extent as those
with stage II and III disease (see below).
Subsequently, only patients with stage II and
III disease should be followed for distant metas-
tases. Another group that should be followed is of
course patients who have been curatively treated
for stage IV disease with a radical resected pri-
mary as well as radically resected metastases to
the liver and/or lung.
35.3 Distant Metastases
The aim of the follow-up programme is to find
patients with recurrences, which are possible to
cure. If there is an extensive spread of occult met-
astatic disease, there is a risk that each individual
cell will create metastases, ending up with a com-
pletely incurable disease. However, this is not the
most common scenario and importantly cannot
be predicted in advance. Therefore, all patients
should be followed, provided they fulfil the crite-
ria depicted above. The most important question
regarding tumour biology is whether metastases
will metastasise or not. No data support this, and,
therefore, one could argue how often patients
L. Påhlman
should be followed. After surgery for stage II and
III disease, several randomised trials have tested
the hypothesis of no or mediocre follow-up ver-
sus a more ambiguous follow-up. Data from
meta-analysis of all these trials indicate that fol-
low-up will increase survival but the timing is not
known [1, 2]. There are programmes with follow-
up every third month or every 6 months or yearly.
Only one randomised trial has addressed the tim-
ing of the follow-up. That is a Danish-Swedish
trial, COLOFOL, where stage II and III patients
are randomised to either a follow-up after 1 and
3 years (the standard arm) or every 6 months, the
first 2 years and then it is 3 years follow-up [3]. In
both arms, a final 5 years’ follow-up is required
including a colonoscopy. At each scheduled fol-
low-up, CT scan over the thorax and liver is rec-
ommended and also a carcinoembryonic antigen
(CEA) test. If the scanning is negative but the
CEA is raising, the patient has to be re-investi-
gated with other methods like PET-CT. In this
trial, the recruitment has just been finished (Dec.
2010) and the end point is overall survival and
possibility to offer curative treatment to those
with metastatic disease. In total, 2,500 patients
have been randomised.
In patients with a stage IV tumour, with radi-
cal resected metastases, it is obvious that such a
tumour has a ‘metastatic capacity’, and therefore,
those patients might be scheduled to a tighter
follow-up. However, no evidence exists, but most
centres used to follow those patients every
6 months over a 2-year period.
35.4 Metachronous Bowel Tumours
In the perioperative workup, the whole bowel must
be examined, excluding synchronous adenomas or
cancers. Having done a ‘clean colon’, the question
arises when the next colonoscopy should be done.
One rather large randomised trial has addressed
this question, the Funen trial. Six hundred patients
were randomised to have a yearly colonoscopy
over a 10-year period in one arm, and in the other
arm patients had a colonoscopy every fifth year. In
that trial, there was no difference in survival
between the two arms, neither any difference
regarding uptake of adenomas or metachronous
35 What Is the Appropriate Timetable for Tailored Follow-up?
cancer [4]. Although this is the only trial but a
rather large one, one can justify that colonoscopy
surveillance is not indicated more often than in
5-year periods. Therefore, those who survive the
disease with no metastatic recurrences should be
scheduled for a colonoscopy 5 years after surgery
and then every fifth year until the age of 75 [5].
The reason why there is no use to follow the
patients longer is that if the bowel is clean from
adenomas or cancers at 75 years of age, it takes at
least 15 years to receive other adenomas and can-
cers in that age group, making the follow-up after
75 years not cost effective.
35.5 Local Recurrence
Provided a centre has an optimal performance, not
more than 5% of the patients will recur locally.
Those who recur are the patients with advanced
disease and with a circumferential resection mar-
gin of less than 1 mm [6]. The problem with local
recurrences is that the majority of them are
difficult to treat after TME surgery and only a
minority is possible to resect. Therefore, it is not
cost-effective to have everyone in a follow-up
programme, but only patients who are fit and will
tolerate major surgery can benefit from such a
programme. Probably, a good history is enough
together with the scheduled follow-up for distant
metastases. Since a local recurrence is rather rare
today, only those with symptoms should be evalu-
ated with specific imaging. The timing is not
known, but with the modern treatment including
neoadjuvant radiotherapy or chemoradiotherapy
data support that some of the recurrences will be
postponed more than 3 years [7]. Therefore, one
could argue to follow patients at risk more after
the period of follow-up for distant metastases
(after 3 years) including a follow-up for local
recurrences at 4 years and at the 5-year follow-up
when the colonoscopy is done.
35.6 Imaging Technique
The question is which technique should be used.
Most recurrences do recur outside the bowel, and,
therefore, there is no real rationale to do endo-
353
scopic follow-up too often. Data do support that,
provided a ‘clean colon’ has been performed
perioperatively, the next colonoscopy can be
postponed to the 5-year follow-up [4].
The liver and lungs should preferably be
scanned with the same method as was used in the
preoperative scanning, giving an opportunity to
compare and evaluate the findings. There are no
strong data supporting a specific method, but for
the liver, contrast-enhanced ultrasound or CT scan
is available. For the lungs, CT scan or thoracic
plain X-ray has been suggested. For detection of a
local recurrence, both endoscopic evaluation and
an imaging technique could be beneficial. The
MRI is probably better than CT scan since fibrosis
is better displayed on MRI. Most patients with a
local recurrence experience pain, and, therefore,
if a patient has pain, he/she should automatically
be scheduled for a follow-up with MRI.
35.7 Tumour Markers
Several follow-up programmes include testing
with tumour markers. The most common used
marker is CEA. Several series have shown that a
rising CEA indicates a recurrence, and this
increase often occurs 6 months before a recur-
rence becomes clinically detectable [2, 8].
Therefore, several programmes have included
CEA testing in-between the imaging controls,
although no studies have shown any clear advan-
tages with such a policy regarding overall sur-
vival or cancer-specific survival.
Conclusion
The available evidence will not support a
specific timetable for tailored follow-up.
Tumour biology is probably more important
than the schedule. If there is a massive spread,
it will not matter how often a patient is sched-
uled for the follow-up to be done since such a
patient is not curable. Therefore, it is probably
enough to see the patient every 6 months or
even less. The COLOFOL trial will answer
that question. Regarding colonoscopy, surveil-
lance data support that only those who have
survived 5 years should be scheduled for a
follow-up every fifth year to the age of 75–80.
354 L. Påhlman

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Majak BM, Vatn MH (1999) Population-based
 How Should Data Be Shared
and Rapid Learning Health Care 36
Promoted?

Ruud van Stiphout, Erik Roelofs, Andre Dekker,

and Philippe Lambin

Contents 36.1 Clinical Decision Making

36.1 Clinical Decision Making .......................... 355
36.2 Electronic Health Record .......................... 356 In the medical field and inherently also in oncol-
36.3 Data Sharing............................................... 357 ogy, clinical guidelines, protocols, and research
36.3.1 Semantic Interoperability............................. 358 are highly regulated. Nevertheless, both treat-
36.3.2 Current Initiatives ........................................ 359 ments and technologies are surrounded by uncer-
36.4 Prediction Applications ............................. 359 tain factors. Evidence is primarily generated by
36.4.1 Predictive Modeling ..................................... 359
the outcomes of randomized clinical trials. This
36.4.2 Current Models ............................................ 361
36.4.3 Knowledge Dissemination ........................... 362 evidence is however often unavailable, inconclu-
36.5 Toward Rapid Learning sive, valid for only a subgroup of patients, out-
Health-Care System ................................... 363 dated, or of insufficient quality. Therefore, this
References ................................................................. 363 process may not always be suitable to fully base
clinical decisions on. Furthermore, there still
exists a translational gap between scientific dis-
coveries and clinical practice.
A transformation of the way in which evidence
is aggregated and applied may be required.
Substantial investments in health information
technology (HIT), comparative effectiveness
research, health-care quality and value, and per-
sonalized medicine support these efforts.
Personalized medicine, i.e., match individual
patient data with detailed evidence available in
real time, is an emerging trend. In parallel, clini-
cal decision making for a single patient has
become more complex due to the increased
amount of data; data required for decision mak-
ing has exponentially increased from 10 to 10,000
R. van Stiphout () • E. Roelofs • A. Dekker • P. Lambin
Department of Radiation Oncology (MAASTRO), facts per decision in the last two decades, if data
GROW – School for Oncology and Developmental from genetics, proteomics, and diagnostic imag-
Biology, Maastricht University Medical Centre+, ing are taken into account. Human cognitive
Maastricht, The Netherlands
capacity is only able to deal with five facts per
e-mail: ruud.vanstiphout@maastro.nl;
rik.roelofs@maastro.nl; andre.dekker@maastro.nl; decision, i.e., decision by clinical symptoms.
philippe.lambin@maastro.nl In Fig. 36.1, examples of data origins are given

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 355

DOI 10.1007/978-3-642-25005-7_36, © Springer-Verlag Berlin Heidelberg 2012
356 R. van Stiphout et al.

Demographics Imaging Pathology Toxicity Blood biomarkers Genomics Proteomics

Rectal
cancer Treatment
patient
Age, gender (Diffusion)-MRI Tumor staging Gastro-intestinal Biological Proliferation Structure
decision
Medical history (Perfusion)-CT Resection quality Dermatology Growth factors Hypoxia Cellular defense
Social status PET / SPECT Genitor-urinary Tumor load Metabolism
Health status Endoscopy Neuropathy Infalmmation RNA processing
Work history Bone-marrow Metabolism Cycle regulation
Lifestyle Cardiac Angiogenesis
Pain Translation

Fig. 36.1 Treatment decision for rectal cancer patients can be based on various data origins, each complementing each
other in capturing disease characterization and progression

for a typical patient diagnosed with (rectal) can-
cer. This increase in decision-making complexity
requires decision support systems (DSS) and
computational support on different levels and
steps in the treatment process [5].
The development of a rapid learning health-
care system may be very effective to achieve this
support [1]. In such a system, data is routinely
generated through patient care and clinical
research and fed into an ever-growing databank
or set of coordinated databases. High-quality data
should be available in real time, simultaneously
used to improve clinical care, yield quality mea-
sures, and focus on research. This system intends
to improve collaborative care, patient safety, and
health-care quality and efficiency and supports
medical and clinical research, training, and pub-
lic health. It would also expand the pace and
magnitude of evidence generation. The steps to
be taken within the rapid learning health-care
system are:
1. Collecting data in standardized manner
2. Analyzing captured data
3. Generating evidence through retrospective
analyses and prospective studies
4. Implementing new insights in clinical care
5. Evaluating outcomes of changes in care
6. Generating new hypotheses for investigation
Many aspects are involved in the develop-
ment of these systems, like setting up and link-
ing registries and databases, implementing an
information technology infrastructure, and
developing applications and interfaces for
patient-centered clinical decision support and
policy issues and implications. Each of these
aspects will be discussed in this chapter. Some
investments have already been made, of which
electronic health record development is most
focused on.
From medical literature of the last two decades
(Fig. 36.2), a steep increase is seen of the number
of publications related to clinical decision mak-
ing, database infrastructure (represented by ontol-
ogy), and data sharing. While clinical decision
making was important before 1990, research
involving data ontology and data sharing
increased only after 2000, in parallel with an
increase of Internet availability and computa-
tional power. Cancer-related publications show a
proportional trend, except that the number of data
ontology and data sharing publications stagnates
the last couple of years.
36.2 Electronic Health Record
Currently, electronic health records (EHR) are
the main focus of investments made to transform
health care. Paper-based records are still the pre-
ferred method of recording patient information
for most hospitals and practices in the Western
countries. Medical professionals experience in
general that it is easier to record data in paper
records than in electronic records. Handwritten
paper medical records however can be associated
with poor legibility, which can contribute to med-
ical errors. Standardization in form design, abbre-
viations, and penmanship were improved to
improve reliability of paper medical records. But
the shift toward digital records is currently inevi-
table in the ongoing globalization of health care.
Paper records require significant amount of stor-
age space, and it is very time consuming and
complicated to collate them to a single location to
36 How Should Data Be Shared and Rapid Learning Health Care Promoted?
Clinical decision making
700
Overall
600 Cancer related
Number of publications
500
400
300
200
100
0 0
1990 1995 2000 2005
Year of publication
Fig. 36.2 Number of publications over the last two decades related to clinical decision making, data ontology, and data
sharing. Overall and cancer-related publications are reported
be reviewed by a health-care provider. Related
copying, faxing, and transporting costs are
required for multiple institutional evaluations.
EHRs on the other hand have increased porta-
bility and accessibility and can be instantly updated
(within certain legal limitations). Furthermore, it
is possible to exchange records between different
EHR systems, and data can be used anonymously
for statistical reporting for quality improvement,
resource management, and public health commu-
nicable disease surveillance. However, the down-
side of the improved accessibility of electronic
records is that unauthorized persons may be able
to access sensitive medical data. This concern
about security is the main reason why resistance is
shown to their widespread adoption.
In current developed EHRs, the quality of data
is still a concern. For example, issues related to
data accuracy, completeness, and comparability
must be addressed before routine EHR-based
quality of care measurement can be done with
confidence [2]. It is expected that if system capac-
ity grows, users become more comfortable with
new health IT systems, and if continuous quality
improvement principles are applied to the EHR-
based data collection-storage-retrieval process,
the quality of data in EHRs will improve.
36.3 Data Sharing
Standardization of data definition and handling
within hospitals and institutes is very important.
As stated, proper development of electronic health
357
Data ontology Data sharing
500 120
Overall Overall
Cancer related Cancer related
100
400
80
300
60
200
40
100
20
0
2010 1990 1995 2000 2005 2010 1990 1995 2000 2005 2010
Year of publication Year of publication
records is the first and most crucial requisite to
achieve this. It becomes however more challeng-
ing when data is shared among institutes on a
regional, national, and international level. Data
warehouses and connected medical software have
to “understand” what the exchanged data means in
order to process it. These machine-machine inter-
actions seem straightforward to humans because
our brain is continuously and unconsciously pro-
cessing information in such a manner, but they are
not. What may give insight is the process of
knowledge generation in decision making
(Fig. 36.3). This process describes the conversion
of data to information by putting it in context, gen-
erating knowledge by making sense of the infor-
mation, and comparing all the knowledge in the
field to find the best path to take in the decision.
For example, if for a rectal cancer patient
cT = 3 is measured (data), one has to know that cT
means clinical tumor stage, which is part of the
TNM classification system, and is measured by
imaging and has a value range of 0–4 (informa-
tion). Subsequently, a physician knows that this
information means that the patient has an
extended tumor without invasion of any sur-
rounding organs but has poorer outcome than
lower staged tumors (knowledge). From litera-
ture, it is known that this kind of patients have the
best outcome when receiving long-course chemo-
radiotherapy (options), thus the patient will
receive this treatment (action).
Machines however are only able to deal with
data and generate information by using terminol-
ogies, definitions, and ontologies. An ontology is
358
Fig. 36.3 Process of
knowledge generation and DATA Analysis
subsequent action for decision
making based on the
Poindexter model
INFORMATION
lteration
a standardized representation of knowledge as a
set of concepts within a domain and the relation-
ships between those concepts.
36.3.1 Semantic Interoperability
To standardize data sharing, semantic interoper-
ability (SIO) is required. In general, SIO is the
ability of any communicating entity (not only
computers) to share unambiguous meaning. For
two computers, this is the ability to exchange
information and have that information properly
interpreted by the receiving system in the same
sense as intended by the transmitting system.
Four levels of semantic interoperability can be
distinguished:
0. None: data cannot properly be transferred to
the receiver
1. Technical and syntactical: only the raw data is
transferred without any translation
2. Partial: some transferred data is converted
with standardized coding
3. Full: sharable context, seamless co-operability
Currently, many data intended for care pro-
vision are still shared by remote access to clini-
cal systems, and for research data spreadsheets
are mainly used, which is still level 1 SIO. Some
systems, as the ones described in Sect. 36.3.2,
explored and implemented level 2 interopera-
bility, but level 3 is and may remain still the
future.
R. van Stiphout et al.
Information is data in context
Sense Understanding what the
making information means
Path Deciding what to
KNOWLEDGE
finding do within constraints
OPTIONS Execution
ACTIONS
There are several standards available to
achieve SIO in health care. The most well-known
and promoted standard for medical terminologies
is SNOMED CT (Systematized Nomenclature of
Medicine – Clinical Terms). This standard was
created in 2002 and is used in many systems like
EHRs, diagnostic imaging services, knowledge
databases for clinical decision support, etc. A
standardized system results in common structure
and terminology and a single data source for
review (less redundant data). It also allows the
use of common tools and techniques, common
training, and single validation of data. It is how-
ever also true that not all standards are of equal
quality. Continuing with bad standards may even-
tually result in decrease in quality of care and
high costs.
Currently, many data sharing systems do not
achieve level 2 or 3 semantic interoperability.
Realizing full SIO may however not necessarily
be a consensual goal in every place and any time
because of social, cultural, and human factors.
SIO emerges gradually and may remain an
incomplete phenomenon, even with the most
optimistic of assumptions. Concerns about pri-
vacy and confidentiality will continue to be a key
limiting factor in interoperability and may impede
developments that would be technically feasible
and beneficial. Anonymization, i.e., the act of
permanently and completely removing personal
identifiers from data, should therefore be applied
in trans-institutional sharing when possible.
36 How Should Data Be Shared and Rapid Learning Health Care Promoted?
36.3.2 Current Initiatives
Several applications of data sharing for
cancer-related data have been initiated in
the last decade.
• EUROCAT (www.eurocat.info): a shared cen-
tralized database of medical characteristics in
cancer patients, tumors, and treatments initiated
by several institutes across Europe. The goals
are to be able to better predict the outcome of
individual cancer treatments and to be assistive
in clinical trial recruitment and analysis.
• MISTIR (www.mistir.info): a secured central-
ized database of annotated images of cancer
patients allowing “multicentric planning stud-
ies” in strictly protocolized “in silico (virtual)
clinical trials” [6]. The MISTIR framework
offers high-quality data by applying tools for
quality assurance and solving data incompati-
bility and transfer and storage issues. The treat-
ment planning analysis is performed centrally
to guarantee accurate and uniform results.
• RODA (www.elekta.com): the Radiation
Oncology Data Alliance is an initiative with the
ultimate goal to create an international radiation
oncology registry for collecting and analyzing
data from practices worldwide and correlating
the data with patient outcomes. An IT infra-
structure, in which data is collected through
electronic health records, de-identified, and
aggregated in near real time to a central data
repository, is provided by Elekta Software.
• Oncospace (www.hopkinsmedicine.org): a
distributed analytic database for structured
information modeled after the successful
SkyServer program for astronomic data. This
is an initiative of the Johns Hopkins University
and the University of Dallas. Despite the fact
that only data for head and neck cancer is
shared between those two institutes and ana-
lyzed, it shows that integration of knowledge
and expertise from outside the medical domain
may boost optimization of the system.
• caBIG (cabig.nci.nih.gov): the Cancer
Biomedical Informatics Grid was initiated by
the National Cancer Institute, and its data
sharing and analyzing infrastructure is focus-
ing on the complete cycle of cancer disease,
359
detection, diagnosis, treatment, and preven-
tion. It is founded on the core principles of
open access, open development, open source,
and federation of resources for either local or
shared control.
• CancerData (www.cancerdata.org): an open-
source driven medical data repository con-
nected to the caGrid. Using some of the caBIG
tools, images and annotations are offered in
public data collections in DICOM and AIM1
format, respectively. Private data collections
are available for project members after log-
ging in. Furthermore, CancerData offers a
platform to exchange data analysis tools and
share information on medical imaging and
knowledge engineering in user forums.
36.4 Prediction Applications
36.4.1 Predictive Modeling
When data is sufficiently available and well
defined and if the data infrastructure allows for
data mining, individualized medicine becomes an
option. This trend in cancer care involves admin-
istration of the most optimal treatment depending
on certain prognostic characteristics of the indi-
vidual patient and the tumor. These prognostic
characteristics for treatment outcome, called fea-
tures, can either be identified from published lit-
erature or learned from the current data (feature
selection). These features will subsequently serve
as an input for a predictive computational model,
which aims at finding the optimal fit of the input
data to the treatment outcome. These models
have a certain accuracy to predict outcome for a
population of patients, and it is important to eval-
uate this accuracy on new data which is not used
during the learning process, preferably an exter-
nal dataset. Some aspects of this process will be
discussed in the following sections.
36.4.1.1 Data Requirements
First of all, large amounts of data are required for
proper statistics. In clinical trials, sample size cal-
culations are performed to determine the minimum
amount of patients required to detect a certain
360
difference in outcome. In model development,
this is not common since there is usually a
restricted amount of suited data available. It is
more important to increase the ratio between
patients and features to avoid overfitting. This
occurs when a statistical model describes random
error or noise instead of the underlying relation-
ship because the model is too complex. There are
no strict guidelines for this ratio because of the
high variety in data heterogeneity, but as a rule of
thumb, 5–10 patients per feature are minimally
required. If increasing the number of patients is
not possible, reducing the number of features is
necessary. The best method for feature reduction
is selection based on knowledge from literature
and medical expertise.
The quality of the data may also affect the
accuracy of the models. After collection, one may
be able to deal with wrongly entered data or miss-
ing data. Typos in data are usually found with
outlier detection, either without prior knowledge
or with prelabeled data (normal or abnormal).
Usually, normal value ranges of prognostic fac-
tors are known from literature. There are many
methods to deal with missing data, but they
mainly involve:
• Imputation: missing values are substituted by
the most likely value, calculated by, for exam-
ple, the mean or expected maximization
algorithm.
• Partial deletion: patients with too many miss-
ing data will be excluded from the analysis.
• Full analysis: the classification method is able
to deal with missing values. Assumptions and
distortions in the data can be avoided.
36.4.1.2 Model Types
In traditional statistics, there is a subset of meth-
ods which are used most frequently for cancer-
related studies. In general, alternative methods
are not easily accepted in the medical commu-
nity, as for example, methods from machine
learning. The method of choice to predict out-
come is dependent on the type of input and out-
put data. Exploratory modeling studies are
required to find the optimal model for the avail-
able data. When distinguishing outcome types,
the following examples can be considered:
R. van Stiphout et al.
• Binary outcome: two outcome labels, like for
example treatment response or no response.
Methods: logistic regression, support vector
machines.
• Ordinal outcome: three or more outcome val-
ues, like for example toxicity grading.
Methods: Naïve Bayes, k-means clustering,
Bayesian nets, decision trees. These methods
can also be applied in binary outcome
prediction.
• Time-to-event: follow-up outcomes like local
recurrence status or overall survival with cor-
responding time-to-event. Methods: Cox pro-
portional hazards (PH) model, Fine and Gray
model (competing risks).
36.4.1.3 Performance Evaluation
Evaluation of the performance of the model is
essential when selecting important features and
comparing classification methods. When a pre-
diction model is developed, reporting the accu-
racy of the model is required for the acceptance
of the model in the target community. In the
simplest case of two outcomes, performance is
usually given as sensitivity, i.e., proportion of
actual positive labels which are correctly
identified as such, and specificity, i.e., the pro-
portion of negatives which are correctly
identified. When however the discrimination
threshold for the classifier is varied, a spectrum
of sensitivities and specificities is generated.
The receiver operating characteristic (ROC)
curve is the plot of sensitivity vs. 1-specificity.
The ROC curve allows selection of the optimal
models because there is always a trade-off
between sensitivity and specificity, and one
might be more important than the other for
specific outcomes (Fig. 36.4). A more robust
measure for performance is the area-under-the-
curve (AUC) of the ROC curve. A value of 1
corresponds to perfect prediction, while an AUC
of 0.5 means random prediction. For time-to-
event–related data, an equivalent of the AUC,
the c-statistic, has to be used to deal with cen-
sored data.
It is very important to calculate the performance
of the model on new data, which was not used in
the training process to guarantee robustness of the
36 How Should Data Be Shared and Rapid Learning Health Care Promoted? 361

Predicted outcome 1
positive negative
0.9
positive

True positive False negative 0.8

Actual outcome

(TP) (FN)
0.7

0.6

Sensitivity
negative

0.5
False positive True negative
(FP) (TP)
0.4

0.3

TP 0.2
Sensitivity = TP + FN Random performance (AUC = 0.50)
0.1 Moderate performance (AUC = 0.70)
TN Good performance (AUC = 0.85)
Specificity = TN + FP 0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
1-specificity

Fig. 36.4 Explanation of the confusion matrix (left) definitions in the confusion matrix. By using different
showing the definitions of patient numbers when compar- thresholds in the model, a range of sensitivities and
ing predicted with actual outcomes (positive vs. negative). specificities result in the ROC curve (right)
Sensitivity and specificity are calculated using the

model. There are several options available to do
this validation step:
• Random and temporal split: the data is split
into two sets, one for training and one for vali-
dation. Usually, 70–90% of the data is used for
training and 10–30% for validation. This split
can be done randomly or based on patient’s
intake date (temporal).
• Cross-validation: involves partitioning the
data into complementary subsets, train the
model on one subset and validating the analy-
sis on the other subset. To reduce variability,
multiple rounds of cross-validation are per-
formed using different partitions, and the vali-
dation results are averaged over the rounds.
Usually five- or ten-fold cross-validation is
performed. Leave-one-out (LOO) cross-vali-
dation is the extreme case in which each round
one patient is the validation dataset. This LOO
method is typically used when dealing with
small amounts of data.
• External validation: comparable data from
another institute or another trial is used for
validation. This method provides least
biased accuracy because the validation set is
independent.
36.4.2 Current Models
For rectal cancer, not many multivariable models
are available in literature. An example of a pre-
diction model for follow-up outcome for locally
advanced rectal cancer was recently published
[8]. In this study, four European trials (N = 2,242)
were used to train a Cox PH model to predict
local recurrences, distant metastases, and overall
survival based on clinical and pathological fea-
tures. The model was externally validation by
another European trial (N = 553). The prediction
models were converted to nomograms for easy
and visual interpretation [4]. The prediction
model performed well on the external dataset
with c-statistics around 0.7. Other examples of
successful multivariable models have been pub-
lished [3, 9]. The upcoming trend of public shared
data also results in published models based on
public repositories [7] (Fig. 36.5).
362 R. van Stiphout et al.

Score
−10 −8 −6 −4 −2 0 2 4 6 8 10

pT-stage
0 1 2 3 4

pN-stage
0 1 2

cT
1+2 3 4
Age [years]
25 35 45 55 65 75 85
Adjuvant chemo
Yes No

Surgery procedure
LAR APR
Radiotherapy dose [Gy]
>45 45 <45
Sex
Female Male

Sum of scores
−20 −10 0 10 20 30
Low Medium High
Probability of death
5 10 20 30 40 50 60 70 80 90 95
within 5 years [%]

Training dataset Vaildation dataset

1 1
0.88
0.9 0.9 0.94 0.94
0.8 0.82 0.8 0.83
0.81 0.81
Overall survival [−]

0.7 0.7
0.67
0.6 0.6 0.62
0.59 0.57
0.5 0.5
0.4 0.4
0.4
0.3 0.3
0.2 0.2
Low risk: N = 261 Low risk: N = 50
0.1 Medium risk: N = 669 0.1 Medium risk: N = 160
High risk: N = 1312 High risk: N = 343
0 0
0 20 40 60 80 100 120 0 20 40 60 80 100 120
Time from randomization [months] Time from randomization [months]

Fig. 36.5 Example of a prediction model for rectal can-
cer: nomogram to predict overall survival for locally
advanced rectal cancer. In the nomogram, the predictor
values for a single patient correspond to a score (upper
scale). The sum of all the scores corresponds to a proba-
bility for death within 5 years (bottom scale). The Kaplan-
Meier curves show for both the training and the validation
datasets what the overall survival is for the three risk
groups provided by the nomogram

36.4.3 Knowledge Dissemination expected in the health-care community. Clinicians

are the main users of these tools, and they prefer
Knowledge representation is as important as to end up with clinically relevant outcomes mea-
knowledge extraction from data. Bad interpret- sures, such as the predicted probability of a cer-
ability of the results may lead to false conclusions tain event within a given time. Avoiding redundant
and wrong decisions. The initiatives described in statistical results from intermediate steps is there-
Sect. 36.3.2 all have their own interface and pos- fore a prerequisite.
sibilities to mine and analyze data, but permis- The most well-known online website with
sion to use it is often restricted to participating interactive prediction tools is Adjuvant! Online
members only. (http://www.adjuvantonline.com). This website
A more public approach is to make prediction aims to provide decision support for adjuvant ther-
models available on the Internet. When interac- apy (chemotherapy, hormone therapy, etc.) after
tive, peer-reviewed models are provided with surgery for early cancer patients. A prediction
sufficient background information, an increase in website which focuses more on decision support
the acceptability and a raised awareness in favor for radiotherapy was recently set up by MAASTRO
of computer-assisted personalized medicine are Clinic (http://www.predictcancer.org). Also, the
36 How Should Data Be Shared and Rapid Learning Health Care Promoted?
Memorial Sloan-Kettering Cancer Center has pre-
diction tools for different cancer types (http://
www.mskcc.org/mskcc/html/5794.cfm).
36.5 Toward Rapid Learning Health-
Care System
As already described in the previous sections,
developing a rapid learning health-care system
requires transformation of IT infrastructure, stan-
dardization of electronic health records, and seman-
tic interoperability between data sharing systems.
Furthermore, development of accurate prediction
models and proper knowledge dissemination are
essential for computational clinical decision sup-
port. Linking data systems to regional and national
registry-based administrative data also allows for
immediate case acquisition and real-time tracking
of care. Technical changes are however not
sufficient for a successful implementation of the
system. First of all, several cultural changes should
be induced:
• Commitment from all levels within and across
organizations
• Community participation for infrastructure
development
• Persuade stakeholders to open up information
silos
• Federal coordination of intellectual capital
and acknowledgements
• Leadership and active management
• Addressing data governance and patient
privacy
• Top research papers and grant funding bodies
which request open-source data sharing
Second, guidelines and quality control consid-
erations are very important. These include uni-
versally accessible EHR, universally accessible
patient treatment plans and patient information, a
common pathology staging system, integrated
clinical/laboratory and pathology modules, a
referral system to clinical trials, quality reporting
and resource commitment to engage ongoing
improvement, assessment of practice patterns,
and signal detection for adverse events.
Thirdly, by promoting patient activation and
empowerment, patient participation in both
363
decision making and care delivery will be
increased. Patients are already using the Internet
to obtain information about the cancer and treat-
ments, investigate providers and institutions,
and network with other patients. Social net-
works can accelerate patient’s access to relevant
information, disseminate clinical trial informa-
tion, expedite recruitment to trials, and thus fos-
ter research opportunities and data collection
from within patient communities.
Some critical hurdles might be encountered
while implementing the system. Adding new data
collection tasks to the already packed clinicians’
schedules may be unrealistic and/or may result in
poor quality of data. The shift of perspective from
current care to efforts for future care may be the
hardest part.
In summary, while research and new discov-
ery are important, the focus needs to be on design-
ing new national data policies and HIT systems,
ensure data interoperability, creating a culture of
sharing with simultaneous respect for patient pri-
vacy, and developing methods to make sense of
information and present it to its end users. This
should ultimately lead to the concept of “rapid
learning health care.”
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 Index

A caudal border of the CTV, 152

Anatomy, 4–5, 32, 35, 38, 61, 68, 78, 117, 120, 131, contouring guidelines, 118
133, 136, 156, 235, 237, 264–266, 328, 351 cranial border of the CTV, 150–151
CTV definition, 125
Diagnosis
B height of tumour, 29, 30
Biochemical and molecular biological factors imaging work-up, 10
for adjuvant and systemic therapy, 45–47 mesorectal fascia, 29, 32, 62, 64,
radiochemotherapy, 42–44 67–71, 262
for surgical decisions, 44–45 T-staging, 32–35
for treatment decisions, 41–47
Brachytherapy
clinical results, 166–167 E
contact x-ray 50kV (CXRT), 165–167 Electronic health record, 356–357, 359, 363
contribution in tailoring treatment, 167–168 Endoanal ultrasound (EAUS), 28–29, 32, 35, 61
elderly patient, 168–169 Epidemiology, 3, 21
endoluminal, 164, 166–168
interstitial, 164, 165, 167, 168
F
Follow-up
C distant metastases (DM), 50, 352
Chemotherapy local recurrence (LR), 50, 51, 280, 282, 297–298,
adjuvant chemotherapy, 15, 41, 45, 46, 50, 52, 97, 352, 353
106, 108, 157, 160, 173, 174, 194–199, 200, 210, metachronous bowel tumours, 352–353
217–223, 314 tumour markers, 353
biologic targeted agents, 181–188
combined EGFR and VEGF, 188
EGFR inhibitors, 182–185 I
metastases, 50, 54, 75, 109, 113, 173–175, 178, 181, Intraoperative radiotherapy (IORT), 118, 155–160,
186, 193, 200, 205–207, 209–214, 219, 221, 292, 166, 280–284
298, 299
oxaliplatin, 173–178, 185, 186, 188, 195, 196, 198,
209–213, 217, 219–222, 276–278 L
upfront chemotherapy, 193–201, 213 Locally advanced primary rectal cancer, 69,
VEGF inhibitors, 186–188 155–156
Clinical decision making, 54, 316, 342–344, 355–357 Local relapse
Computed tomography (CT), 7, 24, 27, 29, 32, CEA surveillance, 97
36–38, 68, 69, 73, 74, 96–102, 117, 118, endoscopy surveillance, 97
121, 124, 125, 131–133, 135, 136, 138, 139, limitations in the imaging detection, 99–100
141, 144, 165, 209, 212, 262, 275, 278, 284, new techniques in the evaluation of local relapse,
287, 295, 305, 344, 352, 353 100–101
role of CT, 98, 99
role of imaging surveillance, 97
D role of MRI, 98–99, 101, 102
Data sharing, 356–359, 363 role of PET, 98, 100
Delineation surveillance and at what frequency, 96

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 365

DOI 10.1007/978-3-642-25005-7, © Springer-Verlag Berlin Heidelberg 2012
366
M EGFR inhibitors, 182, 185
Magnetic resonance imaging (MRI)
diffusion-weighted magnetic resonance imaging
(DWI), 79–87
dynamic contrast-enhanced MR imaging
(DCE-MRI), 87–88
extramural venous invasion (EMVI), 30–32, 200
mesorectal fascia involvement, 69, 70
mesorectal spread, 62–64
pretreatment ADC value, 84–85
qualitative assessment of DWI, 84
Metastases
extra-hepatic disease, 36–38
hyperthermic intraperitoneal chemotherapy
(HIPEC), 213, 278
initially unresectable metastases, 211–212
limited peritoneal disease, 213
liver, 37, 206, 207, 209, 210, 212–214, 352
R0 resectable liver +/− lung metastases, 207,
209–211
N Radiotherapy treatment technique
Nodal metastases, 45, 73–75, 157, 166, 298, 314
Nodal staging, 36, 73–75, 157, 160, 322
P planning target volume margins, 139–141
Pathology
APR grading, 311–312
circumferential resection margin involvement,
310–311
correct procedure for handling the specimen,
305–316
direct tumour spread and pT stage, 309–310
histological typing and grading, 309
key features in the pathology report, 308–316
local peritoneal involvement, 312
lymph node metastases and pN stage, 314–315
mesorectal grade, 309, 311, 312
prognostic value of (y)pN, 319–325
prognostic value of (y)pT, 319–325
prognostic value of TRG, 333–337
specimen after neoadjuvant radiotherapy, 315–316
vascular invasion, 308–315, 323, 324, 328
Pathophysiology, 6–7
Positron emission tomography-computed tomography
(PET-CT)
early response evaluation FDG PET-CT, 89
presurgical FDG PET-CT, 89–91
pretreatment FDG PET-CT, 89
Prediction applications, 359–363
Preoperative long-course chemoradiotherapy
acute and late toxicity of SCPRT and CRT, 111
adjuvant chemotherapy, 106, 108
biologic targeted agents, 114
clinical trials, 109, 113, 114
combined EGFR and VEGF, 188
Index
meta-analysis, 109
oxaliplatin, 174, 175, 177, 178
selection of patients, 109, 113–115
surgical procedure avoidance, 291–300
upfront chemotherapy, 193–201
VEGF inhibitors, 186–188
Preoperative short-course radiotherapy
acute and late toxicity of SCPRT and CRT, 111
clinical trials, 106–108
meta-analysis, 108–109
population-based data, 22, 108
selection of patients, 109, 113–115
Prognostic clinical factors
distance of the tumor to mesorectal fascia, 24–25
histopathology on pretreatment biopsies, 25–26
pretreatment laboratory findings, 26
sex, age, and body mass index, 21–22
tumor size and location, 22–23
R
benefits of IMRT, 132
correcting shape variation, 141–142
IGRT, 129–145
patient orientation and belly board use, 136
possibility of dose escalation, 143–145
prerequisites for IMRT, 132–134
to reduce irradiated small bowel volume, 134–138
reduction of CTV, 136–138
set-up errors, 133, 138, 141, 142
target volume shape variation, 138–139
Rapid learning health, 355–363
Rectal function, 5–6
S
Surgery
APR grading, 311–312
diverting stoma, 257–259
extended resections, 275–287
extralevator abdominoperineal excision,
261–271, 312
laparoscopic, 30, 186, 240, 241, 245, 249–255,
267, 293, 298, 349
nerve-sparing surgery, 233–245
quality of surgery, 177, 229–231, 261, 262, 265,
269, 270, 306, 316, 329, 330
surgical procedure avoidance, 291–300
T
Treatment strategy
cM1, non-synchronous, 15
cM1, resectable synchronous metastases, 14
cM1, unresectable synchronous metastases, 14
Index 367

cT1 N0 M0, 11 Tumour heterogeneity

cT2 N0 M0, 11 based on biological evidence, 50
cT3 (MRF−) N0-2 M0, 12 based on clinical observation, 50–52
cT3 (MRF+) N0-2-M0 or cT4 any N M0, 12 surrogate endpoints, 52–55
local recurrence, cM0, 13