Jesus E. Medina, Nilesh R. Vasan (Eds.) - Cancer of The Oral Cavity, Pharynx and Larynx - Evidence-Based Decision Making-Springer International Publishing (2016)

Cancer of the
Oral Cavity,
Pharynx and Larynx
Evidence-Based
Decision Making
Jesus E. Medina
Nilesh R. Vasan
Editors
123
Cancer of the Oral Cavity, Pharynx and Larynx
Jesus E. Medina • Nilesh R. Vasan
Editors
Cancer of the Oral Cavity,

Pharynx and Larynx
Evidence-Based Decision Making
Editors
Jesus E. Medina Nilesh R. Vasan
Department of Otolaryngology Department of Otolaryngology
College of Medicine College of Medicine
University of Oklahoma University of Oklahoma
Oklahoma City, OK, USA Oklahoma City, OK, USA
ISBN 978-3-319-18629-0 ISBN 978-3-319-18630-6 (eBook)

DOI 10.1007/978-3-319-18630-6
Library of Congress Control Number: 2016948221
© Springer International Publishing Switzerland 2016

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To my wife Libby, a constant source
of inspiration!
To my children Katherine, Joey and Kristine,
their spouses and their children. They are
our joy and pride.
Jesus E. Medina, M.D.
“To my wife Dimple and sons Dylan
and Krish”
Nilesh R. Vasan
Preface
The pursuit of knowledge is one of the fundamental pillars of medical professional-

ism. During the 8–10 years of medical education and residency training, physicians
discipline themselves to acquire the knowledge needed to be able to diagnose and
treat patients with different afflictions. The kind of knowledge we must pursue is
described superbly by Sir William Osler, the late Regius Professor of Medicine at
Oxford, in his book Aequanimitas:
A knowledge of the fundamental sciences upon which our art is based, … not a smattering,
but a full and deep acquaintance, not with all the facts, that is impossible, but with the great
principles based upon them.
With the fast paced advances in medical technology and pharmacology, these
principles evolve almost constantly, and we need to keep pace. Not too many years
ago, conventional surgery and radiation therapy were the only treatment modalities
available to treat cancers of the head and neck region. Today, the treatment of our
patients can include transoral surgery using the laser or robotics, various modalities
of radiation therapy such as IMRT or the proton beam, and a variety of drugs and
bioactive agents. In addition to being able to counsel patients about the relationship
of their cancer with tobacco and alcohol, we now must be able to talk to them intel-
ligently about the human papilloma virus and its relationship to cancer.
An increasingly challenging decision-making process begins as soon as the his-
tory and clinical exam are completed. The clinician is now limited to obtaining only
those diagnostic tests that are supported by evidence. While having an array of treat-
ment modalities is clearly beneficial to our patients, the clinician must have a work-
ing knowledge of the rationale, advantages and disadvantages of each of them. Only
then, each patient will be prescribed the most appropriate treatment.
The purpose of this book is to provide the clinician reader with a comprehensive,
concise discussion of the best evidence available on which to base clinical decisions
necessary in the course of managing patients with squamous cell carcinomas of the
oral cavity, pharynx and larynx. The reason this is a timely addition to the literature
is twofold. First, most clinical decisions in the management of cancers of the head
and neck region are based on the results of a few controlled, randomized clinical
vii
viii Preface
trials (Evidence Level I); most decision making is based on the results of case-
control studies (Evidence Level II), descriptive studies, reports of expert commit-
tees, or opinions of respected authorities (Evidence Level III). Second, this
information is scattered throughout the literature and often intermingled with infor-
mation about other topics. Therefore, there is a need for a publication in which the
evidence pertinent to making decisions regarding a particular clinical problem is
distilled, from the literature, and is presented in a single, concise clinical situation-
driven source.
We are indebted in this endeavour to the members of the Head and Neck Team at
the University of Oklahoma Health Sciences for their valuable contributions.
Oklahoma City, OK, USA Jesus E. Medina

Nilesh R. Vasan
Contents
1 Evidence-Based Medicine......................................................................... 1
Nilesh R. Vasan
2 Oral Cavity Cancer ................................................................................... 3
Jesus E. Medina, Nilesh R. Vasan, and Anthony Alleman
3 Oropharynx Cancer .................................................................................. 27
Nilesh R. Vasan, Jesus E. Medina, and Anthony Alleman
4 Cancer of the Nasopharynx...................................................................... 51
Greg Krempl and Anthony Alleman
5 Cancer of the Hypopharynx..................................................................... 65
Trinitia Y. Cannon and Keren Bartal
6 Larynx Cancer .......................................................................................... 83
Jesus E. Medina
Index ................................................................................................................. 113
ix
Chapter 1
Evidence-Based Medicine
Nilesh R. Vasan
Evidence-Based Medicine
Evidence-based medicine (EBM) can be defined as the application of best available

evidence gained from the scientific method to clinical decision making [1]. Even
though medicine is based on scientific advances, EBM aims to classify the “prac-
tice” of medicine by using levels of evidence based on the rigor of the study or trial
to make either strong or weak recommendations for patient management. This can
be for both diagnosis and treatment for various conditions. The idea for EBM is that
patient management should be founded on the best and strongest available evidence
and not the beliefs or entrenched dogma from physicians or experts.
The term “evidence based” was coined by David M. Eddy for his work on population-
level policies [2]. But the term “evidence-based medicine” developed within clinical
epidemiology. EBM can be applied to individuals as well as populations in regard to the
effectiveness of a diagnostic test or treatment. Subsequently, a number of organizations
developed EBM levels such as the US Preventative Services Task Force (USPSTF), the
Centre for Evidence Based Medicine (CEBM), and the National Guideline Clearinghouse
to name three. The underlying premise is the same in that the most robust and strongest
available evidence is gained from randomized double-blinded control studies or meta-
analyses whereas the weakest are from case reports. In this text, the authors have utilized
the EBM classification from the USPSTF.
N.R. Vasan, M.D. (*)

Department of Otorhinolaryngology, College of Medicine,
The University of Oklahoma, Oklahoma City, OK, USA
e-mail: nilesh-vasan@ouhsc.edu
© Springer International Publishing Switzerland 2016 1

J.E. Medina, N.R. Vasan (eds.), Cancer of the Oral Cavity, Pharynx and Larynx,
DOI 10.1007/978-3-319-18630-6_1
2 N.R. Vasan
This book describes the management of common head and neck malignancies
using the best available evidence to date. The authors would like to challenge read-
ers to critically evaluate their current management strategies using EBM and be
open to new forms of diagnostic assessment and treatment if well-designed clinical
studies demonstrate a significant improvement over current treatment protocols.
References
1. Timmermans S. Health Aff (Millwood). 2005;24(1):18–28.

2. Eddy DM. Practice policies: guidelines for methods. JAMA. 1990;263(13):1839–41.
Chapter 2
Oral Cavity Cancer
Jesus E. Medina, Nilesh R. Vasan, and Anthony Alleman
Decisions in Clinical Evaluation
Clinical Situation
Sixty-year-old man who presents with a squamous cell carcinoma of the left floor of
mouth clinically staged T2N0 (Fig. 2.1a).
The clinician managing this patient will face a number of critical clinical deci-
sions in his diagnostic evaluation and treatment. One of these decisions is concerned
with the appropriate assessment of the relationship of the tumor to the mandible.
What Is the Best Method to Assess Mandibular Invasion?
Accurate determination of the presence and extent of invasion of the mandible is

important for staging purposes and to decide whether a resection of the mandible is
necessary to remove the tumor adequately. If a resection of the mandible is deemed
necessary, the surgeon must then decide whether it is appropriate to perform a mar-
ginal (rim resection), coronal (resection of the lingual table), or a segmental man-
dibulectomy (full-thickness segment of the mandible).
In addition to the clinical exam, several imaging studies are used by clinicians for
this purpose. Considerable debate exists in the literature regarding the optimal
imaging modality or combination of modalities needed for preoperative assessment
J.E. Medina, M.D. (*) • N.R. Vasan, M.D.

Department of Otorhinolaryngology, College of Medicine, The University of Oklahoma,
Oklahoma City, OK, USA
e-mail: jesus-medina@ouhsc.edu
A. Alleman, M.D.
Department of Radiology, College of Medicine, The University of Oklahoma,

DOI 10.1007/978-3-319-18630-6_2
4 J.E. Medina et al.
Fig. 2.1 (a) Squamous cell carcinoma of the anterior floor of the mouth extending on to the lin-
gual surface of the inferior alveolar ridge. (b) CT scan showing the lesion abutting the mandible
without invading it. Notice the intact lingual cortex of the anterior arch of the mandible
of mandibular invasion. The imaging studies that are used include orthopantogram
(panorex), computerized tomography (CT), magnetic resonance imaging (MRI),
and bone scans. To date, there are no randomized studies (EBM level I) comparing
the accuracy of these modalities. Brown et al. performed an analysis of studies,
published up to the year 2001, comparing the accuracy of clinical examination,
perioperative periosteal stripping, and imaging techniques in predicting tumor inva-
sion of the mandible in oral cancers. All the studies analyzed were cohort or case-
control analytic studies (EBML II-2). Table 2.1 shows the range of the sensitivity
and specificity reported by Brown et al. plus the results of studies, similar to those
analyzed by Brown, published between 2001 and 2013. Table 2.2 presents the
median sensitivity and specificity of all reports. These results indicate that neither
the clinical exam nor any of the imaging modalities currently used is ideal to accu-
rately diagnose subtle mandibular involvement by oral cancers, since none of them
is both highly sensitive and highly specific. They also suggest that when dealing
with a clinical situation like the one being considered here, a combination of a
highly sensitive test, i.e., bone scan, and a highly specific test, i.e., CT scan, may be
most helpful.
Unfortunately, most of the studies analyzed did not specify the findings on clini-
cal exam. Furthermore, the imaging studies have several limitations, the most sig-
nificant being artifacts caused by dental amalgams, which commonly create a
shadow that precludes assessment of invasion of the mandibular cortex.
Careful clinical inspection and palpation of the tumor and adjacent structures
may reveal obvious signs of mandibular invasion, such as unquestionable fixation of
the tumor to the mandible, exposure of bone within the tumor, inferior alveolar
nerve paresthesia, or a pathological fracture [4, 13]. Imaging in these cases is geared
toward evaluating the extent and type of mandibular involvement; for instance,
2
Table 2.1 Range of the sensitivity and specificity of the different imaging modalities reported by Brown et al. [1] and similar studies published between 2001
and 2013
Clinical exam Plain X-rays/panorex Bone scan/SPECT CT MRI
Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity
Oral Cavity Cancer
Brown [1] 39–100 (9) 25–100 40–97 (16) 64–100 71–100 43–100 50–100 57–97 39–100 (5) 40–100
(15) (10)
Schimming 85 990 100 92
[2]
Acton [3] 70 72
Rao [4] 92 88
Bolzoni [5] 93 93
Goerres [6] 92 86 92 100
Inaizumi [7] 100 88 96 54
Rajesh [8] 100 50 100 50 100 50
Van Cann [9] 59 74 61 61 100 57 58 96 63 100
Albuquerque 82 87.5
[10]
Dreiseidler 91 40 CB 92 97
[11] MS 80 100
Handschel 83 87
[12]
Mean 80 65 77 80 94 72 79 90 86 73
Median 83 71 79 81 98 72 82 90 94 73
5
Table 2.2 Detection of Sensitivity Specificity

mandibular invasion: median
Plain X-ray/ 79 81
sensitivity and specificity of
panorex
imaging modalities
CT 82 90
Clinical exam 83 71
MRI 94 73
Bone scan 98 72
Fig. 2.2 Orthopantogram showing subtle modeling-type asymmetry of the superior cortex of the
mandibular body (arrow) on the right without obvious cortical erosion
when perineural invasion of the inferior alveolar nerve is suspected, MRI is the
appropriate modality to assess the extent of it.
On the other hand, for tumors of the gums, retromolar trigone, and tumors of the
floor of the mouth that extend to the alveolar ridge, plain radiographs or an orthop-
antogram of the mandible can show subtle mandibular involvement; in that case
additional imaging is not necessary and consideration is given to performing a mar-
ginal resection of the mandible (Fig. 2.2).
In the case shown in Fig. 2.1a, b, the absence of mandibular erosion on the CT
scan indicates that a marginal mandibulectomy is most likely appropriate to remove
the tumor adequately. In fact, that is the operation that was performed as seen in
Fig. 2.3. One of the obvious advantages of a marginal mandibulectomy, when
feasible, is the avoidance of complex reconstruction of the mandible, and the pos-
sibility of immediate dental rehabilitation with a prosthesis anchored on dental
implants placed at the time of the extirpative surgery (Figs. 2.3 and 2.4).
In other cases, such as the one shown in Fig. 2.5, where a carcinoma of the lateral
floor of the mouth abuts but does not invade the lingual aspect of the mandible, a
coronal mandibulectomy, i.e., an en bloc resection of the tumor and the adjacent
lingual table of the mandible is often possible and desirable.
2 Oral Cavity Cancer 7
Fig. 2.3 Orthopantogram showing the bone defect resulting from a marginal resection of the
mandible (Courtesy of George Bohle, DDS)
Fig. 2.4 Photographs illustrating the clinical appearance after a marginal mandibulectomy, with
immediate insertion of dental implants (a), the dental prosthesis (b), and the prosthesis anchored
to the metal implants (c) (Courtesy of George Bohle, DDS)
On the other hand in the cases shown in Figs. 2.6 and 2.7, where the orthopanto-
gram or the CT scan shows obvious invasion of the mandible, it is clear that an
adequate resection will require a segmental mandibulectomy.
When the clinical exam is equivocal, the evidence existing in the literature (EBL
II-2) suggests using a combination of a highly sensitive modality, such as bone
Fig. 2.5 Carcinoma of the lateral floor of the mouth. The CT shows clearly that the tumor abuts
but does not invade the lingual aspect of the mandible
Fig. 2.6 Orthopantogram showing obvious invasion of the mandible on the left body region
Fig. 2.7 Non-contrasted, coronal CT showing erosion of the lingual cortex of the alveolar ridge
and marrow as well as pronounced thinning of the labial cortex
scintigraphy with SPECT and a highly specific modality such as CT scan. A high-
sensitivity test is reliable when its result is negative, since it rarely misdiagnoses
those who have the disease. Thus, in the clinical situation presented here, a negative
bone scan/SPECT may be useful for ruling out mandibular involvement. In that
case the decision to perform a marginal mandibulectomy is in all likelihood onco-
logically sound and may be done to provide a safe margin around the tumor. The
advantages of performing a marginal resection of the mandible include avoidance
of complex reconstruction of the mandible and the possibility of immediate place-
ment of dental implants, as it was done in the case presented here.
On the other hand, a negative result in a test with high specificity, such as a CT
scan, is not useful for ruling out disease, while a positive CT scan indicates a high
probability of the presence of mandibular involvement. In the clinical situation pre-
sented at the beginning of this section, if the CT scan is positive as in the example
shown in Fig. 2.3, the possibility of involvement of the mandible is high and a mar-
ginal or coronal mandibulectomy may not be sufficient to remove the tumor ade-
quately. The surgeon would be inclined to discuss with the patient and be prepared
for the possible need of a segmental mandibulectomy.
Should the Patient Undergo Panendoscopy?
Panendoscopy or triple endoscopy, consisting of laryngoscopy, bronchoscopy, and

esophagoscopy, was considered for a long time a mandatory procedure in any newly
diagnosed patient with squamous cell carcinoma of the upper aerodigestive tract. It
appears that bronchoscopy and esophagoscopy are still commonly performed; a
recent survey revealed that these procedures are performed in 94–100 % of clinics
in Germany [14]. However, the current role of bronchoscopy in the evaluation of an
asymptomatic head and neck cancer patient with a normal chest radiograph, and
especially in a patient with a normal CT of the chest, is seriously questioned in view
of the low rate of lung cancers detected with this procedure [15].
The role of routine esophagoscopy, on the other hand, continues to be debated for
two reasons; first, the procedure is not free of complications, particularly in tertiary,
academic centers where the majority of head and neck cancers are treated. A retro-
spective review of 546 esophagoscopies (276 flexible and 270 rigid) performed at a
tertiary, academic center revealed esophageal perforations in 2.6 % of the cases, all
in association with rigid endoscopy and all in patients with a history of head and
neck cancer. The esophageal perforation rate observed in this study is higher than
that typically reported for rigid esophagoscopy. This is possibly due to the fact that
in academic institutions the esophagoscopy is a procedure often delegated to the
most junior members of the surgical team and, as the authors of this study found, the
rate of esophageal perforation correlates with the level of experience of the surgeon
performing the endoscopy [16].
Second, the prevalence of simultaneous esophageal cancer in head and neck can-
cer patients appears to be site dependent, and it is very low in patients with cancer
of the oral cavity. The available evidence suggests that in the absence of symptoms,
Table 2.3 Prevalence of synchronous esophageal cancer found on esophagoscopy in patients with
oral cavity cancer
Complications of
esophagoscopy
Prevalence of synchronous Rigid Flexible
esophageal cancer (n = 270) (n = 276)
Guardiola et al. [15] France 0% – –
Davidson et al. [18] Canada 0% – –
Grossman [19]. USA 0.8 % – –
Hung et al. [20] Taiwan 0.74 % – –
Tsao et al. [16] USA 0% 2.6 % 0%
an esophagoscopy is not warranted in patients with cancer of the oral cavity. In a

study of 487 patients with squamous cell carcinoma of the upper aerodigestive tract,
Guardiola et al. did not find a single case of esophageal carcinoma in patients with
a cancer of the oral cavity. However, they found an esophageal carcinoma in 1.3 %
of the patients with an oropharyngeal cancer, in 2 % of the patients with a laryngeal
cancer, and in 9.2 % of the patients with a hypopharyngeal carcinoma [17]. Similarly,
in a prospective study of 224 patients with squamous cell carcinoma of the oral cav-
ity, pharynx, larynx, or neck, none of them had a synchronous primary esophageal
cancer [18]. Of 790 patients studied retrospectively by Grossman, 2.3 % developed
a second primary malignancy in the esophagus; however, only 1 of 244 (0.4 %)
patients with cancer of the oral cavity had a simultaneous cancer of the esophagus
[19]. In Taiwan, where the incidence of esophageal cancer is higher than in most
other countries, Hung et al. did a cross-sectional study from the Taiwanese
Longitudinal Health Insurance Database. Among 2965 subjects with oral, oropha-
ryngeal, or hypopharyngeal cancers, they found that an esophageal cancer was diag-
nosed within 3 months of their head and neck cancer diagnosis in 0.74 % of patients
with oral cavity cancer, a significantly lower prevalence than that in patients with
hypopharyngeal cancer (8.89 %) [20].
As seen in Table 2.3, the prevalence of esophageal cancer is very low. Furthermore,
the risk of perforation of the esophagus outweighs the likelihood of finding an
esophageal cancer on routine esophagoscopy, thus bringing into serious question
performing this procedure routinely in the asymptomatic patient with cancer of the
oral cavity.
Should an Ultrasound, CT, or MRI Scan of the Neck Be Obtained?
Most primary squamous cell carcinomas of the oral cavity are treated with surgery.
Removing the lymph nodes, i.e., performing a neck dissection in every patient with
these tumors, is obviously impractical, since not every one of them would have
metastases in the lymph nodes. Ideally, dissection of the lymph nodes would be lim-
ited to those patients that are most likely to have metastases. Unfortunately, detection
of “subclinical,” microscopic metastases in the lymph nodes of the neck in patients
without palpable adenopathy (clinically N0) remains a challenge to the clinician.
Examination of the neck by palpation is not uniformly reliable. It is commonly

accepted that the reported error rate in assessing the presence or absence of cervical
lymph node metastases by palpation ranges from 20 to 50 %. The factors responsible
for this variation are not only the ability and experience of the examiner but also the
patient’s habitus and previous treatment to the neck with surgery or radiation therapy.
In the quest for means to identify those patients who harbor “subclinical metas-
tases” in the lymph nodes clinicians have utilized a variety of resources, spanning
form noninvasive methods such as ultrasonography to more invasive procedures
such as sentinel lymph node biopsy. However, the decision to recommend elective
dissection of the neck is currently based mainly on the probability of lymph node
metastases, which is determined on the basis of the location and stage of the primary
tumor and a few other tumor and patient-related parameters.
In the detection of metastases in lymph nodes, ultrasonography (US), computed
tomography (CT), and MRI have a higher sensitivity and specificity than clinical
examination. In a prospective study of 48 patients who were to undergo neck dissec-
tion, Haberal et al. found that the sensitivity and specificity of palpation for the
detection of metastases in the lymph nodes were 64 % and 85 %, respectively, while
the corresponding values for US were 72 % and 96 % and for CT 81 % and 96 %
[21]. Adams et al. [22] reported similar results for US and CT; in addition, they
reported a sensitivity of 80 % and a specificity of 79 % for MRI. However, in this
and other studies, these imaging modalities failed to detect metastases in 19–28 %
of the patients staged clinically N0. Consequently, a clinician cannot reliably base a
decision to withhold elective treatment of the cervical lymph nodes on a “negative”
US, CT, or MRI of the neck.
There are several reasons for the poor performance of current imaging studies in
the detection of occult metastases in lymph nodes. First is size, which is the crite-
rion used most often to consider a cervical node suspicious for metastasis in an
imaging study. A neck lymph node located in level I or II is considered suspicious
when it is larger than 1.5 cm in maximum diameter; in other levels of the neck nodes
are considered suspicious when they are larger than 1 cm [23]. Although a correla-
tion exists between the size of a lymph node and the presence of histologic metas-
tasis, not all enlarged lymph nodes contain metastatic deposits and nodes smaller
than 1 or 1.5 cm can contain metastases. In fact, 33 % of all metastases from squa-
mous cell carcinomas of the head and neck are found in lymph nodes smaller than
1 cm [25, 26]. Second, 10 % of tumor-positive neck dissection specimens contain
only metastases less than 3 mm in diameter and, more importantly, 25 % of all clini-
cally occult lymph node metastases are too small to be detected by any of the cur-
rently available imaging techniques [25].
Should the Patient Have an Ultrasound (US) of the Neck and US-Guided
Fine-Needle Aspiration of Lymph Nodes?
In an attempt to overcome the lack of sensitivity of morphologic imaging criteria,

ultrasonography was combined with US-guided fine-needle aspiration cytology
(US-FNAB). This technique appeared more promising for the preoperative
evaluation of the N0 neck since it enabled sampling of lymph nodes as small as

3 mm in diameter and added the advantages of cytologic evaluation [27]. Subsequent
studies have shown that the usefulness of this technique is strongly dependent on
the skill, time and zeal of the ultrasonographer, and the experience of the cytopa-
thologist. Furthermore, the outcomes of a wait-and-see policy after negative
US-FNAB have been disappointing. In a study of 92 patients with tumors of the oral
cavity, staged T1 and T2, who were observed after a negative US-FNA, metastases
in neck nodes became apparent subsequently in 19 (21 %) [28]. In a more recent
study, Wensing et al. found that palpation and US with or without US-FNAB missed
occult lymph node metastases in 22 % of the patients with oral cavity squamous cell
carcinoma [29]. These figures are troubling because the incidence of lymph node
metastases in patients with such tumors, who are observed without any intervention
to the neck, is about 25 %.
Should a PET Scan or a PET/CT Be Obtained in This Patient?
Positron Emission Tomography
Prospective studies using 18 fluorodeoxyglucose positron emission tomography

(PET) to assess lymph node metastases from squamous cell carcinomas of the oral
cavity have shown a sensitivity and specificity higher than MRI, CT, and
US. However, current FDG-PET techniques are also limited in the detection of
tumor foci smaller than 1 cm [30–32].
Kyzas et al. [33] performed a meta-analysis of 32 studies that assessed the diag-
nostic performance of PET scans in patients with squamous cell carcinoma of the
head and neck. In patients staged clinically N0, the sensitivity of 18FDG PET scan
was only 50 % (95 % CI = 37–63 %), whereas the specificity was 87 % (95 %
CI = 76–93 %). These authors also compared the performance of PET scan with that
of “conventional diagnostic methods,” i.e., computed tomography, MRI, and
ultrasound with fine-needle aspiration by analyzing studies that had used all these
diagnostic methods on the same patients. The sensitivity and specificity of PET scan
were 80 % and 86 %, respectively, while for the “conventional diagnostic tests” they
were 75 % and 79 %.
Ng et al. [34] showed that the visual correlation of 18FDG-PET with contrast-
enhanced CT/MRI was more accurate than 18FDG-PET alone for the detection of
subclinical lymph node metastases. In 134 patients with squamous cell carcinoma
of the oral cavity who were staged N0 clinically, they found a sensitivity of 51.4 %
for 18FDG-PET, which increased to 57.1 % after visual correlation with CT or
MRI. This increment stemmed from the correction of false-negative 18F-FDG-PET
results caused by necrotic nodes. Ozer et al. [35] reported a sensitivity of 57 % and
specificity of 82 % for the detection of occult metastasis by 18F-FDG-PET-CT in
112 patients with clinically negative necks on physical examination, CT, and/or
MRI.
Liao et al. [36] recently reported a meta-analysis comparing CT, MRI, PET, and
ultrasound for the detection of cervical lymph node metastasis in patients with clini-
cally N0 necks. They found no significant differences in sensitivity and specificity
among these imaging modalities, with the exception that CT had a higher specificity
than ultrasound.
Thus, at the present time, the role for PET scan in the evaluation of the N0 neck
is limited as it will not detect subclinical metastases in 20–50 % of the cases.
Decisions in Treatment
Clinical Situation
Patient with a squamous cell carcinoma of the lateral border of the tongue, clinically
staged T2N0 (Fig. 2.8).
Decisions Regarding the Primary Tumor
Surgery vs. Radiation (Why Is Surgery the Best Treatment Modality?)
According to the NCCN Guidelines, Version 2:2013, “most panel members prefer
surgical therapy for resectable oral cavity tumors, even for more advanced tumors.”
“For patient with early stage oral cavity cancers, the recommended initial therapy
options are surgery (preferred) or radiation therapy” (EBM level III). Unfortunately,
the published guidelines do not state the reasons why surgery is the preferred treat-
ment modality. Knowledge of this information is pertinent to the head and neck
Fig. 2.8 Clinical

photograph of a squamous
cell carcinoma of the
lateral border of the
tongue, clinically staged
T2N0
Table 2.4 Comparison of results with brachytherapy and surgery

Brachytherapy
Low dose High dose Surgery
Stage (n) I (42) II (36) I (8) II (18) I (42) II (29)
Local recurrence (%) 14.3 19.4 25 38.9 9.5 0
Alive without tumor (%) 71 69 50 56 93 97
*Modified from [24]
Table 2.5 Cancer of the Local control (%)

tongue: results of treatment
Delclos Fujita
with external and interstitial
Stage et al. [38] et al. [39]
radiation
T1 94.5 92.9
T2 89.5 81.9
T3 77.8 71.8
Osteoradionecrosis 19 8.4
surgeon, especially since several publications show that the control rates obtained in
T1 and T2 cancers of the oral cavity treated with radiation therapy are similar to
those obtained with surgery. Brachytherapy has been shown to be effective in early
cancers of the head and neck and has become an important therapeutic alternative to
conventional radiotherapy for oral cancer in Japan [37]. While a meta-analysis of a
few randomized studies (EBM I) showed that low-dose (LDR) and high-dose
(HDR) brachytherapy is equally effective, only one retrospective study (EBMII)
has compared brachytherapy and surgery for the treatment of stage I–II squamous
cell carcinoma of the tongue. The results summarized in Table 2.4 show that surgery
was superior in terms of local control [24].
The combination of external beam radiation and interstitial brachytherapy yields
the best results for nonsurgical treatment of T1 to T3 squamous cell carcinoma of the
tongue and floor of the mouth; however, the incidence of osteoradionecrosis of the
mandible following such treatment ranged from 9 to 22 % (Table 2.5). Thus, surgery
is the preferred treatment modality because it yields better results than treatment
with brachytherapy alone and because of the high possibility of osteonecrosis of the
mandible associated with the combination of external and interstitial radiation.
Resection Margins
How Wide a Margin of Normal Tissue Should Be Resected Around the Tumor?
The best available evidence to guide the surgeon regarding the amount of seemingly
normal tissue to be removed around a carcinoma of the tongue was provided by a
prospective study (EBM II-2) by Yuen et al. [40]. The study was aimed at evaluat-
ing the three-dimensional mode and distance of local spread of oral tongue
carcinoma. To that end, 50 glossectomy specimens of squamous cell carcinoma of

oral tongue were examined in the coronal plane in 3 mm thickness sections. They
found that the maximum spread was 1.8 cm with 96 % of the tumors spreading
within 1.2 cm. The distance of spread was not correlated with tumor size, including
the diameter, depth, and volume. Based on these observations the authors recom-
mend a minimum margin of 1.5 cm and a maximum margin of 2 cm; a smaller
margin has significant risk of local recurrence and a larger margin is not necessary
and can increase morbidity.
Should Frozen Section Examination of the Margins Be Used Routinely?
Clinical assessment of the presence of microscopic tumor at the resection margins

is difficult; consequently most surgeons use intraoperative frozen section examina-
tion to guide the adequacy of the resection. However, a recent prospective study
(EBM II-1) compared the efficacy of gross examination of the surgical specimen by
the surgeon with frozen section in determining the adequacy of the resection mar-
gins [41]. In this study, the distance from the tumor to the mucosal margins was
measured in millimeters and the adequacy of the “deep” or soft-tissue margins was
judged by palpation. The authors found that when the surgeon’s measured distance
from the tumor to the margins was 7 mm or more, there was no statistically signifi-
cant difference in the assessment of the adequacy of the margin between the sur-
geon’s measurement and the frozen sections. Based on these findings, they
recommend that the use of frozen section be limited to areas where the measured
margin is less than 7 mm. Another potential tool to limit the use of frozen sections
is staining with toluidine blue, which is a metachromatic dye that is known to bind
DNA of dividing cells and is easily available and economical; it stains atypical and
cancerous cells but not normal oral mucosa [42]. As a result, it is useful in the
screening for “premalignant and early malignant lesions of the oral cavity” [43]. It
may also be a useful adjunct in the screening of mucosal margins of resection, by
limiting the number of frozen sections to only those margins that stain with the dye
(EBM LIII) [44]. These techniques are particularly useful in centers where health
care resources are limited.
What Are the Implications of Having Initially Positive Margins on Frozen

Section?
When tumor is present in the resection margins on frozen section (microscopic

tumor cut-through) additional tissue is usually resected until negative margins are
obtained. This practice brings about two questions pertinent to treatment decisions:
First, does a positive margin on frozen section that is eventually converted to nega-
tive have an adverse effect in terms of local control? Second, is postoperative radia-
tion therapy beneficial in such cases?
Two recent studies address the prognostic impact of intraoperative microscopic

cut-through on frozen section in squamous cell carcinoma of the oral cavity.
Guillemaud et al. [45] studied a cohort of 65 patients retrospectively (EBM L-III);
of these, 45 patients had negative margins on both frozen and permanent section and
20 patients had initially positive margins on frozen section, which were then revised
to negative margins on frozen section and permanent section. Both local control and
disease-specific survival were statistically significantly reduced in patients with
positive intraoperative frozen section despite revision to obtain negative margins
(p = .05). Microscopic tumor cut-through independently predicted poorer local con-
trol and disease-specific survival (p = .05) on multivariate analysis. Patel et al. stud-
ied, also retrospectively, 547 oral cavity cancer patients, of whom 495 (90.5 %) had
negative margins on both frozen and permanent section, and 52 (9.5 %) had 1 or
more positive margin(s) on frozen section that were revised to negative on frozen
section and permanent section. Their results showed that patients with tumor cut-
through and regional disease had significantly poorer local control rates (p < .001)
than patients with no regional disease, irrespective of the presence of tumor cut-
through; they also had significantly (p < .0001) poorer disease-specific survival rates
[46]. There are no studies that have shown, especifically, that adjuvant radiation
therapy is beneficial in patients with margins positive on frozen section that are
revised until negative.
Decisions Regarding the Neck
Observation: Can the Neck Be Observed and Treated Only If Metastases

Become Apparent?
The notion of watching the neck and treating it only when metastases become clini-
cally apparent was supported by two prospective randomized studies (EBML I)
involving cancers of the oral cavity that were published in the 1980s [47, 48]. In
both studies the survival of patients who underwent “elective” neck dissection was
not significantly better than the survival of patients who underwent a delayed thera-
peutic neck dissection. Unfortunately, these studies did not resolve the controversy;
in fact, they have been criticized because the number of patients studied was insuf-
ficient to be conclusive.
More recently, observation of the neck has been compared with elective selective
neck dissection in a prospective randomized study done in Brazil (EBM I). The
study population consisted of a mixed cohort of oral cavity cancers that included
carcinomas of the tongue and floor of the mouth. It showed significant survival
benefit of elective neck dissection [49]. On the other hand, in the past 5 years, one
prospective (EBML I) and one retrospective study (EBML II-2) have shown that
regional control of tumor and survival when the N0 neck is observed, and is dis-
sected only if metastases develop subsequently, are comparable to those obtained
with elective neck dissection. It should be noted that in the prospective study con-
ducted by Yuen et al., 95 % of the patients whose neck was observed and in whom
lymph node metastases became apparent subsequently were salvaged with surgery
and, in most instances, radiation and/or chemotherapy. This remarkable result is
probably due to the strict follow-up, which consisted of monthly evaluations for the
first year and US examination of the neck every 3 months for the first 3 years [50,
51].
Sentinel Lymph Node Biopsy
Is it Feasible, Is It Effective, Is It Practical?
Sentinel lymph node biopsy (SLNB) is feasible and useful as a staging procedure in
patients with early carcinomas of the oral cavity and in particular for patients with
cancers of the oral tongue. Proponents of this technique point out that it allows
accurate histopathologic staging of the neck by examining the SLN with serial sec-
tioning and immunohistochemistry, and it avoids unnecessary neck dissection and
its possible complications.
Early studies in patients with squamous cell carcinomas of the mucosal surfaces
of the head and neck investigated the methodology and feasibility of SLNB [52–
55]. In a multicenter study (EBML II-1), Ross and associates investigated SLNB in
134 patients with squamous cell carcinoma of the oral cavity and oropharynx,
staged T1/T2N0 [54]. Lymphoscintigraphy was performed preoperatively; blue dye
and a gamma probe were used intraoperatively to aid in the identification of sentinel
nodes. Sentinel nodes were identified in 93 % of the cases. The number of sentinel
nodes varied, but in a previous series of 48 patients studied by Ross et al. [56], the
mean number of sentinel nodes harvested was 2.4.
Subsequent studies have examined the utility of SLNB in patients with oral cav-
ity or oropharyngeal cancers staged T1/T2 N0. The sensitivity of the procedure is
90 % when the histopathology of the sentinel node is compared with that of the neck
dissection specimen [57]. It results in histopathologic upstaging of the clinically N0
neck in 36 % of the patients when the nodes are examined with routine hematoxy-
lin–eosin staining; serial sectioning and immunohistochemistry upstage an
additional 8 % of the cases [53]. The detection of micrometastases can be further
enhanced by using highly specific tumor markers and molecular methods [58, 59].
Recently, Civantos et al. reported the results of a North American Multi-
Institutional Prospective Study that evaluated the utility of SLNB in T1/T2 oral
SCCs [60]. The study included 140 patients (68 % oral tongue, 19 % floor of mouth)
from 25 institutions who underwent SLNB and SND (levels I-IV). The negative
predictive value (NPV) was 94 % when the SLNs were examined with hematoxy-
lin–eosin stains and 96 % when they were examined with serial sectioning and
immunocytochemistry [60]. The NPV among experienced surgeons was 100 % ver-
sus 95 % for less experienced ones. The SLN was the only positive node in 51 % of
the cases with a positive SLN. The false-negative rate was 9.8 % overall. Interestingly,
however, the false-negative rate was 10 % in patients with cancers of the oral tongue,
but was 25 % in patients with cancers of the floor of the mouth. In the experience of
the University of Miami [61], the NPV of SLNB was 88.5 % in patients with cancers
of the FOM, and 95.8 % when these patients were excluded. Similarly, Ross et al.
have reported that the identification of SLNB in patients with FOM cancers was
lower (86 %) than in patients with tumors in other locations (97 %); the sensitivity
of SLNB in FOM cancers was also lower (80 %), compared with other tumor loca-
tions (100 %) [55]. It appears that lymphoscintigraphy in cancers of the FOM is not
as helpful in identifying the SLN; this is most likely due to the shine-through effect
of the radioactivity at the primary, which obscures the lymph nodes in level I, the
primary echelons of lymphatic drainage for the FOM and lower gum. Obviously,
this limits the utility of SLNB in patients with tumors in these locations.
Selective vs. Modified Radical Neck Dissection
Why Is Selective Neck Dissection the Operation of Choice?
A selective neck dissection (SND) is currently the preferred type of neck dissection
for the elective surgical management of the neck in patients with squamous cell
carcinomas of the oral cavity. This practice is supported by the results of a multi-
institutional prospective randomized study (EBML I) comparing selective neck dis-
section (supraomohyoid neck dissection) (SND) to modified radical neck dissection
(MRND) performed by the Brazilian Head and Neck Cancer Study Group [62], in
patients with oral cancer and clinically N0 neck. The regional control and overall
5-year actuarial survival rates were 87.5 % and 67.0 % for the SND group vs. 89.5 %
and 63.0 % for the MRND, respectively. The differences were not statistically sig-
nificant. In addition a number of retrospective studies (EBML II-2) have shown that
when SND is utilized for the elective treatment of the regional lymphatics, regional
control and survival rates are similar to those of more extensive neck dissections
[63–73].
Should Lymph Nodes in Level IV Be Included Routinely?
The need to remove routinely the nodes in level IV in patients with cancer of the
oral tongue is controversial. Byers et al. [74] reported finding “skip metastases” in
15.8 % of patients with oral tongue cancer. In these cases, metastases to either level
IV or level III were the only manifestation of the disease in the neck. In a similar
more recent review of 119 neck dissections in patients with cancer of the oral cavity,
De Zinis et al. [75] found metastases in level IV nodes in 15 % of the patients and
28 % of them were skip metastases. In another study of 49 patients with cancer of
the oral cavity, staged N0, undergoing “extended supraomohyoid” neck dissection,
occult metastasis in level IV was found in 10 % of the cases [76]. These and other
authors contend that the supraomohyoid neck dissection is inadequate for a com-
plete pathologic evaluation of all the nodes at risk, and they recommend dissecting
the nodes in level IV when performing an elective neck dissection in patients with
cancer of the oral tongue.
The opposing point of view has been advanced by Khafif et al. [77] whose prac-
tice has been to dissect level IV only when a suspicious node is found at level III or
there are multiple obviously involved lymph nodes in level II, III, or both. They
reported their findings in a cohort of 58 patients with squamous cell carcinoma of
the oral tongue (stage T1–T2 N0). The node dissections performed included levels
I through III in 42 patients (69 %), levels I through IV in 16 patients (26 %), and
levels I through V in 1 patient (5 %). A positive node was found in level IV in only
one instance (1/54, 1.8 %), and no recurrences were observed in level IV. Ambrosch
et al. [63] reported similar observations in a study of 167 patients with cancer of the
oral cavity and oropharynx of whom 82 had a clinically staged N0 neck. They dis-
sected level IV only when multiple metastases were suspected during the neck dis-
section. At a median follow-up of 34 months, the rate of regional recurrence in that
series was 5.4 %. Shah et al. [78] studied radical neck dissection specimens per-
formed as elective treatment for oral cavity tumors and found metastatic involve-
ment of level IV in 3 % of the patients. Li et al. [79] studied 153 patients who had a
radical neck dissection for oral cavity cancer (60 therapeutic and 93 elective) and
found metastases to level IV in 3.2 % of the patients. Wang et al. [80] studied 116
patients with oral tongue cancer, staged N0, who underwent comprehensive neck
dissections and 5 patients who had SND. Metastases in levels IV or V were found
in only one patient each. Interestingly, there were five cases with level III involve-
ment as a first echelon of metastasis. These studies and others have shown that the
risk of metastases to level IV in patients with cancer of the oral tongue with clini-
cally negative neck is low; thus there is controversy about the routine inclusion of
this level in such patients.
Decisions Regarding Adjuvant Therapy
Postoperative Radiation
What Are the Indications Supported by Evidence?
Several retrospective studies have suggested that the presence of certain histopatho-
logic features was associated with decreased local regional control and that the
addition of postoperative radiation (PORT) was beneficial (EBML II-2). These fac-
tors include microscopically positive or close surgical margin [81–83] and perineu-
ral invasion [84], although it should be noted that, to date, there are no studies in the
literature that have stratified cases by the type or quality of PNI in OSCC, particu-
larly as it relates to prognosis [85], the number and location of positive lymph nodes
[86, 87], and the presence of extracapsular extension (ECE) of the tumor in the
lymph nodes [87, 88]. A phase III trial conducted at the University of Texas
M.D. Anderson Cancer Center, which was designed to determine the optimal dose
of conventionally fractionated postoperative radiation in patients with advanced

head and neck carcinoma [89] also determined the relative significance of various
adverse features identified from these retrospective studies (i.e., ECE was the only
significant independent variable and combinations of ≤2 risk factors were associ-
ated with a progressively higher risk of recurrence). These findings formed the basis
of the treatment assignments in another prospective trial [90], the results of which
showed that patients with no adverse surgical/pathologic features did not need
PORT, because the 5-year actuarial LRC and survival rates achieved with surgery
alone were 90 % and 83 %, respectively. Patients with one adverse feature other than
ECE who received 57.6 Gy PORT had 5-year actuarial LRC and survival rates of
94 % and 66 %, respectively. This finding is consistent with the outcomes of the
previous trial and justifies the use of a moderate RT dose for patients having an
intermediate risk of recurrence, particularly in view of the finding that 57.6 Gy
induced a lower incidence of acute and late morbidity than did 63 Gy. However,
high-risk patients such as those with extracapsular extension of tumor or ≥2 other
adverse features had 5-year actuarial LRC and survival rates of 68 % and 42 %,
respectively, despite having received a higher radiation dose (63 Gy).
Thus, it would appear that for patients who are at high risk for local-regional
failure after surgery, postoperative RT alone may not significantly improve disease
control above the clavicles and survival.
What Is the Ideal Timing of Radiation?
Timing of the initiation of radiotherapy is important; delays beyond 6 weeks may

compromise tumor control. The results of a meta-analysis of seven studies, involv-
ing 851 patients, aimed at determining the association between delays in radiother-
apy and outcome in terms of locoregional tumor control, distant metastases, and
overall survival, showed that the risk of locoregional recurrence was higher among
patients in whom radiotherapy begun >6 weeks after surgery compared to those in
whom radiotherapy began within 6 weeks [91]. Recently, a statistically more com-
prehensive meta-analysis on the relationship between waiting time for radiotherapy
and clinical outcome was published by Chen et al. [92] In a sample of three high-
quality studies that had adequately controlled for confounding factors, the relative
risk (RR) for local recurrence following postoperative radiotherapy was 1.28 per
month of delay (95 % CI, 1.08–1.52). In addition, there was a marginally significant
decrease in survival with increasing waiting times found in five studies, with an RR
of 1.16 (95 % CI 1.02–1.32) for death per month of delay.
What Is the Ideal Dose of Radiation?
A prospective, randomized trial (EBM I) by Peters et al. [89] was designed to deter-
mine the optimal dose of conventionally fractionated postoperative radiotherapy for
advanced head and neck cancer in relation to clinical and pathologic risk factors.
Their analysis was based on 240 patients, of whom 221 (92 %) had AJC stage III or
IV cancers of the oral cavity, oropharynx, hypopharynx, or larynx. The patients
were stratified by postulated risk factors and randomized to one of the three dose
levels ranging between 52.2 and 68.4 Gy, all given in daily doses of 1.8 Gy. Patients
who received a dose of ≤54 Gy had a significantly higher primary failure rate than
those receiving ≥57.6 Gy (p = 0.02). No significant dose response could be demon-
strated above 57.6 Gy except for patients with extracapsular nodal disease in the
neck in whom the recurrence rate was significantly higher at 57.6 Gy than at ≥63 Gy.
Dose escalation above 63 Gy at 1.8 Gy per day did not appear to improve the thera-
peutic ratio.
Postoperative Chemotherapy and Radiation
What Are Indications Supported by Evidence?
In patients with high-risk resected squamous cell carcinoma of the oral cavity, sev-
eral phase III trials (EBL I) have shown that the addition of cisplatin-based chemo-
therapy to radiotherapy can improve locoregional control, disease-free survival, or
survival, compared to postoperative radiotherapy alone [93–97]. Unfortunately the
definition of high-risk pathological features was not uniform in these studies, but
included the involvement of several lymph nodes, extracapsular extension, and
involved margins. A subsequent analysis of two of these studies suggested that the
addition of cisplatin to postoperative radiotherapy was most beneficial when extra-
capsular spread or positive margins were present [98]. Furthermore, two meta-
analysis that included jointly 87 trials with several thousand patients with SCCHN
have shown that the addition of chemotherapy to locoregional treatment improves
survival at 5 years in patients with tumors of each major primary site, including the
oral cavity, who have stage III or IV disease [99, 100]. Multiple lymph node metas-
tases might be considered an optional indication for concurrent chemoradiation in
patients with oral SCCa with multiple-node metastases without extracapsular
spreading or positive resection margins, especially when the cumulative cisplatin
dose reaches 200 mg/m2 [101].
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Chapter 3
Oropharynx Cancer
Nilesh R. Vasan, Jesus E. Medina, and Anthony Alleman
Clinical Situation 1
A 39-year-old man presents with a recently diagnosed squamous cell carcinoma of

the right tonsil, staged T2N1. He has a history of smoking half a pack of cigarettes
per day for about 20 years and minimal alcohol use. The CT scan of the neck is
shown in Fig. 3.1.
The clinician managing this patient will face a number of clinical decisions in his
diagnostic evaluation and treatment. One of the early decisions in his management
is whether or not the tumor should be tested for human papilloma virus (HPV), fol-
lowing which the clinician must be prepared to address the implications of a posi-
tive or negative result.
Should Oropharyngeal Carcinomas Be Tested for HPV?
The incidence of oropharyngeal cancer (OPC) has increased dramatically over the
last four decades and is predicted to overtake the incidence of cervical cancer by
2020. This has been attributed to increasing rates of HPV infection since the sexual
revolution in the 1960s. The proportion of OPCs that are associated with HPV
N.R. Vasan, M.D. (*) • J.E. Medina, M.D.

e-mail: nilesh-vasan@ouhsc.edu
A. Alleman, M.D.
Department of Radiology, College of Medicine, The University of Oklahoma,

DOI 10.1007/978-3-319-18630-6_3
28 N.R. Vasan et al.
Fig. 3.1 Axial, contrast

CT showing an enhancing
lesion in the right tonsil
area that measures about
2.5 cm and appears to be
confined to the tonsillar
fossa. There is also an
enlarged node in level II,
which is fairly
homogeneous in
appearance and measures
about 3 cm in largest
diameter
differs significantly among countries, being less than 20 % in Eastern Europe, over
50 % in the Western part of the world, and up to 80 % in Scandinavian countries [1].
HPV is a common sexually transmitted virus whose carriers are usually asymptom-
atic. Malignant transformation is due to HPV proteins E6 and E7 destabilizing p53
and retinoblastoma tumor-suppressor proteins, respectively [2]. HPV has over 100
subtypes; however HPV 16 has been found in more than 90 % of HPV-related squa-
mous cell carcinomas (SCC) of the head and neck.
In a study of fixed tissue, Hammarstedt et al. [3] have confirmed this increase in
the presence of HPV in tonsil SCC over the last 40 years (Fig. 3.2) [3]. The presence
of HPV has been observed in as many as 72 % of patients with OPC, particularly in
carcinoma of the tonsil [4, 5]. HPV16 is the most common type found in association
with OPC, while types 18, 31, 33, and 35 are also associated, but are rare.
Studies have attributed the increase in the prevalence of OPC to the population
accepting and engaging more frequently in certain sexual practices. Patients with OPC
may have greater than nine sexual partners or greater than four oro-genital sexual part-
ners over their lifetime significantly more often than patients with non-oropharyngeal
head and neck cancer [6]. (EBM II-2) This data is also supported by a cross-sectional
survey performed on 5579 participants aged between 14 and 69 who had an oral rinse
for the detection of HPV by polymerase chain reaction and subsequent interviews for
demographic and behavioral data [7] (EBM II-2). The results clearly identified that the
risk of HPV infection is correlated with the number of lifetime sexual partners as well
as with oral sex. Furthermore, this study demonstrated a higher incidence of OPC in
men and a bimodal distribution with higher incidence in patients in their early 30s and
also in the early 60s. The actual cause for this is unknown at this time.
Unquestionably the incidence of OPC is increasing and it is mainly due to HPV-
related carcinomas. The evidence suggests that in patients such as the one discussed
here testing for HPV is appropriate.
3 Oropharynx Cancer 29
Tonsil Cancer
Age-standardized incidence rates (to the 1970 Swedish
population) 1970−2002
(EBM II-2)
a 3
b
0,9
2,5 0,8
Standardized incidence
Standardized incidence
0,7
rate (1/100 000)
rate (1/100 000)

2 0,6
0,5
1,5
0,4
1 0,3
0,2
0,5 Male Female
0,1
0 0
1970-1979 1980-1989 1990-1999 2000-2002 1970-1979 1980-1989 1990-1999 2000-2002
Calender years Calender years
Hammarstedt Let al. Int J Cancer 2006,119:2620-23
Fig. 3.2 Tonsil cancer: incidence trend
Table 3.1 Characteristics of the methods used to diagnose HPV in tissue

Sensitivity Specificity
Viral product detected Method High Low ? High Low ? Other
HPV DNA PCR + + Cumbersome
HPV DNA ISH + +
E6/E7 mRNA RT-PCR + + Cumbersome
Fresh frozen tissue
E6/E7 protein IHC + + Technically difficult
p16 IHC + + Widely available
How Should the Tumor Be Tested?
The preferred method of detecting HPV infection is still being debated. The various
methods available to test for HPV have different advantages and disadvantages.
Each test measures a specific point at which HPV affects the normal cell. The viral
product and the characteristics of each of the methods currently used have been
extensively described by Allen et al. [4]. Their findings are summarized in Table 3.1.
The identification of the E6 and E7 oncoprotein mRNA expression is the gold
standard against which the sensitivity and specificity of all other tests are compared
[2]; however, this test is time consuming and expensive and it is performed by
reverse-transcriptase (RT)-PCR or by nucleic acid sequence-based amplification
(NASBA). Most HPV detection in tissue specimens utilizes techniques that detect
the presence of genomic HPV material, which includes polymerase chain reaction
(PCR), in situ hybridization (ISH), and immunocytochemistry (IHC) for p16.
PCR is both highly sensitive and specific, whereas ISH is highly specific but less
sensitive than PCR. Both of these methods aim to detect HPV DNA, which by itself
does not indicate whether or not HPV is genetically active [8]. On the other hand,
RT-PCR, which targets HPV mRNA (E6/E7), reflects virus activity within the
tissue.
At the present time, P16 IHC is widely available, easy to perform, and relatively
cost effective. P16 expression is generally inhibited by the retinoblastoma protein;
however, the E7 protein that is produced by HPV binds to and inactivates the retino-
blastoma protein, thus causing overexpression of p16 [8]. This is a very sensitive
surrogate marker for HPV, but is not specific. It has been validated as an indepen-
dent prognostic biomarker which correlates strongly with HPV-positive status [9,
10]. HPV antibody detection in serum and in oral swabs has been described and
may be of use epidemiologically in the future, but has not yet been validated for
clinical use [2].
Currently, the consensus regarding tumor testing for HPV is to perform a p16
IHC as a screening test and then correlate with other data such as histology and
patient history. If necessary, HPV ISH is done as a confirmatory test, since this is
highly specific. These collaborating tests are important, as approximately 20 % of
tumors may express p16 in the absence of HPV measured by PCR or ISH [8].
What Are Prognostic Implications of a Positive and Negative Result?
Ang et al. [11] performed a prospective randomized study comparing fractionated

radiation therapy with standard radiotherapy (RTOG 0129). This trial failed to show
a difference in the two groups. However, the authors performed a subsequent retro-
spective analysis of their collected data (EBM II) regarding HPV status, assessed by
p16IHC, in patients with stage 3 and stage 4 OPC. This study showed that overall
survival and locoregional control were significantly better in HPV-positive patients.
They also noted that the frequency of a second primary was significantly lower in
these patients compared with the HPV-negative ones. From their analysis they strat-
ified patients based on HPV status, smoking, and tumor stage. They identified three
risk levels: low, intermediate, and high risk. Low-risk patients had a 3-year overall
survival rate of 93 % compared to 46.2 % for the high-risk group (Table 3.2).
Based on the results of this study and quite a few others, it is clear that patients
with HPV-positive oropharyngeal carcinoma have a lower risk of dying, a lower risk
of recurrence, and lower risk of developing a second primary tumor.
Are There Any Treatment Implications of an HPV-Positive or -Negative

Result?
At the present time there is no definitive evidence to suggest that HPV-positive

patients can be treated with less intense regimens; in fact, it is possible that the
prognosis of these patients is as good as it is because the current treatment is
adequate.
Table 3.2 Oropharyngeal cancer: prognostic implications of HPV and smoking status [11]
Risk category HPV status Smoking Other factors 3-Year overall survival (%)
Low + − 93
Intermediate + + N2b–3 71
− − T2–T3
High − + 46
Since HPV-positive patients present at a younger age and are expected to live
longer, treatment-related morbidity both from open surgery and chemoradiation,
such as dysphagia with gastrostomy tube dependence, fibrosis, xerostomia, and
dental complications, has led investigators to study de-intensification of therapy
with the intent of minimizing complications without compromising survival.
A number of treatment de-intensification studies have been undertaken. ECOG
1308 was a multicenter phase II study of 80 patients with OPC, HPV-positive,
resectable, stage IIIA/IIIB and IVA/IVB tumors which was designed to determine
the safety of reducing the radiotherapy dose to the primary site and involved neck
nodes. These patients were treated with induction chemotherapy (paclitaxel, cispla-
tin, and cetuximab) followed by concurrent cetuximab and radiotherapy. Patients
who had a complete response (CR) to the induction regimen were given a reduced
dose of radiation of 54 Gy plus cetuximab, whereas partial responders (PR) received
69.3 Gy with cetuximab. In the group that received 54 Gy plus cetuximab, the
23-month progression-free survival was 84 % with a 2-year OS of 95 % [12]. This
study also highlighted the importance of patient selection, as those patients with
>10-year pack smoking history, and T4a cancers did poorly.
De-escalation chemotherapy trials are also being performed to avoid the side
effects of cisplatin. RTOG 1016 is a phase III, non-inferiority randomized study which
has enrolled 987 patients with HPV-positive OPC to receive accelerated radiation
therapy (70 Gy) with either cetuximab or high-dose cisplatin. This trial has completed
accrual. Results are awaited. A review of ongoing and recently accrued de-escalation
studies is summarized by Bhatia and Burtness [13] and Wierzbicka et al. [14].
Even though de-escalation or de-intensification of treatment may result in simi-
lar control and survival for specific groups of HPV-positive OPC patients, all inves-
tigators agree that any treatment modifications, at this time, should be performed in
a clinical trial setting.
Are Smokers with OPC at Higher Risk of Failure?
HPV-positive patients who have a significant history of smoking lose the prognostic
benefit conferred by HPV association. Ang et al. have shown that smoking is an
adverse prognostic factor and included it as a factor in their analyses of prognosis
[11]. Maxwell et al. demonstrated that current smokers were at significantly higher
risk of recurrence than “never” smokers (p = 0.038) [15]. Similar findings were
shown by Gillison et al. in an analysis of p16+ and p16− patients previously enrolled
in RTOG 9003 and 0129. In both studies, the risk of death increased by 1 % per pack
year (p = 0.002) [16]. It is therefore imperative that all patients are counseled regard-
ing smoking cessation and methods to achieve this.
Are There Behavioral Implications of a Positive HPV Testing?
Clinicians managing patients with cancer of the oropharynx today often face
questions from the patient, the patient’s spouse or sexual partner, and other rela-
tives that are unique in regard to HPV and must be answered based on the best
evidence available to date [2]. In spite of this obvious need, only 26 % of head
and neck clinicians claim to know enough about HPV to be able to counsel their
patients [17]. To address this lack of knowledge, an educational mini-seminar
was held at the Annual Meeting of the American Academy of Otolaryngology
Head and Neck Surgery Foundation in 2014. The published report [17] presents
appropriate evidence-based answers to questions that are commonly asked by
patients and their relatives when they learn that their cancer is related to HPV. The
reader is referred to this excellent review for the details of the evidence available
to address each question. However, we do present a summary of evidence regard-
ing the following pertinent questions:
Is my spouse or a new sexual partner at risk for cancer? Can we engage in
sexual activity? Current evidence does not support abstinence between stable part-
ners; ceasing sexual activity after diagnosis of cancer is not likely to affect the
sharing of HPV that has already occurred. No study has been undertaken to assess
the development of OPC in a partner of a newly diagnosed HPV-positive OPC
patient. Thus, it is the patient’s prerogative to inform any new partner, as the risk
of developing HPV-positive cancer via sexual transmission is unknown. For that
reason, using barrier methods with new partners may diminish the risk of
transmission.
Should my spouse or sexual partner be tested for oral/oropharyngeal HPV
infection? Currently there is no FDA-approved test for HPV infection within the
head and neck. The study of HPV 16 E6 antibodies may hold promise for the future
as a marker of oncogenic infection, since about one-third of HPV-positive cancer
have detectable levels prior to diagnosis [18]. Patients should also be informed that
HPV is found commonly in individuals with no history of risky sexual activity and
they may test positive.
Can the “infection” be passed to my children? Hugging, light kissing, and gen-
eral family contact do not result in transmission of the virus [19].
Do I need to inform my past partners? There is no need to inform past partners.
Exposure to HPV is very common among sexually active individuals (>80 %), the
majority of HPV infections clear spontaneously within 6–12 months, and the risk of
developing cancer among those previously infected is very low [17].
Should the Patient Undergo an Initial Panendoscopy?
In some instances when a biopsy of an oropharyngeal cancer cannot be performed

in the office, as it is often the case in patients with cancer of the base of the tongue,
the biopsy may need to be done under general anesthesia, in the operating room. In
such cases, communication with the anesthesiologist is imperative to avoid a poten-
tially fatal airway emergency. The safest way to proceed may be an awake, fiber-
optic intubation or a tracheostomy.
The other issue is whether or not a direct laryngoscopy, esophagoscopy, and
bronchoscopy are essential, particularly in a patient whose tumor is HPV positive,
in whom a biopsy can be obtained readily with local anesthesia in the outpatient
setting. It is now clear that a bronchoscopy is not indicated in the evaluation of an
asymptomatic patient with OPC with a normal chest radiograph [20]. In regard to
esophagoscopy, a retrospective study (EBM II-2) [21] of 790 patients who under-
went this procedure as part of their evaluation of a head and neck cancer, a synchro-
nous esophageal cancer was found in only 1.3 % of the patients with oropharyngeal
cancer (EBM II-2); however, this study was performed in an era prior to the promi-
nent association of HPV and OPC. The data from RTOG 0129 [11] showed that the
frequency of a second primary tumors was significantly lower in HPV-positive
patients compared with those that were HPV negative. In addition, a recent retro-
spective review of 406 patients with OPC treated in Alberta, Canada, in whom HPV
status of the tumors was determined using immunohistochemistry staining for p16,
the overall rate of second primary tumors was significantly lower in p16-positive
patients (0.7 per 100 patient-years vs. 8.5 in p16 negative, p < 0.0001) [22].
It, therefore, appears that if an oropharyngeal cancer is accessible for biopsy
transorally using local anesthesia in the outpatient setting, and the pharynx can be
thoroughly examined with video-endoscopy, there is no need to perform an endos-
copy under general anesthesia, unless the clinician is seeking specific information
regarding ease of exposure or resectability.
Should a CT or MRI Scan Be Obtained?
The incidence of cervical metastases with OPC is high; thus a CT scan with contrast is
usually recommended to assess the primary cancer and the cervical lymph nodes. With
the increasing incidence of HPV-related cancers, slight differences have been noted
between HPV-positive and HPV-negative OPC. In a EBM II-2 retrospective analysis
Cantrell et al. showed that HPV-positive carcinomas often had primary lesions with
well-defined borders and cystic nodal metastases, whereas HPV-negative tumors had
poorly defined borders and invasion of adjacent muscle on CT scan more often [23].
The soft-tissue resolution of MRI is very useful in the determination of the extent
and depth of invasion of oropharyngeal tumors, particularly in patients that are being
considered for transoral surgical resection. In that regard, Park et al. [24], using
T1-weighted images, found that the depth of invasion determined by MRI correlated
with histologic depth of invasion in tumors of the base of tongue, but not in tumors
of the tonsil. (Pearson’s correlation coefficient .941 vs. 0.578). MRI is also useful
when there is concern of perineural invasion or base of the skull involvement.
A 59-year-old woman presents with a squamous cell carcinoma of the right tonsil,
staged T2N0. She is healthy otherwise and has a history of smoking half a pack a
day for 30 years. Biopsy reveals SCC, which is p16 negative (Fig. 3.3).
A 42-year-old business man is referred for management of a T2N2a tonsil cancer.

He is a non-smoker and a previous biopsy confirms that the tumor is a poorly dif-
ferentiated squamous cell carcinoma, which is p16 positive (Fig. 3.4).
The options available for treatment of the primary tumor in these patients are
radiation therapy alone, concomitant chemoradiation, conventional open surgery,
and transoral surgery. In deciding which modality is best, the clinician needs to
answer the following questions: Under what circumstances is one modality favored
over the other? What is the role of hyperfractionated accelerated radiation therapy?
What is the role of IMRT? What is the role of chemotherapy and how it is best
timed? What is the functional impact of these treatment modalities?
There has been a paradigm shift in the management of oropharyngeal cancer
over the last 20 years. At one time, open, often termed “radical,” surgery was per-
formed routinely and was usually followed with postoperative radiation therapy. In
the last two decades, treatment evolved initially in the direction of radiation therapy
and subsequently towards combinations of radiation and chemotherapy, which, at
the moment, are considered the standard of care. However, the pendulum has begun
to swing back towards surgery, this time transorally, with assistance of the laser, the
operating microscope, and the robot.
Conventional “Open” Surgery
These operations usually require approaches to access the oropharynx with subse-
quent extirpation of the tumor. Depending upon the location of the tumor and the
preference of the surgeon, the oropharynx may be approached through a
Fig. 3.3 (a) Ulcerated lesion in right tonsil. (b) Axial, contrast CT. (c) PET/CT both showing the
lesion localized to the tonsillar fossa and no evidence of lymph node metastases
Fig. 3.4 Axial CT

showing a 2.48 cm lesion
in the left tonsil with a
nearly 4 cm
inhomogeneous node in
left level II
pharyngotomy, lateral or transhyoid, or more commonly through a paramedian

mandibulotomy. In addition, a neck dissection is performed on one or both sides of
the neck and, more often than not, elaborate procedures such as regional or free
flaps are required for reconstruction. Unfortunately, these procedures frequently
result in aesthetic alterations and functional disabilities that include dysphagia, dys-
arthria, aspiration, and trismus.
As a result of the morbidity associated with this type of surgery other treatment
modalities have been investigated over time. Parsons et al. [25] performed a retro-
spective analysis (EBM II-2) of 51 studies for the treatment of SCC of the tonsil and
base of tongue (BOT). Treatment modalities included conventional surgery with or
without radiation and radiation therapy with or without neck dissection. Table 3.3
summarizes the local regional control and 5-year disease-specific survival. As it can
be seen, the outcomes were similar for surgery plus radiation therapy with or with-
out a neck dissection for both tonsil and BOT, with the exception of local regional
control in BOT, which was significantly better in the radiation ± neck dissection
Table 3.3 SCC of the tonsil and base of tongue (BOT) treatment outcomes in 51 studies [25]
Surgery ± XRT XRT ± ND
Outcome Tonsil BOT Tonsil BOT
Local control 70 % 79 % 67 % 75 %
Local-regional control 64 % 63 %* 68 % 74 %*
5 years cause specific survival 58 % 58 % 62 % 63 %
*p = 0.002
Table 3.4 SCC of the tonsil and base of tongue (BOT) complications of treatment in 51 studies
[25]
Surgery ± XRT XRT ± ND p Value
BOT
Severe 34 % 3.2 % <0.0001
Fatal 2.4 % 0.4 % 0.02
Tonsil
Severe 22 % 4.4 % <0.0001
Fatal 2% 0.4 % 0.0036
patients. However, as noted in Table 3.4 the incidence of severe or fatal complica-
tions was significantly reduced in the radiation therapy group. This data illustrates
the rationale for the advent and current use of nonsurgical regimens in the manage-
ment of oropharyngeal cancer.
Radiation Therapy
The treatment of OPC has been revolutionized in the past few years with evolving
radiation therapy techniques and the use of three-dimensional planning, with CT- or
MRI-based simulations. With the development of IMRT it is now possible to deliver
curative doses of radiation to a tumor, in a way that spares surrounding normal tis-
sues and prevents chronic complications. Currently, IMRT is considered the stan-
dard in the treatment of oropharynx cancers. This came to be because of several key
randomized studies. In a phase II trial (RTOG 00-22) [26], 69 patients with T1-2N0-1
oropharynx cancers were treated with IMRT (66 Gy in 30 fractions, delivered at
2.2 Gy/fraction). With a median follow-up of 2.8 years for living patients, the 2-year
locoregional control rate was 91 %. The conclusion of this trial was that moderately
accelerated IMRT was feasible with excellent outcomes for early OPC and less
toxicity than previous studies. Then, the parotid-sparing intensity-modulated versus
conventional radiotherapy in head and neck cancer trial (PARSPORT) randomized
94 patients (85 % of whom had OPC) between conventional radiation therapy and
IMRT, with the goal of sparing the parotid. With a median follow-up of 44 months,
patients treated with IMRT had significantly less xerostomia and significantly better
quality of life [27]. In addition to the RTOG 00-22 trial, several institutions have
reported obtaining local control rates and survival rates >90 % in the treatment of
early-stage OPC with IMRT [28, 29].
In order to obtain similar favorable outcomes in the treatment of advanced OPC,
it was necessary to intensify the treatment by either altering the fractionation of
radiation or adding chemotherapy or biologically active agents to the radiation
regimen.
Hyperfractionated/Accelerated Radiotherapy
The RTOG 9003 Randomized Prospective Trial (EBM: 1) compared conventional

radiation therapy with hyperfractionation, accelerated radiation therapy, and accel-
erated radiation therapy with a concomitant boost. The results for the different regi-
mens tested are summarized in Table 3.5. As it can be seen in the table,
hyperfractionation and accelerated radiation therapy resulted in a significant
improvement in locoregional control at 2 years [30]. However, the toxicity was also
higher for these groups. A meta-analysis performed by Bourhis [31] (EBM 1),
which analyzed 15 randomized trials including 6515 patients, of which 44 % had
oropharyngeal cancers, also showed that altered fractionation led to a significant
improvement in locoregional control and overall survival. Unfortunately, the rate of
complications is high. Selek et al. [32] reported that 16 % of patients suffered sig-
nificant complications such as ulceration, osteoradionecrosis, skin ulcerations, as
well as esophageal strictures.
Chemoradiation
An initial study by Calais et al. [33] (GORTEC 94-01) compared in a randomized

trial concomitant chemoradiation vs. radiation therapy alone for stage III and IV
oropharyngeal cancers (EBM 1). The results summarized in Table 3.6 show a
Table 3.5 RTOG 9003 trial: summary of results [30]

Standard Hyperfractionation Accelerated split Accelerated boost
Outcome (268) (263) course (274) (268)
2-year LR 46 % 54 % 48 % 55 %
control p = 0.045) p = 0.05
2-year DFS 32 % 38 % 33 % 39 %
2-year OS 46 % 55 % 46 % 51 %
Gd 3+ 35 % 55 % 51 % 59 %
toxicity
LR loco-regioanl, DFS Disease free survival, OS Overall survival
Table 3.6 GORTEC 94-01 trial: summary of outcomes oropharynx cancer stage III–IV
XRT (%) Concomitant chemoradiation (%) p Value
Overall survival 3 years 31 51 0.02
Dis.-free survival 3 years 20 42 0.04
Local-regional control 66 42 0.03
Distant metastases 11 11 NS
Grade 3 and 4 mucositis 36 67 0.005
significant improvement in overall 3-year survival, disease-free survival, and local

regional control. The complication rate of grade 3 and grade 4 mucositis was nearly
double in the concomitant group compared to the radiation therapy group, 67 % and
36 %, respectively [33].
The Meta-Analysis of Chemotherapy In Head And Neck Cancer (MACH-NC)
[34] has collected data on over 16,000 patients with head and neck cancer treated in
87 randomized trials (37 % of these patients had OPC, the most common site over-
all); the available data included in 50 concomitant chemoradiation trials and 31
induction chemotherapy trials were analyzed to determine the effect of different
regimens of chemotherapy (neoadjuvant, concurrent, or adjuvant). The analysis
showed that chemotherapy resulted in a significant benefit in OS, the hazard ratio of
death being 0.88 (p = 0.0001) and an absolute benefit of chemotherapy at 5 years of
4.5 %. Regarding the timing of chemotherapy, the analysis showed that concurrent
chemotherapy was superior to neoadjuvant or adjuvant chemotherapy in both indi-
rect and direct comparisons; in the 50 trials that included concurrent chemotherapy,
the hazard ratio of death was 0.81 (p = 0.001) with an absolute benefit of concurrent
chemotherapy at 5 years of 6.5 %. The analysis also showed that chemotherapy regi-
mens that included concurrent cisplatin had the most significant beneficial effect,
and that this effect was independent of the radiation fractionation. Finally the
analysis showed that concomitant chemotherapy improved locoregional control
whereas induction chemotherapy had a significant effect on reducing distant
metastases.
The beneficial effect of the various chemotherapy regimens was also evaluated in
the EORTC 34971/TAX323 trial, in which about 46 % of patients had OPC. This
trial compared induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil
(TPF) versus cisplatin and 5-fluorouracil (PF) followed by definitive radiation ther-
apy [35]. OS was statistically significantly better in patients treated with TPF (18.8
vs. 14.5 months, p = 0.02). Also, PFS was significantly better in the PTF group (11.0
vs. 8.2 months, p = 0.007).
Finally, in a pivotal study, Bonner et al. [36] investigated the role of cetuximab,
an antibody against epidermal growth factor receptor (EGFR), in the management
of SCC of the head and neck. This study compared radiation plus cetuximab vs.
radiation therapy alone for head and neck SCC, of which approximately 60 % of
patients had oropharyngeal cancer. They noted that approximately 80 % of patients
in either the radiation only or radiation with cetuximab had detectable EGFR. They
demonstrated that there was a significant improvement in locoregional control both
at 1 and 2 years in the chemoradiation group. In a 5-year update of the study [36], a
subgroup analysis demonstrated that the benefit of CTX was more evident for
patients younger than 65 years old with a good Karnofsky performance status of
90–100 %. Then, in a 10-year update in 2010 [36], the OS at 5 years (45.6 % vs.
36.4 %) and the median survival (49.0 vs. 29.3 months; p = 0.018) remained signifi-
cantly better in the group of patients treated with concurrent radiation and cetux-
imab compared with the group treated with radiation alone. An advantage of this
concurrent regimen is that patients do not develop the severe mucositis or dyspha-
gia, which is common in patients treated with concurrent chemoradiation. In
exchange, however, cetuximab causes an acne-like skin rash. Interestingly, the
development of a severe rash correlates with improved survival.
While concomitant chemoradiation with cisplatin and concomitant cetuximab
has not yet been compared in randomized trials, retrospective studies in which these
two regimens have been compared have shown worse locoregional control, failure-
free survival, and OS in patients treated with CTX [37]. Furthermore, there is a
recent report of a phase II study comparing radiation with either cisplatinum 40 mg/
m2 once per week or cetuximab 400 mg/m2 as loading dose followed by CTX
250 mg/m2 [38]. Unfortunately, the study as reported is considerably underpowered;
the number of patients needed to provide the study with an 80 % power was 65 per
arm; however, the study was stopped after 35 patients were enrolled in each arm,
because of slow accrual. Nevertheless, this study has shown two intriguing and
somewhat unexpected findings; first was a problem with compliance to treatment,
which was worse among patients treated with cetuximab. Second was the occur-
rence of serious adverse events related to treatment, which were higher in the CTX
arm (19 % vs. 3 %, p = .044) and included four versus one toxic deaths, mainly due
to sepsis.
Transoral Surgery
Transoral laser microsurgery (TLM): Rich et al. [39] in a retrospective analysis

of transoral laser microsurgery for stage 3 and 4 tumors (EBM II-2) demonstrated
excellent overall survival and disease-specific survival at 2 and 5 years (Fig. 3.5).
Transoral robot-assisted surgery (TORS): With the advent of robotic surgery,
investigators from the University of Pennsylvania developed techniques for address-
ing tonsil and base of tongue carcinoma using this modality. Initial studies have led
to the FDA approval of TORS for early-stage oropharyngeal cancers as well as
benign tumors of the upper aerodigestive tract.
Robotic surgery using the Da Vinci surgical system (Intuitive Surgical, Sunnyvale,
CA) takes advantage of excellent high-definition optical camera positioned within
the pharynx with 3D magnification to remove tumors. The instruments placed tran-
sorally have 540° of tremor-free movement which allows precision resection of
tissue en bloc in areas previously hard to access, such as the oropharynx. More
recently other robotic systems such as the Flex Robotics System (Medrobotics,
Fig. 3.5 Transoral laser microsurgery ± adjuvant therapy. Outcomes: Stage III/IV (n = 84) [39]
Raynham, MA) that utilize a flexible camera arm have demonstrated excellent
access and visualization in TORS procedures. Robotic surgery outcomes in general
improve with experience with lower complication rates (hemorrhage, airway com-
promise, nerve injury), readmissions [40], and quicker discharge times [41].
Complications have been noted to drop significantly after the first 40–50 cases [40].
Oncologic outcomes have been favorable, especially for early-stage lesions (T1/
T2). An analysis of 11 studies involving 190 patients showed an aggregate local
control rate of 96.3 % and overall survival rate of 95 % for T1/T2 OPCs, at a mean of
19.9 months [42]. It should be noted, however, that there was considerable variation
between studies regarding the indications for neck dissection and adjuvant therapy.
In a more recent similar review of the data on 410 patients treated with TORS at 11
different institutions [43], in which 88.8 % of the patients had OPC and 83.5 % of all
patients had T1 and T2 tumors, local recurrence occurred in 4.4 % and regional
recurrence occurred in 3.7 % of the patients, with a mean follow-up of 20 months.
In terms of functional results following TORS, the reported need for tracheos-
tomy and gastrostomy for 12 months or longer is 0 % and 5 %, respectively [42].
However, recovery following TORS is not without morbidity. In a study by
Leonhardt et al. [44], in which a questionnaire was given to 38 patients that under-
went TORS, patients reported worsening in swallowing, speech, and diet at 6
months, with many of them reporting a return to baseline by 1 year (EBM II-2).
Other investigators have demonstrated improvement in quality of life scores 1 year
after TORS. It has been noted that patients older than 55 and patients that require
extensive resections (of >1 oropharyngeal subsite) are more likely to require a gas-
trostomy for a prolonged time (EBM II-2) [45].
What Margins Are Required to Adequately Resect the Primary Cancer?
TORS surgery involves excision of the cancer en bloc with frozen section analysis
of the margins to ensure complete removal of the tumor. The oropharynx is small
but there are areas where it is more difficult to remove a cancer, such as the base of
the tongue.
There is still debate regarding what the optimal margin is for oropharyngeal
tumors removed transorally; in general, however, the margins tend to be small espe-
cially once the tissue is fixed. In a multicenter prospective study, some institutions
defined a close margin as one that is <2 mm, while others considered a margin close
when it was <5 mm [46]. Despite the difference in margin definition, positive mar-
gins occurred in only 3.8 % of OPCs which is comparable to other transoral
approaches [46]. In the more recent review of 410 patients treated at 11 institutions,
once again the surgeons did not agree on the definition of a close margin [43]. While
there was a significant difference in local control between patients with negative and
positive margins, the authors did not analyze the outcomes according to margins of
<2 and <5 mm, which would have provided valuable information. Also, they did not
report the percentage of patients with positive and negative margins that received
adjuvant therapy. In a retrospective analysis of 877 TORS procedures in the National
Cancer Database, outcomes were compared with those in 4269 patients who were
treated with non-robotic surgery. Positive margins were less common in the TORS
group (20.2 % vs. 31 % (p < 0.01)), and the rate of positive margins was even lower
(15.8 %) in high-volume centers; this suggests that the ability to obtain clear mar-
gins with TORS is related to the experience of the surgeon [47].
In general, favorable outcomes have been obtained with margins between 2 and
5 mm, which may be a reflection of favorable tumor biology of HPV-related carci-
nomas of the oropharynx.
Does HPV Have Any Bearing on Outcome Following TORS in These

Patients?
It has been established that HPV + nonsmoker OPC patients tend to have a better
prognosis than HPV – and/or smoker OPC patients, irrespective of treatment modal-
ity. A study of TORS in 81 patients with adjuvant radiation as indicated, HPV + OPC
had DFS rates of 92 % and 89 % at 2 and 4 years, respectively [45] (EBM II-2).
Other studies have shown excellent outcomes with the use of TORS regardless of
HPV status in OPC patients [48].
Advocates of TORS point out that even though the outcomes with TORS are
similar to those of other treatment modalities, one advantage of TORS, a relatively
less invasive surgery, is that it allows better staging of the cancer and, thus, it allows
for better individualized treatment. In a retrospective analysis of 48 patients treated
initially with TORS, Moore et al. [49] found that postoperative chemoradiation was
required in only 56 % of the patients, while 18 % required radiation therapy only.
A number of prospective trials are currently in progress to address the role of
de-intensification of adjuvant treatment based on surgical pathology following
TORS. Trials include ADEPT and ECOG 3311 which will both randomize adjuvant
treatment, i.e., radiotherapy ± chemotherapy based on histopathological features
from the resected primary and neck specimen. ADEPT is a phase III trial which will
enroll 496 patients with p16+ OPC, who have had all known disease removed surgi-
cally by a minimally invasive approach, and who have extracapsular spread in meta-
static neck nodes. These patients will be then randomized to receive IMRT (60 Gy)
alone or IMRT + cisplatin. ECOG 3311 is a phase II trial in which 377 patients with
p16 + OPC are stratified into four arms according to their surgical pathology. Patients
with intermediate histopathological risk factors will be randomized to either low-
dose (50 Gy) or standard-dose IMRT (60 Gy) [50].
The frequency and the distribution of lymph node metastases in patients with OPC
have regained relevance with the recent impetus in transoral surgery, and with the
notion of unilateral treatment of the neck with radiation therapy.
The oropharynx contains abundant lymphoid tissue (Waldeyer’s ring) and has a
prominent network of lymphatics, which communicate freely across the mid-line.
This explains the propensity of tumors of this region to metastasize to the regional
lymph nodes, as well as the relatively high frequency of bilateral lymph node metas-
tases. The lymphatic drainage of the oropharynx occurs predominantly towards the
upper and mid-jugular lymph nodes (level II and III). The retropharyngeal nodes are
a less known but important echelon in the lymphatic drainage of the oropharynx.
For many decades, the study of Linberg [51], published in the 1970s, was the
main source regarding frequency and distribution of adenopathy in head and neck
cancer patients. Unfortunately, these figures were based on clinical exam alone,
which we now know is not reliable. The best data available today regarding fre-
quency of lymph node metastases has been provided by Woolgar et al. [52], who
reported a retrospective review (EBM II-2) of the histological findings in 526 neck
dissections performed in 439 previously untreated patients. The frequency of
lymph node metastases in OPC, according to T stage, is shown in Table 3.7.
Unfortunately, this author did not present data for the different sites in the orophar-
ynx. Nevertheless, it is clear that the frequency of nodal metastases in OPC is high,
even for T1 tumors. Obviously the therapeutic implication of this observation is
that the regional lymph nodes need to be addressed when managing a patient with
OPC, regardless of the stage.
The next issue is how often the contralateral nodes are involved, and, thus, when
they need to be considered in the treatment planning as well. To that end, the study
by Olzowy et al. [53] provides valuable information, albeit retrospectively gathered
(EBM II-2), since it is based on histopathological examination of a large number of
bilateral neck dissection specimens of patients with OPC. The results of this study
are summarized in Table 3.8. From this data, it appears that only T1 or T2 tumors of
the tonsil and T1 tumors of the base of tongue have a low incidence of bilateral
cervical metastases. Consequently, in these patients it would be reasonable to treat
only the ipsilateral side of the neck, when the primary is treated with either surgery
or radiation with or without chemotherapy.
Several authors have reported results after irradiating only the ipsilateral side of
the neck in lateralized oropharyngeal tumors; the incidence of contralateral failure
Table 3.7 Oropharyngeal carcinoma incidence of lymph node metastases by stage (based on
histopathology of neck dissection specimens) [52]
Percentage of patients with lymph node metastases
T1 T2 T3 T4
40 % 55 % 71 % 69 %
Table 3.8 Oropharyngeal carcinoma incidence of bilateral lymph node metastases [53]
Percentage of necks with node metastases
Site of primary tumor T1 T2 T3 Ta All stages
Tonsil 3.3 10.7 17.6 8.6 9.4
Base of tongue 14.3 23.9 27 15.8 21.9
Pharyngeal walls 50 33.3 50 0 31.3
Soft palate 10 25 11 50 20
is very low. O’Sullivan et al. [54] found contralateral neck recurrences in 3.5 % of
patients with lateralized carcinoma of the tonsil treated by primary ipsilateral radia-
tion. Kagei et al. [55] reported no contralateral recurrences in 32 patients with ton-
sillar and soft palate carcinomas treated by unilateral irradiation.
Retropharyngeal lymph node metastases (RPM) are also a concern in
OPC. Ballantyne et al. [56] in a retrospective (EBM II-2) analysis found in a series
of advanced SCC of the pharyngeal walls that the retropharyngeal nodes were
involved in 44 % of the cases. It is unclear why the incidence was so high in that
study. Since then, Hasegawa et al. [57] found that 36 % of patients with advanced-
stage III–IV cancer had RPM. However, in patients whose neck was staged N0 the
incidence of RPM was 0 %, whereas 30 % of patients had N+ neck RPM [57]. A
recent analysis of 185 patients with HPV + OPC showed that 16 % had RPM. With
a median follow-up of 49 months, the 5-year OS, DFS, and distant metastasis-free
survival were significantly lower (57 % vs. 81 % (p = 0.02), 63 % vs. 80 % (p = 0.015),
and 70 % vs. 91 % (p = 0.002)) for patients with RPM than for patients without them.
These results suggest that in HPV + OPC, RPM is an independent prognostic factor
for distant metastases and OS [58].
Interestingly, the prognosis of patients with HPV-positive tumors and nodal
metastases may not be discriminated well by the AJCC staging system. A recent
EBM II-2 retrospective analysis examined 156 patients treated definitively with
chemoradiation in whom the metastases in the neck were re-classified as follows:
HPV + N1 as a single node <6 cm, ipsilateral, contralateral, or bilateral; HPV + N2
single node ≥6 cm or ≥2 nodes, ipsilateral/contralateral or ≥3 nodes bilateral; and
HPV + N3 as matted nodes. Significant differences in DSS (100 %, 92 %, and 55 %,
respectively; p = .0001) and OS (100 %, 96 %, and 55 %, respectively; p = .0001)
were found when the disease was classified in this manner. On the other hand, there
was no significant difference in DFS or OS when the AJCC classification was used
[59]. Spector et al. also have recently shown that the presence of matted nodes is an
independent prognostic factor in advanced OPC [60].
The management of the N+ neck when the primary cancer is treated with radia-
tion with or without chemotherapy is still somewhat controversial. Some clinicians
advocate performing a neck dissection as part of the treatment plan, irrespective of
the response of the cancer in the neck. Their rationale is twofold. First, the clinical
and pathological responses of the tumor in the neck correlate poorly with each
other. Second, in a study by Brizel et al. [61], a planned neck dissection appeared to
confer a disease-free survival and overall survival advantage in patients with N2–N3
disease undergoing chemoradiation. Other clinicians argue that it is not necessary to
perform a “planned” neck dissection when the cancer in the neck undergoes a com-
plete response to the treatment [62, 63], because less than a third of patients with
clinically positive nodes before therapy have histological evidence of metastases at
neck dissection [64], even when there is residual clinical or radiological “adenopa-
thy” in the neck after completion of (chemo)radiation [65, 66], and when the cancer
in the neck undergoes a complete response to the treatment, the probability of an
isolated recurrence in the neck is low (0–11 %) [62, 67–69].
Currently, PET scanning is used in the evaluation of patients following treatment
[70]. Several studies have shown that a PET scan obtained 1 month after completion
of treatment is often inaccurate [71, 72]. In contrast, a PET scan done 12 weeks after
completion of treatment with radiation or chemoradiation is more useful [73]. The
reported negative predictive value of PET for viable disease in a residual anatomic
abnormality in the neck is 97 %. Recently, Corry et al. [74] reviewed their experi-
ence with N2/N3 disease following CRT in 102 patients. Of the 28 patients in whom
there was a CR within the primary and a PR in the neck, 11 patients demonstrated
resolution of their adenopathy with continued observation, 1 was diagnosed with
metastatic cancer prior to any further therapy, and 16 patients had a neck dissection
of which 9/16 (65 %) were pathologically negative. In another study, patients with a
clinical complete response to chemoradiation who were observed rather than having
a neck dissection demonstrated a regional failure rate of 3–8 %, and if negative PET
imaging was included as part of the definition of a complete response, the regional
failure rate decreased to 0–3 % [75]. Thus, it appears from this information that
observation with a PET-CT obtained at least 12 weeks after completion of chemo-
radiation is a reasonable alternative to a “routine” planned neck dissection [75].
When a neck dissection is deemed appropriate the type of neck dissection
depends on the extent of the disease in the neck. Low recurrence in the neck has
been reported following comprehensive neck dissection [76], selective neck dissec-
tion, and even “superselective neck dissection” [68, 77–79].
Considering the information discussed, regarding the patient in Clinical
Situation 2, if the clinician elects to treat the primary tumor with surgery, the resec-
tion should be done transorally with either LMS or TORS. In addition, given the
frequency and distribution of lymph node metastases in OPC, a selective neck dis-
section (II–III–IV) would be appropriate. An ipsilateral neck dissection would suf-
fice, since the tumor is a T1 tumor and the frequency of contralateral metastases in
such cases is very low. For any other T stage, however, the dissection would have to
be bilateral.
On the other hand, if the clinician elects to treat the patient with a nonsurgical
modality, treatment would be done preferably with IMRT alone. The addition of
chemotherapy has not proven to provide additional benefit in stage 1 and 2
OPC. Consideration may be given to irradiating only the ipsilateral side of the neck.
Regarding the patient in Clinical Situation 3, tumor is amenable to transoral
surgery; however, the extent of the disease in the neck, as seen in the CT scan, is
such that if a neck dissection is done as part of the initial surgical treatment, it will
require most likely resection of the internal jugular vein, possibly the spinal acces-
sory nerve and perhaps even the hypoglossal nerve. Consequently, surgery as the
initial treatment modality does not seem ideal in this case. The standard, accepted
treatment is a platinum-based concurrent chemoradiation regimen. Concurrent radi-
ation and cetuximab is an option only if the patient is unfit to receive platinum.
Considering that cetuximab appears to be more effective in younger patients and
considering the recent reports of potential fatal toxicity, such regimen would be
prescribed with caution.
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Chapter 4
Cancer of the Nasopharynx
Greg Krempl and Anthony Alleman
Nasopharyngeal carcinoma (NPC) is an uncommon malignancy, with distinct geo-

graphical variation. Worldwide, the incidence of new cases is approximately 86,500 or
about 0.6 % of all cancers. The vast majority (70 %) are diagnosed in East and
Southeast Asia, with a smaller portion occurring in South-Central Asia, and North and
East Africa [1]. In the USA there are approximately 3200 cases diagnosed each year.
Clinical Situation
A 57-year-old Asian male presents with a non-keratinizing poorly differentiated

carcinoma of the right lateral wall of the nasopharynx (Fig. 4.1). On examination he
has an ipsilateral middle-ear effusion, the cranial nerves are intact, and he has a
4 cm lymph node in the ipsilateral level 2.
The clinician managing this patient will face a number of critical clinical decisions in
his diagnostic evaluation and treatment. For proper staging of nasopharyngeal carci-
noma one must determine whether or not there is bone involvement and extension into
the sinuses, the skull base and intracranial cavity, and the oropharynx. In addition to the
clinical examination, which includes fiber-optic evaluation of the nasopharynx and oro-
pharynx, several imaging techniques are available to assess the extent of the disease.
G. Krempl, M.D. (*)

e-mail: greg-krempl@ouhsc.edu
A. Alleman, M.D.
Department of Radiological Sciences, College of Medicine, The University of Oklahoma,

DOI 10.1007/978-3-319-18630-6_4
52 G. Krempl and A. Alleman
Fig. 4.1 Axial post-contrast T1-weighted images (a) and axial T2-weighted fat-suppressed
images (b) of right lateral wall of nasopharyngeal and a retropharyngeal node. Right Eustachian
tube obstructed. (c) Fluid in mastoid air cells and middle ear
What Is the Best Method to Assess Skull Base Involvement

and Parameningeal Spread?
When a patient is being evaluated with a newly diagnosed nasopharyngeal carci-

noma (NPC), the amount of tumor visible on fiber-optic examination is often a
small portion of the overall tumor volume. Therefore, the clinician relies heavily on
imaging studies to determine the extent to which the tumor has spread in different
directions and to assess the volume of the entire tumor. Imaging is ideally obtained
in axial, coronal, and sagittal views for the best assessment of bone erosion and
4 Cancer of the Nasopharynx 53
intracranial extension. Liao et al. [2] reviewed retrospectively (EBM II 2) 420

newly diagnosed NPC patients who had both CT and MRI within a 2-week window.
MRI was found to provide a more accurate assessment of the skull base than CT
(20 % more involvement) and intracranial extension (12 % more frequent), but they
were equivalent in the assessment of paranasal sinus involvement. Overall these
authors found that 49 % of the cases had a change in T stage when MRI was com-
pared to CT. As a result, Liao and others consider MRI the optimal imaging tech-
nique for studying the extension of local disease in NPC [2, 3]. This is reflected in
the NCCN guidelines that recommend MRI as the primary modality of imaging [4].
Should a PET Scan Be Routinely Ordered for All Stages of Disease?
PET/CT has been evaluated in comparison to MRI for assessment of the extent of
primary disease at the skull base and found to be less accurate [5]. The role of PET/
CT in the initial evaluation of NPC is in the detection of distant metastasis, since the
rate of distant metastases is higher for NPC than carcinomas in other areas of the
head and neck.
Prior to the introduction and widespread use of PET scans the “traditional” diag-
nostic screening for distant disease consisted of abdominal ultrasound, chest CT,
and bone scan. In one direct comparison of these methods with PETCT there was no
significant difference [5]. However, PET/CT has replaced the “traditional” screen-
ing as it is an expeditious, sensitive, and accurate diagnostic method to detect distant
metastases. In a recent meta-analysis, which included 13 studies, the diagnostic
accuracy of PET/CT in the diagnosis of distant metastasis in patients with NPC, the
overall sensitivity and specificity were 0.87 (95 % CI, 0.83–0.90) and 0.96 (95 % CI,
0.95–0.97) [6].
The NCCN guidelines call for imaging to evaluate for distant metastasis in select
patients [4]. The clinician must decide then what patients would benefit from this
additional testing. A number of retrospective reviews have identified various factors
that might be associated with the presence of distant metastatic disease at presenta-
tion, and the subsequent development of distant metastasis after treatment. A prog-
nostic model was developed by Chen et al. [7] based on a cohort of 230 patients and
validated in another set of 115 patients. Age >45, N3 stage, hemoglobin (Hb)
<11.0 g/dL, and lactic dehydrogenase (LDH) ≥240 U/L were the factors identified
on multivariate analysis. Other studies have also identified non-keratinizing histol-
ogy, N2-3, and stage III–IV disease as the most predictive factors. Given the evi-
dence available at this time it would seem prudent to utilize PET scans as the method
for screening for distant metastasis at presentation when a patient has N2 or greater
nodal staging, has non-keratinizing histopathology, is less than 45 years old, and has
Hb <11 or LDH > 240 (EBM II-2) [8]. Where PET is readily available a single
modality to screen for distant disease is appropriate.
In our representative patient however, a PET scan would not be indicated based
upon his age >45 and N1 disease.
Should Epstein–Barr Virus (EBV) or Human Papilloma Virus (HPV)

Testing Be Considered?
Epstein–Barr Virus: Since the original description of the association of EBV with
NPC nearly 50 years ago, there have been more than 1000 articles written attempt-
ing to classify the association and identify a clinical role for EBV testing and treat-
ment modification. The tumorigenesis of the viral infection remains undefined and
intriguing; while the rates of infection /exposure to EBV worldwide are ubiquitous,
high rates of associated NPC are seen in only a few select populations. Much of the
research recently has focused on viral interactions with host tissues, and a number
of theories remain viable. Many studies have focused on the use of various markers
as screening tools for initial disease association and if positive subsequent use as a
tumor marker for possible recurrent disease. As testing methodologies have evolved
so has the number of specific mutations/variations of EBV that have been identified
and associated with NPC. The support in the literature has been variable for testing
at all outside of a research context as described in a 2015 article that reviewed over
100 of the publications evaluating the role of EBV in NPC [9]. It is outside of the
scope of this chapter to comprehensively review those; however, there are several
summary statements that can be made regarding EBV: Clinical use of EBV as a
biomarker in NPC is increasing. Quantitative assessment of circulating EBV DNA
is being used for population screening, prognostication, and disease surveillance
[10]. Plasma EBV DNA, which is universally associated with the non-keratinizing
subtype of NPC, provides good prognostic information, but may also be useful for
assessing treatment response and detecting disease relapse [11]. In fact, some insti-
tutions are using EBV DNA >4000 copies/mL as a criterion to prescribe treatment
with chemoradiotherapy vs. radiation alone [12]. Phase 3 trials are under way inves-
tigating the role of EBV DNA in stratification of patients for treatment intensifica-
tion and deintensification [13].
Human Papilloma Virus: HPV has been associated with increasing numbers of
oropharyngeal carcinomas. Given the close proximity of the nasopharynx and the
similarity of the tissue in the region of Waldeyer’s ring, it would seem intuitive that
there would be a similarly high association of NPC with HPV. This has not been
the case; the reported rates of association have ranged from 10 to 30 % with some
geographic variation. The prognostic implications of the association also vary [14].
Stenmark et al. from the University of Michigan report that in their population of
61 patients, 30 % of whom were EBV negative and HPV positive, HPV positivity
correlated with grade 2 tumors, older age, and smoking (all at p < .001). This is
strikingly different from the HPV population seen in oropharyngeal tumors where
the patients tend to be younger and nonsmokers. Not surprising then was their
finding that NPC patients that are HPV positive had poorer outcomes than the
EBV-positive patients, and similar to the EBV-negative ones. This can be con-
trasted to the report from the University of Pittsburgh that included 90 patients
from four institutions of which only 9 (10 %) were HPV positive. In their report
these HPV-positive patients demonstrated overall survival that was comparable to
the EBV-positive patients and significantly better than the EBV-negative patients
(p = .004) [15].
In summary, the results thus far are mixed and do not warrant routine testing for
HPV association in NPC. If one would like to screen, it likely should be minimized
to those who are EBV negative.
Utility of Other Biomarkers: Targeted therapies are being used in clinical trials
with agents targeting epidermal growth factor receptor (EGFR) and vascular endo-
thelial growth factor (VEGF) with early clinical efficacy. One phase 2 study of
cetuximab (monoclonal antibody against EGFR) combined with carboplatin in
patients with advanced and refractory nasopharyngeal carcinoma reported almost
half of their patients showing no significant tumor growth over 4 months, and mea-
surable tumor shrinkage in 12 % and for them progression-free survival of approxi-
mately 6 months [16].
Sunitinib, a broad tyrosine kinase inhibitor including the VEGF receptor, showed
some clinical efficacy in a preliminary investigation of recurrent nasopharyngeal
carcinoma patients [17]. The future likely will see the development of novel immu-
notherapies targeted at immune checkpoints and EBV-specific tumor antigens.
From that perspective it may be reasonable to collect EBV data so that retrospective
cohorts may be used for comparison of treatment outcomes.
At this time, there is no evidence (level II or higher) supporting a role for system-
atic testing for EBV in any specific population of NPC patients for surveillance, nor
is there a targeted therapy available yet for use in EBV-associated tumors. Within
the context of clinical trials this is an active area of research particularly in endemic
regions.
Should a PE Tube Be Inserted to Manage the Middle-Ear Effusion?
Otitis media with effusion (OME) occurs in roughly one-fourth of the patients with
NPC and, unfortunately, the conventional treatment with radiotherapy does not
change significantly the percentage of patients that end up with chronic OME. Chronic
OME is usually treated with myringotomy and ventilation tube placement; however,
this is controversial in patients with NPC because of the high rate of complications.
Therefore the clinician treating patients with NPC must decide whether or not to
perform a myringotomy with tube placement, assessing the risk/benefit ratio based
upon the available literature. There are no level 1 randomized controlled trials (RCT)
comparing long-term outcomes with observation vs. tube placement; however, a
single RCT has compared simple aspiration of fluid vs. myringotomy vs. myringot-
omy with tube placement [18]. This trial showed that each method has advantages
and disadvantages and the authors recommended a step-by-step management plan
beginning with aspiration. However, at the end of 2 years of follow-up, 30 of the 132
ears (22.7 %) included in the study had chronic otitis media. In another step-by-step
strategy, 85 nasopharyngeal carcinoma patients with post-irradiated OME were
studied prospectively (EBM II-1) [19]. All patients were initially managed by close
observation and a hearing aid for those with hearing loss. Patients that continued to
be bothered by aural fullness, tinnitus, or hearing loss, and did not want to continue
conservative treatment, had tympanostomy plus aspiration; insertion of ventilation
tubes was recommended only to those patients that had persistent OME after
repeated tympanostomy for at least 3 months. After a mean follow-up of 842 ± 49 days
from the completion of radiotherapy, OME was present in 52.9 % of the patients and
18.8 % of the entire cohort studied had chronic discharging ears with or without
perforated eardrums. Only 17.6 % of patients were free of OME, and one of these
patients had a dry perforated eardrum.
These results suggest that conservative management is a sound choice. The clini-
cian should exercise caution when recommending myringotomy with or without
ventilation tube insertion, due to the high rate of chronic otitis media and the diffi-
culty in healing associated with radiation. In the future, perhaps new approaches can
result in better outcomes. A study in a small number of patients suggests that laser
myringotomy, followed by once-weekly administration of steroids (0.5 mL dexa-
methasone at a concentration of 5.0 mg/mL) into the middle ear for three consecu-
tive weeks, resulted in long-lasting dry eardrum perforation in 41 % of ears treated.
The authors suggest that this regimen allows for adequate middle-ear ventilation
and drainage and relief of symptoms [20].
Once the tumor has been staged, the clinician must decide the most appropriate treat-
ment. In the clinical situation presented in this chapter, a newly diagnosed poorly
differentiated T2N1M0 non-keratinizing carcinoma, there are several treatment
decision points regarding the primary tumor. These decisions include whether to use
radiation alone or chemoradiation; if the latter is chosen, the clinician must decide
which drugs and what treatment sequence to use; finally, it should be decided whether
to recommend proton irradiation or intensity-modulated radiation therapy (IMRT).
Radiation therapy has for many years been the foundation for treatment of NPC. As
techniques have evolved, IMRT has become the current standard of treatment for
NPC, with target doses of 70 Gy to the gross tumor volume. Randomized controlled
trials comparing IMRT with conventional two-dimensional RT have shown superior
disease control rates with reduction in the rates of xerostomia, and other treatment-
related complications [21]. This is possible because IMRT makes it possible to sculpt
the high-dose area, i.e., the tumor, and spare most if not all of the critical normal
structures in close proximity to the tumor, at the skull base. Local control rates can be
expected to exceed 85 % with appropriate dosimetry [11]. The next question concerns
the value of adding chemotherapy to the radiation treatment regimen.
For treatment of early-stage NPC there is limited data on the addition of chemo-
therapy to radiation. However, it is unlikely that there would be any advantage in
adding chemotherapy given the extremely high success of IMRT. For example, Su
et al. treated 198 patients with stage I to II NPC with IMRT alone. The control rates
for T2N0, T1N1, and T2N1 disease were 98.8 %, 100 %, and 93.8 %, respectively.
With such little room for improvement in local control of the disease, the addition
of chemotherapy would only add significant morbidity to the treatment.
For the treatment of more advanced disease, at least nine randomized clinical trials
to date have compared chemoradiation (CRT) to radiation therapy alone (RT)
(EBM I). A recent meta-analysis (EBM I) included a total of 4798 patients, the major-
ity of whom had at least stage III disease [22]. The conclusion was that the addition
of chemotherapy resulted in an overall survival benefit of 6 % at 5 years and 8 % at 10
years; it also resulted in improvement in progression-free survival, locoregional con-
trol, and distant control.
As a result, the current standard of care consists of concurrent radiotherapy and
cisplatin (100 mg/m2) × 3 cycles, followed by Cisplatin: 80 mg/m2 plus 5FU: 1000
mg/m2/day for 4 days) × 3 cycles. However recent studies have shown that, at least
in endemic areas where type III undifferentiated carcinomas are more prevalent, the
adjuvant chemotherapy does not add to the effectiveness of the concomitant chemo-
radiation portion of this regimen [23].
Is There a Role for Induction Chemotherapy Prior to Starting CRT

in Stage III to IVB NPC?
In a phase 2 trial using docetaxel and cisplatin as an induction regimen, Hui et al.
[24] reported a 26.5 % absolute improvement in 3-year OS over concurrent chemo-
radiation (EBM I). Unfortunately the study was underpowered and despite the
seemingly dramatic results, it was not followed by a phase 3 study. However, at
least four randomized studies have been initiated or reported, but none to date has
shown an overall survival benefit at 3 years [25–27]. A definitive trial is not likely
to occur for several reasons. First, since the potential survival advantage is small,
the sample size required is very large. Second is the issue of compliance; in one
trial, 37 % of the patients enrolled did not complete the full course of treatment
when adjuvant chemotherapy was added.
In short, there is not sufficient data to date to support the use of induction chemo-
therapy in the treatment of advanced-stage NPC.
Thus, for the patient in this chapter’s clinical situation, whose tumor was in stage
III (T2N1), the most appropriate treatment is CRT and not radiation therapy alone.
Evaluation of the Response to Treatment
The next question facing the clinician is whether or not the treatment has been effec-
tive. Traditional assessment of response to CRT has been done 6–12 weeks after the
completion of treatment. The problem this creates is that the assessment is made
after the treatment has been fully completed. Recent interest has focused in deter-
mining if there is an accurate way to assess treatment response earlier, which can
perhaps allow the treatment course to be modified; for example, if a poor early
response is seen, intensification of treatment may result in a better overall response
to treatment than would have been achieved by finishing the original treatment plan.
In this line of research comparisons have been made between functional MRI and
PET CT, looking at metabolic activity early in the course of treatment. 18F-FDG
PET/CT imaging has been found to be more accurate than MR imaging in the
assessment of early treatment response [28]. The timing of such early assessment is
still not fully determined; however Lin et al. [29] have reported that a 75 % reduc-
tion in SUVmax was observed by mid to late treatment period (50 Gy of radiation).
Following completion of CRT, in approximately 10 % of patients there will be
residual fibrotic tissue in the nasopharynx that is clinically difficult to differentiate
from residual tumor. Initial failure to control the tumor may be as high as 13 %;
therefore, assessing for persistent disease is key in early detection and precise
localization of the residual tumor. Imaging plays an essential role in this differen-
tiation, as well as in assessing the tumor volume beneath the surface, since in the
majority of cases most of the tumor volume is not initially visible on endoscopic
examination.
While MRI is the most useful imaging modality for initial staging of NPC, its
role in posttreatment assessment is not as strong. MRI imaging has limitations in
differentiating between residual tumor/recurrent tumor and posttreatment fibrosis
because of radiation-induced anatomic distortion, alteration in normal signal inten-
sity pattern, inflammatory reactions, and scarring, leading to a false-positive result
in 46–58 % of patients in the initial 6-month posttreatment period [30]. On the other
hand, 18F-FDG PET/CT imaging has shown significant promise in the differentia-
tion between residual disease and post-chemoradiation fibrosis [28]. Intrinsically
this makes sense and has been validated in other organ sites where fibrotic tissue
post-radiation demonstrates low SUV values. However, in the nasopharynx the
degree of inflammation after radiation has been attributed to the relatively higher
rates of false positive on PET scans.
In the clinical situation’s case, the patient had a 4 cm palpable lymph node, which
is a very common scenario; most patients with NPC have either clinical or radio-
graphic evidence of lymph node metastasis at the time of presentation.
The N0 neck: If the patient does not have palpable or radiologically evident
metastasis (stage N0) the clinician must decide if the lymph nodes should be treated
electively, and if so whether the treatment should be unilateral or bilateral. The pat-
tern of lymphatic drainage of the nasopharynx has been described usually using
the five Roman numeral level designation to locate the lymph nodes in the neck.
In 2014, the lymphatic mapping for head and neck tumors was revised jointly by
several organizations and ten distinct nodal basins were identified [31]. Wang et al.
[32] used this updated terminology and reviewed 3100 cases of NPC, 86 % of
whom had lymph node metastasis at presentation. The metastasis was bilateral in
45 % of cases. The basin with the highest overall number of positive nodes was
level II, followed sequentially by VII, III, and then V in descending order.
Metastasis to levels VI, IX, and X was found in less than 1 % of their patients.
Further evidence to support the treatment of both sides of the neck can be found
in an older retrospective study by Lee et al. In that study, stage I NPC patients did
not receive elective neck irradiation and 30 % (57 out of 189) of them subsequently
developed recurrence in the cervical lymph nodes [33].
Recently, the issue of the extent of elective irradiation of the neck has been raised
[34]. A prospective randomized trial (EBM I) was completed in which 301 patients
with NPC, staged N0, were randomly assigned to receive primary plus prophylactic
upper neck irradiation (153 patients) or primary plus whole - neck irradiation (WNI)
(148 patients). Patients in both groups received irradiation to the primary tumor and
the upper neck nodal regions, and patients in the WNI group also received irradia-
tion to the lower neck. The purpose of the study was to compare recurrence rates in
the lower neck between the two groups. With a median follow-up of 39 months
(range, 6–84 months), no patient in either group had recurrence in the neck. The
authors concluded that elective irradiation of the upper neck (II, III, VA) is suffi-
cient for patients with node-negative NPC [35].
What to Do When a Palpable Lymph Node Persists After Chemoradiation?
Persistent tumor in neck nodes is a rare occurrence in NPC. In retrospective studies

of large numbers of patients with NPC, only 2 % had persistent nodal disease at a
median of 12 weeks after treatment with radiation therapy [36], and less than 5 %
following combined chemoradiation [37]. However, in patients with advanced
nodal disease on presentation, failure in the neck following concurrent chemoradia-
tion has been reported is as many as one-third of the patients [38]. When this
occurs, however, the clinician will need to decide whether the residual adenopathy
is due to tumor or fibrosis and whether to recommend treatment with re-irradiation
or neck dissection. There are reports touting the success of PET/CT to make this
decision when dealing with tumors in other areas of the head and neck [39].
However, since these studies included only a few patients with NPC, it is not pos-
sible to make recommendations based on evidence regarding the role of PET/CT in
the posttreatment decision making regarding persistent adenopathy. The current
consensus of opinion is that if palpable adenopathy persists for 12 weeks, it is very
likely to be metastatic in nature. The preferred treatment then consists of a compre-
hensive neck dissection (levels II–V), which in most instances is a radical neck
dissection. The reported 5-year tumor control rate in the neck is 66 % and the 5-year
actuarial survival is 38 % [40].
Recurrence at the Primary Site
Approximately 10 % of NPC patients will at some point have residual disease iden-
tified in the nasopharynx. The clinician must properly counsel these patients on
their treatment options and must be candid with them about the specific risks associ-
ated with treatment in a setting of prior radiation therapy.
There are two generally accepted methods for treating residual/recurrent disease
at the primary site: re-irradiation or endoscopic nasopharyngectomy. At select high-
volume sites one might consider additional open approaches that could be offered to
patients with more extensive disease; however as a general rule surgical treatment
via endoscopic techniques is reserved only for patients that are limited to the naso-
pharyngeal cavity, the postnaris or nasal septum, the superficial parapharyngeal
space, or the base wall of the sphenoid sinus. A case-matched comparisons with 72
patients in each group evaluated the endoscopic technique compared to IMRT and
they reported equivalent local–regional control between the two groups. They did
however note several differences in quality of life and complications where endo-
scopic nasopharyngectomy was better tolerated in longer term evaluation [3]. While
this is promising the limitations in terms of the extent of disease amenable to endo-
scopic resection will limit its overall use.
Re-irradiation with IMRT has broader application as it is not limited to the surgi-
cal shell boundaries; however patients must be well informed of the potential com-
plications associated with it. In the prior study comparing surgery with re-irradiation
it is interesting to note that of the 53 patients who died during the study period, 29
(54 %) died of treatment-related complications while only 37 % succumbed to dis-
ease progression. The most common complication that resulted in death was naso-
pharyngeal necrosis and subsequent hemorrhage followed by necrosis of the
temporal lobe. A number of patients suffered significant morbidity from xerosto-
mia, hearing loss/deafness, trismus, and cachexia and while not mentioned in their
report, there is a significant risk for visual loss as well depending on the location of
the residual disease. That said the overall survival at 5 years was 40–60 % for the
two techniques [3].
Potential Novel Therapies
This type of therapy must be considered in the context of clinical trials until FDA
approval or pivotal trials are published. Targeted therapy based upon gene expres-
sion is the most exciting basis for testing existing biologic therapy for effectiveness
in nasopharynx cancer. Cetuximab is the earliest targeted therapy that has shown
significant response in previously treated NPC as it targets EGFR [16]. Gefitinib,
another target for EGFR, has also been evaluated and shows promise [16]. VEGF is
another common target for targeted therapy and it has targeted with bevacizumab in
a multi-institutional study where it demonstrated feasibility with potential to extend
survival in some cases [41].
Tsang et al. published a comprehensive review of the known potential targets in

NPC for biologic targeted therapy [42]. Lan et al. went further by combining the
data from a number of microarray publications into a protein-protein interaction
network used to identify bottleneck genes in nasopharynx carcinoma tumorigenesis
[43]. Then using a connectivity map technique they matched current drugs available
with the gene expression series based upon their targets. In this report they identi-
fied 87 potential agents against nasopharynx carcinoma. Several of the agents have
known antitumoral effects already tested in refractory NPC, while others have
known antineoplastic effects for other histologic variations.
The other target for therapy that has been explored is the association of NPC with
EBV. Autologous EBV-specific T-cells have been tested for the treatment of EBV-
associated malignancies such as post-transplantation lymphoproliferative disease
(PTLD) where it is shown to add to overall control rates [44].
There is now also data testing the use of cytotoxic T lymphocyte (CTL)-based
therapy to NPC with traditional salvage treatment and several phase I and phase II
clinical trials expanding the use of CTLS with some benefit for refractory patients [45].
Given these preliminary results it is possible that in the next decade further
advances will lead to widespread immunotherapy for EBV as a regular part of mul-
tidisciplinary individualized cancer therapy for those with EBV-associated tumor.
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Chapter 5
Cancer of the Hypopharynx
Trinitia Y. Cannon and Keren Bartal
Clinical Situation
Squamous cell carcinoma of the medial wall of the pyriform sinus clinically staged
T3N1 (Fig. 5.1).
The evaluation of such a patient requires of course a thorough clinical examina-
tion including a video-assisted endoscopy in the office. There is, however, informa-
tion that cannot be provided by this examination, information that is key for staging
purposes and for treatment selection. In the remainder of this section we address the
most pertinent questions the clinician must answer to perform a proper pretreatment
evaluation of the patient.
What Is the Best Method to Assess the Extent of the Primary Tumor?
For the detection of extralaryngeal spread, it is of utmost importance to know and

understand the complex anatomy in this area and the imaging features of commonly
occurring extension patterns (namely thyrohyoid membrane, inferior constrictor
muscle, and cricothyroid membrane).
Thyroid cartilage invasion and extralaryngeal extension determination are criti-
cal for staging and treatment planning for hypopharyngeal tumors; these findings
are often considered contraindications to organ preservation approaches, unless car-
tilage destruction is minimal, as it appears to be the case in our clinical situation
(Fig. 5.1).
T.Y. Cannon, M.D. (*) • K. Bartal, M.D.

Department of Otorhinolaryngology, College of Medicine, University of Oklahoma,
e-mail: trinitia-cannon@ouhsc.edu

DOI 10.1007/978-3-319-18630-6_5
66 T.Y. Cannon and K. Bartal
Fig. 5.1 Right pyriform

sinus carcinoma abutting
the thyroid cartilage with
destruction of it posteriorly
The reported sensitivity and specificity of CT for detecting thyroid cartilage

invasion range between 46–67 % and 68–92 %, respectively, with a modest improved
precision when different diagnostic imaging criteria are applied [1].
Should a CT or MRI Scan of the Neck Be Obtained?
MR imaging is more sensitive than CT for detecting thyroid cartilage invasion

(sensitivity up to 96 %), but with low specificity of 56–65 % [2].
Beitler et al. showed that extralaryngeal spread without thyroid cartilage penetra-
tion was more common than previously expected with 40 % of cases showing
extralaryngeal tumor spread [3].
In a retrospective study, Imre et al. showed that preservation of the retropharyn-
geal fat plane on MRI reliably predicts the absence of prevertebral space involve-
ment with a negative predictive value of 100 and specificity of 95.2 % (compared to
99.2 and 88.2 %, negative predictive value, and specificity of CT) [4].
Should a PET/CT Be Obtained?
PET-CT can be useful in detecting regional and distant metastatic disease in

advanced-staged hypopharyngeal cancers. It has been suggested that PET-CT may
play a role in determining if a contralateral neck dissection is warranted. Shin et al.
suggested that PET-CT and CT/MRI might play a role in identifying patient groups
at low risk of contralateral neck metastasis since none of the patients with radio-
logically negative ipsilateral neck were found to have metastatic nodes on the
contralateral neck dissection [5].
5 Cancer of the Hypopharynx 67
Between 7 and 10 % of patients with hypopharyngeal carcinoma show distant

metastatic disease during treatment, with most frequent location being the pulmo-
nary parenchyma (45–55 %), followed by bone (3–10 %) and liver (<5 %) [6]. In a
meta-analysis comprising 1276 patients, mean sensitivity and specificity of 18FDG-
PET/CT in detecting extra-cervical locations during initial head and neck cancer
staging were 88 % and 93.3 %, respectively [7].
Ng et al. compared the sensitivity of (18)F-FDG PET for detection of distant
metastases and found that it was 1.5-fold higher than that of multi-detector row CT
(MDCT) (76.9 % vs. 50.0 %, p = 0.039), while its specificity was slightly lower
(94.0 % vs. 97.8 %, p = 0.125). Side-by-side visual correlation of MDCT and (18)
F-FDG PET improved the sensitivity and specificity up to 80.8 % and 98.5 %,
respectively, leading to alteration of treatment in 13.1 % of patients. Understandably
there was a significant difference in survival rates between patients with positive
and negative results [8].
For lung nodules larger than 1 cm, in head and neck cancers, there was no sta-
tistical difference between PET and CT. However for nodules smaller than 1 cm,
high-resolution CT (HRCT) is more sensitive in evaluating pulmonary metastasis
than PET [9].
Is a Direct Pharyngolaryngoscopy and Esophagoscopy Warranted?
First, carcinomas of the hypopharynx frequently extend, often superficially, into the
cricopharyngeal and cervical esophageal regions, which, in most centers, are not
amenable to examination in the office. Determining tumor extension to these area is
essential to decide the extent of the radiation fields or, if surgery is anticipated, to
determine the inferior limit of the resection and the type of reconstruction that may
be needed. Thus, rigid esophagoscopy under general anesthesia or fiber-optic
endoscopy is often necessary.
Second, hypopharyngeal location of a carcinoma and alcohol abuse are both known
as factors that increase risk for a second primary in the esophagus. Guardiola et al.
studied retrospectively 487 patients with carcinomas of the head and neck, including
63 patients with hypopharyngeal carcinomas. They found a synchronous esophageal
carcinoma in 9.2 % of hypopharyngeal carcinoma patients, while they did not find a
single case of esophageal carcinoma in patients with a cancer of the oral cavity [10].
Other studies of large numbers of patients have shown similar results [11, 12].
For these reasons esophagoscopy is warranted in patients with hypopharyngeal
carcinoma. Rigid esophagoscopy is perhaps the best way to visualize the cricopha-
ryngeal area, since it allows the examiner to displace the larynx forward with the tip
of the scope and open the cricopharyngeus for inspection, something that is not easy
to do with the fiber-optic scope. Unfortunately, rigid esophagoscopy requires a gen-
eral anesthetic and it is not free of complications; the rate of perforation of the esoph-
agus was 2.6 % in a cohort of patients treated at a tertiary academic center [13].
Obviously, early detection of esophageal cancer offers the best prognosis. However,
early detection is difficult by conventional endoscopic white light imaging (WLI).
Lugol staining can be used to detect superficial esophageal lesions, but it causes
unpleasant adverse effects such as severe chest pain and chest discomfort [14]. The
narrow-band imaging (NBI) system is an innovative optical image-enhanced technol-
ogy that uses narrow-bandwidth NBI filters. In a prospective study performed by
Muto et al. of 320 patients, NBI detected superficial cancer more frequently than
white light imaging (WLI) in the esophagus (97 % vs. 55 %, p < .001, respectively).
The sensitivity of NBI for diagnosis of superficial cancer was 100 and 97.2 % [15].
Interestingly, Haerle et al. compared PET/CT with panendoscopy for the
detection of synchronous second primary tumors in patients with head and neck
squamous cell carcinoma. The sensitivity of panendoscopy and of PET/CT were
74 % and 100 %, respectively, while the negative predictive values were 98 % and
100 %. The author suggests that if the PET/CT is negative endoscopic evaluation
is not warranted [16].
Typical Clinical Situation
43-year-old female smoker, diagnosed with a 1.8 cm squamous cell carcinoma of

the lateral wall of the right pyriform sinus. She has no adenopathy in the neck.
Is Transoral Resection a Viable Option for Hypopharynx Cancer?
Hypopharyngeal cancers are often detected at an advanced stage. Because of this,

the role of endoscopic resection, often reserved for early-staged tumors, is lim-
ited. Endoscopic resection of early-stage HP cancers is less invasive and offers
the potential to improve quality of life in regard to swallowing and aspiration.
Martin et al. [17] reviewed 172 patients with untreated SCCa of the HP who
underwent transoral laser microsurgery (TLM) from 1986 to 2003. Eighty-five
percent were stage III and IV. They evaluated overall survival, recurrence-free
survival, organ preservation, and control rates. They also assessed the need for
tracheostomy, complication rate, and feeding tube dependency. Oncologic and
functional results compared favorably, while morbidity and complication rates
tended to be lower. They concluded that TLM is a valid option when compared to
conventional surgery. In 2001, Meyers et al. looked at the effectiveness of organ
preservation by TLM in piriform sinus cancers. Of the 129 patients retrospec-
tively reviewed between 1981 and 1996, the majority (74) were pT2. They report
an 87 % local control rate. The 5-year overall survival rate was 71 % for stage I
and II and 47 % for stages III and IV tumors. They concluded that TLM was an
effective method for function-preservation in piriform sinus carcinomas. Park
[18] used transoral robotic (TORS) hypopharyngectomies for ten patients with T1
or T2 pyriform sinus or posterior pharyngeal wall cancers. The goal was to assess
the feasibility of using the da Vinci robot for transforal exposure. They were able
to successfully perform the surgery in all ten patients with no significant postop-
erative complications. They report return to swallow within 8.3 days and decan-
nulation approximately 6.3 days after surgery. They concluded that TORS was not
only feasible, but ontologically safe for early hypopharyngeal cancers.
Typical Clinical Situation
Patient with a squamous cell carcinoma of the pyriform sinus clinically staged
T3N1 (the hemilarynx is partially mobile).
Organ Preservation with Chemoradiation Therapy vs. Surgery?
For many years the preferred treatment for advanced-stage, resectable hypopharyn-
geal cancer was surgery followed by adjuvant radiation or chemoradiation. In the
past two decades the option of organ-preserving treatment has come into play.
A randomized phase III trial conducted by the European Organization for
Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group tested
if larynx preservation with induction chemotherapy (ICT) was safe in the treatment
of squamous cell carcinoma of the hypopharynx and compared a larynx-preserva-
tion approach to immediate surgery in hypopharynx and lateral epilaryngeal carci-
noma (EORTC 24891). The first results of this trial were published in 1996 [19]. In
2012, Lefebvre et al. [20] reported the 10-year results of it. With a median follow-up
of 10.5 years on 194 eligible patients, disease evolution was seen in 54 and 49
patients in the surgery and chemotherapy arm, respectively, and 81 and 83 patients
had died. The 10-year overall survival (OS) rate was 13.8 % in the surgery arm and
13.1 % in the chemotherapy arm. The 10-year progression-free survival (PFS) rates
were 8.5 % and 10.8 %, respectively. In the chemotherapy arm, the 10-year survival
with a functional larynx (SFL) rate was 8.7 %.
They concluded that this strategy did not compromise disease control or sur-
vival, which remained poor, and allowed more than half of the survivors to retain
their larynx.
This final analysis confirmed the preliminary results published in 1996, except
for the median overall survival, which was significantly longer in the experimental
(CT) arm: 44 vs. 25 months in the surgical arm, in the first analysis. The OS difference
disappeared with the longer follow-up, mainly due to the development of distant
metastases (36 %) which was delayed in the CT arm. This led to an OS similar in
both groups: about 33 % at 5 years and 13 % at 10 years with more than half of the
survivors in the CT arm retaining a functional larynx. For patients who had to
undergo surgery due to an incomplete response to CT, the quality of the surgical
resection was not compromised with the same rate of negative margins (95 %).
Conversely, the postoperative course did not differ as the median time to wound
healing was similar in both arms and postoperative irradiation was equally tolerated.
For patients who underwent irradiation after CT, there was no increased toxicity.
A matter of concern is the excess of cancer-unrelated/unknown deaths
observed in the experimental arm. While in the surgery arm 11 patients died of
another disease without cancer evolution and 8 died of an unknown cause, in the
CT arm, 17 died of another disease without any cancer evolution and 10 of an
unknown cause [20].
A second EORTC phase III trial (EORTC 24954) compared alternating CT (plati-
num and 5FU) followed by RT with IC (platinum and 5FU) followed by RT in patients
with resectable, locally advanced laryngeal or hypopharyngeal cancer (T2–T4 and
N0–N2 that would have otherwise required total laryngectomy). A total of 450 patients
were randomized and the median follow-up was 6.5 years. There was no statistically
significant difference in the main end point of the trial, survival with a functional lar-
ynx (median of 1.6 vs. 2.3 years for IC arm vs. alternating arm, respectively; HR = 0.85,
95 % CI: 0.68–1.06). Likewise, OS and DFS were similar [19].
Based on the results of this and other prospective randomized trials [21, 22] the
outcomes of organ-preservation CRT are comparable to surgery plus radiation ther-
apy for locally advanced hypopharyngeal cancer. To this point induction chemo-
therapy was followed by radiation therapy. Then came the era of larynx preservation
in hypopharyngeal cancer with induction chemotherapy followed by chemoradio-
therapy, as well as the introduction of Taxanes and biochemotherapy.
Posner et al. [23] analyzed outcomes in the subgroup of 166 patients with
advanced larynx and hypopharynx that had been enrolled in TAX 324, a phase III
trial of sequential therapy comparing induction chemotherapy with docetaxel plus
cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by
carboplatin-based chemoradiotherapy [24].
Of the 166 patients 90 received TPF and 76 PF. Patient characteristics were simi-
lar between both groups. Median OS for TPF was 59 months [95 % confidence
interval (CI)] vs. 24 months (95 % CI: 13–42) for PF. Median PFS for TPF was 21
months (95 % CI: 12–59) vs. 11 months (95 % CI: 8–14) for PF. Three-year
laryngectomy-free survival with TPF was 52 % vs. 32 % for PF. The authors con-
cluded that the use of sequential TPF followed by carboplatin chemoradiotherapy is
a treatment option for organ preservation or to improve survival in locally advanced
hypopharynx cancer.
In a randomized phase II TREMPLIN larynx-preservation trial, Lefebvre et al.
compared the efficacy and safety of induction chemotherapy (ICT) followed by
chemoradiotherapy (CRT) or bioradiotherapy (BRT) for larynx preservation (LP).
Previously untreated patients with stage III to IV larynx/hypopharynx squamous
cell carcinoma received ICT. Poor responders underwent salvage surgery.
Responders were randomly assigned to concurrent chemoradiotherapy with cispla-
tin or concurrent cetuximab. The overall toxicity of both CRT and BRT was sub-
stantial following ICT. However, treatment compliance was higher in the BRT arm;
there was no significant difference in LP at 3 months between arms (95 % and 93 %,

respectively), LFP (87 % and 82 %, respectively), and OS at 18 months (92 % and
89 %, respectively). There were fewer local treatment failures in arm CRT than in
arm BRT; salvage surgery was feasible in arm B only [26].
Whether patients with vocal fixation should be included in larynx-preservation
trials is somewhat controversial. However, findings from some studies suggest that
patients with vocal cord fixation have worse outcomes [25].
While CRT has been proven feasible for laryngeal preservation in larynx and
hypopharynx cancer, the ideal treatment regimen is still to be defined. However, a
great deal of useful knowledge has emerged from the clinical research in this area.
Sherman et al. [25] reviewed three prospective studies in an attempt to develop and
validate a simple prognostic model that would help predict larynx-preservation out-
come. They developed a model that added one point for each poor prognostic variable
(shown in parentheses) and was given the acronym TALK: T stage (T4), albumin (<4 g/
dL), maximum alcohol/liquor use (≥6 drinks/day or heavy drinking), and Karnofsky
performance status (<80 %). The 3-year larynx preservation rates by TALK score were
65 % (score = 0), 41 % (score = 1–2), and 6 % (score = 3–4) (p < .0001); on validation,
the TALK 3–4 group was particularly well demarcated on validation.
Kim et al. [21] analyzed treatment outcome after local and/or regional failure
after chemoradiation (CRT) or surgery plus radiation (SRT). Their results suggest
that salvage treatment after CRT was more effective in comparison with SRT. In the
CRT group, six out of eight patients were salvaged through resection of the primary
tumor or recurrent cervical lymph nodes: three of these six patients were still alive
without disease and three patients died of intercurrent disease without evidence of
recurrence. The results in the SRT group were less favorable: 8 of the 13 patients
that failed in this group were treated with chemotherapy or re-irradiation, 3 patients
did not receive any treatment, and only 2 patients had surgery. Two patients were
salvaged successfully with re-irradiation and neck dissection, and the others died of
disease progression.
Regarding the need for a prolonged or permanent tracheostomy after CRT, a
recent study investigated possible predictors and outcomes for chronic tracheos-
tomy after chemoradiation for advanced laryngohypopharyngeal cancer. Multivariate
analysis showed that persistent tracheostomy was associated with pretreatment tra-
cheostomy and feeding tube dependency in hypopharyngeal primaries. Tracheostomy
dependence did not impact local control, progression-free survival, or overall sur-
vival on univariate analysis [27].
In summary, CRT offers patients with advanced hypopharyngeal carcinoma an
opportunity for cure and larynx preservation. Unfortunately this comes at a price and
the clinician treating these patients must be aware of it. Denaro et al. [28] performed a
systematic review of randomized clinical trials, published between 1991 and 2013.
They point out problems of heterogeneity of patients and outcomes in these trials and
suggest the ways for future trials. They express concerns about what they called “toxic
deaths” in patients treated with concomitant chemoradiation that are followed for up to
10 years. These treatments may have led to a higher incidence of sepsis (27 % causes
of death), pneumonia (10 %), many patients suffer from silent aspiration related to
dysphagia and swallowing impairment and other inflammatory diseases. Others have
shown that severe dysphagia requiring alternative feeding occurs in 7–13 % treated
with CRT [22]. CRT can be associated with permanent tracheostomy, and salvage sur-
gery-related complications such as intractable pharyngocutaneous fistulas in a signifi-
cant proportion of patients. However, recent advancements in surgical techniques and
the use of microvascular free flaps can be useful for function preservation.
Finally, financial considerations should be a factor in making treatment decisions in
this era of skyrocketing cost of cancer treatment. Cetuximab is quite expensive com-
pared to platinum. As a result of a recent systematic review of the topic, Gyawali et al.
state that “to consider and prefer Cetuximab over Platinum, this approach should be
either clearly more effective or clearly less toxic. However, Cetuximab-RT has not yet
been directly compared with platinum based concomitant chemotherapy” [29].
What Is the Role for Accelerated or Other Modifications of Radiation

Therapy?
The advent of intensity-modulated radiation therapy (IMRT) has brought about

interesting results. Mok et al. compared 91 patients treated with IMRT to a cohort
of 90 patients treated with 3D conformal RT. The locoregional control rate after
IMRT (75 %) was significantly better than the rate observed in the 3D-RT group
(58 %) (p = .003) [30]. In 2016, Edson et al. [31] reported their results in 98 patients
treated with IMRT. The 3-year actuarial OS, locoregional control, and distant
metastasis rates were 67 %, 74 %, and 18 %, respectively. The estimated 5-year
locoregional control and functional laryngeal preservation rates were 74 % and
75 %, respectively. This compares favorably to published studies.
In an open-label phase three randomized trial [32, 33] treated patients with locally
advanced, stage III and IV (non-metastatic) HNSCC were randomized to receive con-
ventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days’ concomi-
tant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6
weeks plus two cycles of 5 days’ concomitant carboplatin-fluorouracil), or very accel-
erated radiotherapy alone (64.8 Gy [1.8 Gy twice daily] in 3.5 weeks). The primary
endpoint was progression-free survival (PFS). They found that chemotherapy had a
substantial treatment effect when given concomitantly with radiotherapy. Acceleration
of radiotherapy could not compensate for the absence of chemotherapy.
What Is the Role of Surgery?
Primary surgery plays a role in early-stage disease and in extensive disease when
voice and swallowing have been compromised. Surgical options include partial or
total laryngectomy, partial or total pharyngectomy, partial or total esophagectomy,
and reconstruction [34].
Surgical management of hypopharynx cancer depends on the lesion’s extension
and the subsites involved. The article by Mura et al. gives decision making in the
approach for partial resections, complete resections, and reconstruction options based
on the defect [35]. Resectability has evolved over time. Criteria for unresectability of
the hypopharynx includes fixation to the spine or prevertebral muscles and involve-
ment of the brachial plexus and of course patient factors such as significant medical
comorbidities or the expectation of poor functional outcomes may preclude surgery.
An extended supraglottic laryngectomy can be used for tumors arising in the
upper pyriform sinus or aryepiglottic fold. A hemipharyngectomy, hemilaryngec-
tomy (HPHL) with tracheostomy, and reconstruction are indicated for large tumors
arising in the lateral hypopharyngeal wall which require vertical resection in the
posterior pharyngeal wall [36]. One half of the larynx/pharynx must be tumor free.
The key concept of the HPHL is the midline. The commissure and postcricoid
region must be free of tumor. The lateral limit is the carotid artery.
Limitations of the HPHL include the following:
• The anterior and posterior laryngeal commissure and the postcricoid region must
be free of disease.
• The pre-epiglottic space, epiglottis, and vallecula must be tumor free.
• The posterior pharyngeal wall must not be completely resected.
• The upper esophagus should not be resected because it cannot easily be repaired
with remnant mucosa from the pyriform sinus.
• The narrow strip of residual hypopharyngeal mucosa precludes any use of the
spared hemilarynx for true vocal purposes.
In 2005, Bova et al. [37] reviewed their experience with total pharyngolaryngec-
tomy (TPL) in 180 patients with hypopharyngeal squamous cell carcinoma recon-
structed with a free jejunal interposition graft. TPL is used for advanced
hypopharyngeal cancers and for patients with medical comorbidities that preclude
organ-sparing approaches. In addition, TPL is needed in patients with symptoms of
organ dysfunction (severe dysphagia, compromised voice), malnutrition, and airway
compromise.
The margins of resection are an important consideration in hypopharyngeal cancer,
because of their frequent superficial multifocality and submucosal extension. Wei
recommends that the margins of normal mucosa should be at least 2 cm superiorly,
3 cm inferiorly, 2 cm on either side of the tumor, and >1 mm radially [38].

What Lymph Node Levels Should Be Resected on the N0 Neck?
Occult nodal metastasis occurs in approximately 20 % of patients with postcricoid

and pyriform sinus apex tumors that are clinically N0 [39].
In elective treatment of occult regional metastasis, the low incidence of disease
found in levels I and IIb justifies preservation of these levels in the N0 neck.
Layland et al. [40] retrospectively reviewed a subset of 507 patients with primary
squamous cell carcinoma of the hypopharynx. Two hundred and twenty-five were
N0 (44.4 %) and 282 were N+ (55.6 %). Lymph node status significantly affected
disease-specific survival (DSS). The DSS for patients with N0 and N+ disease was
57.1 % and 29.7 %, respectively. None of the four current approaches to treatment of
the N0 neck (observation, surgery, irradiation, and combination surgery and irradia-
tion) produces a significant survival advantage. Close observation with later treat-
ment for subsequent neck disease produced the same statistical survival (DSS and
CDSS) as the three elective treatments and was determined to be a valid form of
management [40, 41].
What Lymph Node Levels Should Be Resected in the N+ Neck?
The hypopharynx has an extensive lymphatic network. Therefore, hypopharyn-

geal cancers have a high tendency to metastasize to cervical lymph nodes. In
1972, Lindberg described the lymphatic drainage of the hypopharynx. The lym-
phatic network that courses through the thyrohyoid membrane can seed level II
and III nodal basins. The posterior lymphatic network penetrates the superior
constrictor muscles and empty into the paratracheal and lateral retropharyngeal
lymph nodes [42].
Buckley and MacLennan prospectively examined neck dissection specimens
from 100 consecutive patients who received 160 dissections for laryngeal and
hypopharyngeal carcinoma. Fifty-eight patients treated by unilateral or bilateral
selective dissection of levels I to IV ± VI for N0 disease and 42 by comprehensive
dissection for N+ disease were analyzed for the prevalence and distribution of histo-
logic cervical node metastasis. Level VI nodes were included for tumors involving
the glottis/subglottic larynx, pyriform fossa apex, and the postcricoid region. They
found that hypopharyngeal cancers metastasized more often with histologic metasta-
ses in 56 % of ipsilateral and 47 % of contralateral dissection in N0 disease. All dis-
ease was confined to levels II, III, IV, and VI. Metastases to levels I and V were
infrequent, even in N+ disease. They support II to IV selective neck dissections for
N0 disease, as well as in patients with small palpable nodal metastases (N+), and the
inclusion of level VI for subglottic, pyriform sinus apex, and postcricoid tumors [39].
When Should Lymph Node in Level IB and Level V Be Included?
Mercante et al. examined the prevalence of histologically proven metastasis in level

I in 100 patients with squamous cell carcinoma of the larynx and/or hypopharynx
who underwent 150 neck dissections. Lymph node metastases were never detected
in either level I (sublevels Ia and Ib) or level V. Lymph node metastasis was concen-
trated within levels II–IV in 92.2 % of pathologic N+ necks. The risk of marginal
mandibular and hypoglossal nerve injury does not justify the dissection of level I
with either laryngeal or hypopharyngeal carcinoma [43].
Should Level IIB Be Resected?
Gross et al. performed a retrospective review of 65 cases, including 14 hypopharyn-

geal carcinomas, to analyze the distribution of lymph node metastasis. They specifi-
cally focused on level IIB to determine whether this sublevel could be safely omitted
in the N0 neck in an effort to decrease postoperative shoulder syndrome (SS) associ-
ated with spinal accessory nerve injury. In addition, they reviewed 18 published
studies for a total of 1114 necks. In their patient population, 53 % were elective neck
dissections and 47 % were therapeutic. Nine (17 %) cN0 neck dissections were node
positive upon pathologic evaluation, as were 33 (69 %) cN+ necks. Similar to other
studies, the distribution of lymph node metastasis mostly limited to II, III, and IV
sublevels. The incidence of level IIB metastasis was 10 %. There was no correlation
between disease found in levels IIA and III as a predictor for disease found in level
IIB. With respect to the literature review, of the 17 articles, only 2 analyzed hypo-
pharyngeal carcinomas alone. The overall rate of level IIB LN metastasis from the
literal review for hypopharyngeal carcinoma was 11.6 %. Specifically, the rate of
level IIB lymph node metastasis was 3.3 % and 20 % in cN0 and cN+ necks, respec-
tively. They concluded that level IIB could be safely omitted in the neck dissection
for cN0 necks; however, in the cN+ neck, level IIB should be dissected for optimal
treatment [44].
When Should the Retropharyngeal and/or Paratracheal Nodes

Be Included?
Metastasis to the thyroid gland and paratracheal lymph nodes occurs in 30 % of

patients with hypopharyngeal tumors [45].
Joo et al. retrospectively evaluated the prevalence and prognostic importance of
paratracheal lymph node metastasis in 64 patients with squamous cell carcinoma of
the hypopharynx. All 64 patients had an ipsilateral paratracheal node dissection and
42 of the patients had bilateral paratracheal nodal dissection. Fourteen out of 64
patients (22 %) had ipsilateral paratracheal lymph node metastasis with the majority
noted in tumors of the postcricoid region (57 %). Contralateral lymph node metastasis
was present in 2 % of cases. Postcricoid (67 %) and pyriform sinus (22 %) were most
often the primary site. Patients with paratracheal node metastasis had a high frequency
of cervical metastasis and a poorer prognosis. Routine ipsilateral paratracheal node
dissection is recommended during surgical treatment of patients with postcricoid and/
or pyriform sinus squamous cell carcinomas with clinical metastases [46].
Amatsu et al. evaluated the role of the planned retropharyngeal lymph node
(RPLN) dissection in 162 patients with squamous cell carcinoma of the hypophar-
ynx and cervical esophagus. Information on 82 patients who underwent neck dis-
section between 1980 and 1997 was reported. The great majority of the patients had
pyriform sinus carcinoma. Sixteen patients (20 %) had positive retropharyngeal
lymph nodes at the time of surgery. Four of these patients had bilateral disease.
They noted that the majority of patients with RPLN metastases had an N+ neck.
There was a higher rate of retropharyngeal recurrence in the 69 patients who did not
undergo RPLN dissection because it was not yet standard of care. Although RPLN
dissection did not improve the cumulative 5-year survival rate, it did significantly
decrease the number of patients who died of RPLN metastasis [47].
Decision Regarding Reconstruction
While reconstruction of the hypopharyngeal defect is complex, there are many options
including local or regional cutaneous flaps (adjacent cervical myocutaneous, superfi-
cial temporal artery flap, deltopectoral), regional myocutaneous flaps (pectoralis
major flap), visceral transposition techniques (gastric pull-up and colon interposition),
and free flap (radial forearm, anterolateral thigh and jejunal free flap).
When Is Primary Closure an Option?
After total laryngectomy with partial pharyngectomy, the pharyngeal defect can be
repaired primarily depending on the amount of pharyngeal tissue remnant available.
Hui et al. looked at 52 patients after partial pharyngectomy to determine the mini-
mum width of the pharyngeal remnant that could be safely closed without impairing
swallow. They concluded that the narrowest widths of pharyngeal remnant were
1.5 cm relaxed and 2.5 cm stretched. However, this study was limited by the lack of
a postoperative swallowing evaluation.
When Can a Regional Flap be Used for Reconstruction and What Are
the Options?
For select patients, free microvascular flaps are an established method of recon-
struction of the total or near-total pharyngeal defect. Not every patient can undergo
free flap reconstruction. Regional flaps such as the pectoralis major myocutaneous
are a well-established method for reconstructing the pharynx. In 2005, Morshed
et al. [43] reviewed 11 patients with hypopharynx and larynx cancer who underwent
total pharyngo-laryngectomy and reconstruction with pectoralis major myocutane-
ous flap. The skin island on the flap was approximately 7–9 cm wide and 7–11 cm
long. It was turned inward forming a new pharynx by suturing it to prevertebral
muscles. All patients had a nasogastric tube for feeding for at least 14 days. 54.4 %
of patients had no complications and were able to initiate oral feeds after 2 weeks.
Pharyngo-cutaneous fistula developed in five patients, 46 %. This is similar to the
fistula rate, 50 %, reported by Ko and Sheen [48, 49] after using tube-shaped pec-
toralis muscle flaps. Fistulas closed spontaneously after 1 month. Neopharyngeal
stenosis was seen in one patient who required repeated dilation. All patients returned
to feeding. Pectoralis major flap offers a single-stage approach for patients who are
not candidates for free flap.
Shen et al. [50] in 2001 described a method of using the superficial temporal
artery flap to reconstruct the hypopharynx of three patients after resection of a T3
posterior hypopharyngeal wall carcinoma. All patients underwent laryngeal func-
tion preserving surgery with removal of the posterior pharyngeal wall via lateral
pharyngectomy. The flap is based off of the superficial temporal artery (STA), a
branch of the external carotid artery, which originates at the level superior to the
zygomatic arch. The artery averages about 12 cm in length and 2 mm in diameter.
Doppler is used to map the artery and a median forehead flap is designed according
to the defect. The flap is harvested with skin, subcutaneous tissue, and frontalis
muscle. The flap is dissected and turned under the zygomatic bone and tunneled into
the hypopharynx via the parapharyngeal space. The donor site was closed using a
free flap from the abdomen. Patients were fed via NGT for 14 days. Swallow
improved with therapy. All patients were decannulated after adjuvant therapy.
No necrosis or complications were reported.
When Should a Free Flap Be Used for Reconstruction?
The literature in this area is extensive. Fortunately, Piazza et al. [51] have presented
a comprehensive review of the reconstructive options after total laryngectomy with
subtotal or circumferential hypopharyngectomy and cervical esophagectomy. They
put forth the following key points:
1. When dealing with partial hypopharyngectomy that does not significantly extend
to the oropharynx and/or the cervical esophagus, no specific pedicled or free flap
provides peculiar advantages, and the reconstructive choice should be purely
driven by the preference of the patient and the surgeon.
2. In the case of circumferential hypopharyngectomy, fasciocutaneous free flaps
(and particularly the anterolateral thigh, except in obese patients) seem to repre-
sent the first-line option because of their low perioperative mortality, donor-site
morbidity, and overall complication rate. The gastro-omental free flap is an
emerging reconstructive tool which, in spite of its not negligible mortality and
morbidity, appears to have unique properties in minimizing life-threatening
complications in difficult scenarios like salvage surgery after chemoradiation.
What Are the Alternatives to Free Flap Reconstruction?
When a hypopharyngeal tumor extends into the cervical esophagus, the inferior
margin of resection and the esophageal cut often end up to be quite low and into the
mediastinum. In such cases an anastomosis of the remaining esophagus to a free
flap may be technically very challenging. Furthermore, the risk exists that a dehis-
cence of this anastomosis could result in mediastinitis. A time-honored reconstruc-
tive alternative in such cases is a gastric transposition, also known as gastric pull-up
and pharyngogastric anastomosis.
A series of 48 patients who underwent pharyngolaryngo-esophagectomy and

reconstruction with a gastric pull-up was reviewed by Puttawibul et al. in 2004.
Most of the patients studied had hypopharyngeal cancer (79.2 %), 8.3 % had cervi-
cal esophageal involvement while another 4.2 % had extension into the thoracic
esophagus. In this two-team approach operation, the reconstructive surgeons mobi-
lize the stomach, while preserving the right gastric and gastroepiploic vessels,
through an upper midline incision. The stomach is transected at the esophagogastric
junction. The proximal esophagus is bluntly dissected from the membranous tra-
chea and the fundus of the stomach is brought through the posterior mediastinum
into the neck. Continuity is restored via a single-layer pharyngogastric anastomosis.
All patients required feeding jejunostomy until after adjuvant therapy was com-
plete. All patients required nasogastric tube for 1 week. At postoperative day 7, a
gastrografin study is obtained prior to starting feeding; there were no operative
deaths, but one patient died from a carotid artery blow-out 3 months after surgery.
Wound infection was the most common complication; it occurred in 8.3 % of the
patients. Fistula rate was 4.2 %. The most dreaded complication, gastric necrosis
and leakage, occurred in 2.1 % of the cases. In a study by Spiro et al., stomach
necrosis and leakage were reported in 3–13 % of cases. The mortality rate of this
operation can be as high as 15 % as reported by Wei et al. [52–54].
Decisions Regarding Adjuvant Therapy
Two prospective randomized studies have demonstrated that postoperative concur-

rent radiotherapy and chemotherapy significantly improve locoregional control and
survival, compared with traditional postoperative radiotherapy in patients with
advanced-stage head and neck cancer including hypopharyngeal carcinoma, in
patients who have extracapsular spread of tumor in the lymph nodes and positive
surgical margins [55, 56].
In the North American trial, between 1995 and 2000, patients with head and neck
cancers were randomized into two postoperative treatment groups: radiotherapy
alone and concurrent chemotherapy. In this trial, 12 % of the patients had hypopha-
ryngeal cancers. The median follow-up was 45.9 months. The rate of local and
regional control was significantly higher in the combined-therapy group than in the
group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61;
95 % CI: 0.41–0.91; p = 0.01). The estimated 2-year rate of local and regional con-
trol was 82 % in the combined therapy group, as compared with 72 % in the radio-
therapy group. Disease-free survival was significantly longer in the combined-therapy
group than the radiotherapy group (hazard ration for disease or death, 0.78; 95 % CI:
0.61–0.99; p = 0.04); but overall survival was not (hazard ratio for death, 0.84; 95 %
CI: 0.76–1.09; p = 0.19). They concluded that among high-risk patients with resected
head and neck cancer, concurrent postoperative chemotherapy and radiotherapy
significantly improved the rates of disease control and survival with increase in
adverse effects [55].
In the European trial, Bernier et al., patients with stage IIII or IV head and neck
cancer were randomized to receive either concomitant cisplatin and radiation or
radiotherapy alone as adjuvant treatment. The rate of progression-free survival was
significantly higher in the combined-therapy group (p = 0.04 by the log-rank test;
hazard ratio for disease progression, 0.75; 95 % CI: 0.56–0.99). The overall survival
was also significantly higher in the combined group while the relapse rates were
significantly lower [56].
Subsequently, Bernier et al. did an analysis of these two studies. Their result sug-
gested that the addition of cisplatin to postoperative radiotherapy was beneficial
when extracapsular spread or positive margins were present [57]. It should also be
noted that, in both trials, the acute toxicity was nearly twice as common in patients
treated with concomitant chemoradiation.
The results of these trials have corroborated by two meta-analysis that included
jointly 87 trials and several thousand patients [33, 58].
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Chapter 6
Larynx Cancer
Jesus E. Medina
Clinical Situations
Supraglottic Carcinoma
61-year-old man who has had soreness of throat and left otalgia for about 2 months.
He is healthy otherwise, except for arterial hypertension. He used to smoke half a
pack of cigarettes per day for about 50 years, but quit 1 year ago. Drinks socially.
Examination shows an exophytic lesion involving the laryngeal surface of the epi-
glottis and the left false cord (Fig. 6.1). The motility of the cords is normal. He has
no palpable adenopathy in the neck. A biopsy done elsewhere revealed squamous
cell carcinoma.
Glottic Carcinoma
66-year-old female reports hoarseness for about 1 year, which she attributed to 50
years of smoking half to one pack of cigarettes per day. Two weeks prior saw an
otolaryngologist because of an ear infection and he found a “left vocal cord lesion.”
Direct layngoscopy and biopsy revealed invasive, well-differentiated squamous cell
carcinoma. She now reports continued mild ache in her left ear and denies dyspha-
gia, odynophagia, otorrhea, weight loss, or neck masses.
On examination, the lesion involves most of the left vocal cord (Fig. 6.2), but
does not extend to the anterior commissure. The motility of the cord is limited
J.E. Medina, M.D. (*)

Department of Otorhinolaryngology, College of Medicine,
The University of Oklahoma, Oklahoma City, OK, USA
e-mail: jesus-medina@ouhsc.edu

DOI 10.1007/978-3-319-18630-6_6
84 J.E. Medina
Fig. 6.1 (a) Seemingly exophytic lesion involving the laryngeal surface of the epiglottis and the
right false cord. (b) Limited visualization of the vocal cords that appeared uninvolved by tumor. (c)
Contrast CT showing that the lesion infiltrates deeply involving the pre-epiglottic and paraglottic
spaces and abuts and thins the thyroid ala anteriorly (arrow) and possibly involves superficially the
inner aspect of it in the midportion (arrow)
Fig. 6.2 (a) Exophytic lesion involving most of the left vocal cord, the anterior portion of the cord,
and the anterior commissure are seemingly not involved. (b) Axial contrast CT showing that the
lesion appears to extend submucosally up to the level of the anterior commissure. (c) CT showing
the tumor involving the paraglottic space where it abuts the inner surface of the thyroid cartilage
6 Larynx Cancer 85
slightly apparently by the bulk of the lesion. She has no palpable cervical
adenopathy.
In managing these patients, the clinical and imaging evaluation will provide
information that is essential to make a number of critical decisions properly.
In both cases, accurate determination of the presence and extent of invasion of
the thyroid cartilage is important for staging purposes; it is also critical to decide
whether the tumor can be treated with radiation alone or concomitant chemoradia-
tion, as well as to determine whether or not partial laryngeal surgery is an appropri-
ate option. In both instances imaging may be useful in the assessment of the regional
lymph nodes.
In the case with a supraglottic carcinoma, determining whether or not the tumor
extends to the pre-epiglottic space is key for staging; the imaging criterion that
defines a stage T3 supraglottic carcinoma is extension into the pre-epiglottic space,
irrespective of vocal cord mobility. On the other hand, determining the extent of
involvement of the paraglottic spaces is necessary to determine the feasibility of a
supraglottic laryngectomy.
In the case of the glottic carcinoma imaging may be the only way to determine if
the tumor extends into the laryngeal ventricle; it will also be useful to determine the
presence and extent of subglottic extension.
Assessment of the Pre-epiglottic and Paraglottic Spaces
Submucosal involvement of the pre-epiglottic and paraglottic spaces is difficult to

evaluate clinically and endoscopically. Fortunately, the pre-epiglottic space can be
visualized and assessed adequately with either CT or MRI. In our clinical situations,
CT scan shows clearly the involvement of the pre-epiglottic and paraglottic spaces.
In the case of the supraglottic tumor, the findings on CT would stage the tumor at
least a T3 (Figs. 6.2 and 6.3). In a recent study the sensitivity of MRI in the diagno-
sis of infiltration of the pre-epiglottic involvement was 89 % and the specificity was
97 % [1]. On the other hand, the reported sensitivity of MRI in the assessment of
involvement of the paraglottic space ranges between 93 and 95 %; however, the
specificity is as low as 50–76 %, most likely due to the lack of standards and over-
estimation of the tumor volume caused by peritumoral inflammation [1, 2]. While
both the pre-epiglottic and paraglottic spaces can be adequately assessed on axial
images, additional views may be used to better delineate tumor involvement (coro-
nal images for the paraglottic space and sagittal images for the pre-epiglottic space).
What Is the Best Method to Assess Thyroid Cartilage Invasion?
Tumor erosion limited to the inner cortex of the thyroid cartilage is compatible with
a T3 lesion, as is the case in this chapter’s supraglottic clinical situation. Erosion of
the outer cortex of the thyroid cartilage defines a T4a tumor (Fig. 6.3). Therefore,
accurate staging requires diagnosis of subtle cartilage invasion. Unfortunately, the
86 J.E. Medina
Fig. 6.3 Axial contrast CT scans showing through and through tumor invasion of the thyroid
cartilage at the level of the anterior commissure (a) and in mid-portion of the thyroid ala (b)
thyroid cartilage is the most difficult laryngeal cartilage to evaluate for such invasion
because it is variably ossified. Thus, there is debate among clinicians regarding the
optimal imaging modality or combination of modalities needed for preoperative
assessment of thyroid cartilage invasion.
The findings that have been considered indicative of thyroid cartilage invasion
include cartilage sclerosis, obliteration of the medullary cavity, serpiginous contour,
bowing, cartilaginous blow-out, and the presence of tumor adjacent to nonossified
cartilage. A prospective study of 111 patients [3] evaluated which of these factors
had the highest degree of reliability in evaluating the thyroid, cricoid, and arytenoid
cartilage using cross-sectional histopathologic findings of the resected specimens as
the gold standard. Sclerosis was the most sensitive (83 %) in all of the cartilages.
While its presence enables the detection of early perichondrial invasion or micro-
scopic intracartilaginous tumor spread, more often than not histopathology shows
only reactive inflammation. Therefore, the specificity of sclerosis varies consider-
ably from one cartilage to another, being lowest in the thyroid cartilage (40 %).
Extralaryngeal tumor and erosion or lysis of cartilage yielded the highest specificity
(83 % specificity with a sensitivity of 71 %) for thyroid cartilage invasion. The iden-
tification of tumor adjacent to nonossified cartilage, a serpiginous contour, and an
obliteration of marrow space also were relatively specific (86–95 %) findings for
arytenoid and cricoid cartilage invasion but not for the thyroid cartilage with a spec-
ificity of only 41–55 %. Combining the presence of extralaryngeal tumor, sclerosis,
and lysis provided the highest degree of accuracy, approximately 80 % for the
thyroid cartilage.
A recent systematic review of the literature aimed to assess the diagnostic value
of computed tomography (CT) in detecting cartilage invasion among patients with
laryngeal carcinoma was recently reported by Adolphs et al. [4]. In this review, the
6 Larynx Cancer 87
only studies selected were those that compared cartilage invasion on CT with histology.
Four studies were included in the final analysis. Only one study examined the posi-
tive predictive value and negative predictive value for invasion of any laryngeal
cartilage, and they were 87 % and 56 %, respectively. The positive predictive value
and negative predictive value for thyroid cartilage invasion were investigated in
three studies and ranged from 44 to 80 % and from 85 to 100 %, respectively. The
authors felt that the negative predictive value was likely underestimated due to
selection bias, whereas the positive predictive value was likely overestimated.
In the analysis of imaging studies for thyroid cartilage invasion, it should be
borne in mind that the utility of CT varies with the age of the patient and the degree
of ossification of the thyroid cartilage, which is quite variable. Several of these nor-
mal variations can be indistinguishable from induced new bone formation and oste-
olysis of the cartilage adjacent to bone [5]. Furthermore, in a study of 100
normal-larynx CT scans, Dadfar et al. [6] found that nonossified cartilage has a
homogeneous appearance with a characteristic density, which unfortunately is quite
similar to that of tumor tissue.
The MRI findings that are considered more accurate in detecting laryngeal carti-
lage invasion are high signal intensity within the cartilage on fat-suppressed fast-
spin echo T2-weighted scans and cartilaginous enhancement on T1-weighted
fat-suppressed scans [7]. Kinshuck et al. [8] reviewed 81 magnetic resonance scans
(MRI) of patients undergoing total laryngectomy for squamous cell carcinoma, in
order to determine the accuracy of MRI in assessing thyroid cartilage and thyroid
gland invasion. They retrospectively compared the histopathology results with the
imaging findings. There were 22 laryngectomy patients who had thyroid cartilage
invasion verified histologically and 1 patient with thyroid gland invasion. However,
two independent radiologists, blinded to the histopathology results, interpreted the
MRI as showing apparent thyroid cartilage invasion (17 false positives), giving a
sensitivity, specificity, and positive and negative predictive values of 64 %, 71 %,
45 %, and 84 %, respectively. These authors concluded that MRI over-diagnoses,
thus, has limited effectiveness in diagnosing subtle thyroid cartilage invasion by
squamous cell carcinoma in laryngectomy patients.
A number of studies [2, 5, 9] comparing MRI and histopathological findings
have found that MRI is more sensitive than CT (89 % vs. 64 %) in the detection of
tumor invasion of laryngeal cartilage. Unfortunately, the specificity is relatively low.
In fact, in all the studies reported, the specificity of CT is higher than MRI. This was
confirmed on a meta-analysis performed by Yousem and Toufano [10] to assess the
ability of CT and MRI in detecting laryngeal cartilage invasion. The results are
summarized in Table 6.1.
Table 6.1 Detection of laryngeal cartilage invasion by CT and MRI

Sensitivity (%) Specificity (%) Accuracy (%)
CT 64.3 89.3 80.8
MRI 92.4 79.1 83.6
88 J.E. Medina
Consequently, when it is critical to determine if thyroid cartilage invasion is

present, potentially combining the two modalities begining with an MRI may be the
most effective strategy [11]. If the MRI is “positive,” a corroborating CT scan is
performed. If the MRI is negative, CT is not necessary because the risk of a false-
negative MR imaging result is less than 10 % [10].
Given the limitations of both imaging modalities, some authors have sug-
gested using alternative methods such as dual-energy CT and diffusion-weighted
MRI, which may yield better results in evaluating patients for subtle cartilage
invasion [12].
Should an Ultrasound, CT, or MRI Scan of the Neck Be Obtained?
In patients with a tumor staged N0 (clinically and with conventional imaging),

FDG PET has not shown consistent usefulness in detecting subclinical
(<1 cm) lymph node metastases in the lateral compartment of the neck. Some
larynx cancers, particularly those that originate in or involve the subglottis
and “transglottic” tumors, metastasize to the lymph nodes in the central com-
partment of the neck. Thus, imaging that provides reliable information about
the status and location of these nodes may be useful in treatment planning.
Unfortunately, neither CT/MRI nor 18F-FDG PET/CT is sensitive and spe-
cific in detecting lymph node metastases in the central compartment of the
neck. In a recent study, both (18)F-FDG PET/CT and CT/MRI demonstrated
low sensitivity for detecting central compartment metastases (58 % vs. 42 %,
respectively, compared with histopathology) [13]. Others have shown that the
sensitivity of CT and MRI increases when the maximal diameter to consider
a node positive is lowered from 9 to 5–6 mm; however, when this is done the
specificity drops to 9 % for CT and 32 % for MRI [14].
Tumor Volume and Prognosis
A number of retrospective studies have suggested that primary tumor volume mea-
sured by CT or MRI has a strong prognostic value in patients with larynx cancer
[15–17]. One of the aims of a randomized trial in patients with advanced carcinoma
of the larynx, comparing accelerated radiotherapy (AR) with accelerated radiother-
apy with carbogen breathing and nicotinamide (ARCON) for hypoxic sensitization,
was to analyze the impact of primary tumor volume and nodal volume on prognosis
in a large and homogeneous cohort of patients [18]. Interestingly, the prognostic
value of tumor volume was not confirmed in patients treated in this prospective
randomized trial (EBML I). Also, in patients with pathological lymph nodes, there
was no correlation between total nodal volume and regional control.
6 Larynx Cancer 89
What Other Imaging Studies Are Appropriate?
The Society of French Otolaryngology [19] has put forth evidence-based guidelines
that provide concrete guidance in this regard: In patients at high risk of distant
metastases, such as those with stages III and IV disease with multiple or low-lying
adenopathy, a chest CT (EBML II) is indicated and a chest X-ray is not recom-
mended in these patients (EBML II). A PET/CT is indicated in these patients or in
cases in whom the chest CT is inconclusive (EBML III). Others have suggested that
FDG PET should also be used for staging patients with stage I and II who have
unexplained or suspicious symptoms [20]. Liver US scan, bone scintigraphy, or
cerebral CT scan are not recommended (EBML III) [19].
Should the Patient Undergo Panendoscopy?
Panendoscopy, i.e., direct laryngoscopy, bronchoscopy, and esophagoscopy, has

been considered an integral part of the diagnostic evaluation of patients with cancer
of the larynx. A large meta-analysis of multiple prospective studies published in
1992 found a small advantage to panendoscopy in detection of second primary
tumors (EBM II) [21]. However, most centers today do not perform these procedures
routinely, for the following reasons:
1. Bronchoscopy is not warranted in the asymptomatic patient with a normal chest
radiograph, and especially in a patient with a normal CT of the chest; the rate of
detection of cancer with this procedure is very low [22].
2. Rigid esophagoscopy is not free of complications, particularly in tertiary, aca-
demic centers where most head and neck cancers are treated. The reported rate
of esophageal perforations is 2.6 % [23].
3. The incidence of synchronous primary tumors in patients with squamous cell car-
cinoma of the larynx is relatively low. For instance Hujala et al. [24] found a syn-
chronous primary tumor in 7.4 % (5/67) of patients with larynx cancer. In a
retrospective review of 240 patients with T1/T2 squamous cell carcinomas of the
larynx (72 % glottic, 27 % supraglottic, 1 % subglottic) Holland et al. [25] found a
synchronous second primary tumor in 4.1 % of the cases. The majority of them
were in the lung and other sites in the head and neck. In a 10-year retrospective
study of 838 head and neck cancer patients who, as part of the initial staging of the
tumor, had a neck and chest CT scan, 487 patients were examined by bronchos-
copy and 588 patients were examined by upper GI endoscopy. Among 198 patients
who had larynx cancers 2.5 % were found to have a synchronous tumor in the
lungs and 1.5 % had a synchronous tumor in the esophagus [26]. In a prospective
study of 154 patients with head and neck cancers who underwent “panendoscopy”
as part of their initial disease assessment, 4 of 72 (2.6 %) patients with larynx
cancer had a synchronous second primary tumors. Two of these tumors were
located in the mucosa of the head and neck and two were located in the lung; there
were no synchronous esophageal tumors [27].
90 J.E. Medina
4. It has not been established to date that early identification of second primary tumors
prolongs patient survival, reduces morbidity, or improves quality of life [27].
5. With the widespread use of flexible, fiber-optic laryngoscopy and nasopharyn-
goscopy to examine the nasopharynx, larynx, and hypopharynx in the office set-
ting, clinicians feel less compelled to examine these sites under general
anesthesia. However, it remains to be determined by a systematic direct compari-
son whether or not fiber-optic endoscopy can detect synchronous primary tumors
in the upper aerodigestive tract as well as endoscopy under anesthesia.
Based on the best available evidence (EBML II 2-3), routine bronchoscopy and esoph-
agoscopy do not seem warranted in patients with larynx cancer, in the absence of justifying
symptoms.
Clinical Situation
52-year-old man who present with hoarseness of 6-month duration, minimal throat
discomfort, no otalgia or odynophagia. Has a 30-pack-year history but quit at age
35. Three weeks prior he underwent a direct laryngoscopy and stripping/biopsy of
what was described as a hyperkeratotic lesion involving the anterior 2/3 s of the
vocal cord. Histopathology revealed carcinoma in situ and superficially invasive
squamous cell carcinoma. The tumor was clinically staged T1N0 (Fig. 6.4).
According to the NCCN Guidelines, Version 2:2014, all patients with T1–T2 laryngeal
cancer should be treated, at least initially, with the intent of preserving the larynx
[28]. The principal treatment options for these patients include radiation therapy,
Fig. 6.4 Abnormal appearance of the left vocal cord following recent “stripping,” normal vocal
cord mobility
6 Larynx Cancer 91
transoral microsurgery (with or without the laser), and open partial laryngeal surgery.
The outcomes on which the clinician will base his recommendation to a particular
patient are first and foremost local control, followed by survival, ultimate laryngeal
preservation, voice quality, complications, and costs.
Are the Outcomes of Transoral Microsurgery and Radiation

Comparable in the Treatment of T1–T2 Larynx Cancers?
Local Control and Survival
There is only one randomized trial (EBML I) that included a substantial number of
patients randomized to open surgery, radiotherapy, or a combination of radiotherapy
and chemotherapy after stratification by anatomical site (glottis or supraglottis) and
tumor stage (T1 or T2). This was a multicenter randomized controlled trial under-
taken in Eastern Europe (the former Soviet Union, Hungary, and Czechoslovakia)
[29]. Two hundred and sixty-nine patients were evaluated, of whom 234 had glottic
laryngeal cancer. Patients were followed up for 5 years and recurrence-free and
survival rates were reported. Five-year survival rates for T1 tumors were 91.7 %
following radiotherapy and 100 % following surgery and for T2 tumors, 88.8 % fol-
lowing radiotherapy and 97.4 % following surgery. There were no significant differ-
ences in survival between the two groups. Five-year locoregional control rates For
T1 tumors were 71.1 % following radiotherapy and 100.0 % following surgery, and
for the T2 tumors, 60.1 % following radiotherapy and 78.7 % following surgery.
Only the latter comparison is statistically significant (P value = 0.036). Unfortunately,
the results of this trial have been criticized because of deficiencies in the reporting
of the study design and analysis, because some patients were inadequately staged
prior to therapy, and because radiotherapy may have been suboptimal. Furthermore,
follow-up was poor and differences between groups may have been biased by dif-
ferential follow-up [30]. There are no randomized studies in which transoral micro-
surgery and radiation have been compared with respect to local control or survival
for patients with T1 glottic cancer. The best available, most recent evidence com-
paring these two treatment modalities is provided by a systematic review of the lit-
erature between 1996 and 2011, published by Yoo et al. in 2014 [31]. In this review
focused on T1 glottic cancer, 2 systematic reviews, 1 with meta-analysis, and 20
primary studies were analyzed. The results indicate that local control rates at 5 years
ranged between 73 and 100 % for patients treated with radiation, and between 71
and 92 % for patients treated with endolaryngeal surgery; however local control and
survival rates were not significantly different between patients treated with radia-
tion or endolaryngeal surgery, with or without the laser. Consequently, when all con-
ditions are equal, the clinician’s recommendation will have to take into account other
factors or outcomes, predominantly the resulting quality of voice, and to a lesser
extent the possibility of preserving the larynx in the long term.
92 J.E. Medina
Quality of Voice
In the review by Yoo et al. [31], posttreatment quantitative acoustical and aerodynamic
voice measurements favored radiation, while patient perception of voice quality
was not significantly different between treatment modalities. In a more recent sys-
tematic review of the literature and meta-analysis, 18 publications were identified
that reported Voice Handicap Index (VHI) data following surgery and radiotherapy
for T1 glottic carcinoma. No studies were randomized. Eight retrospective cohort
studies describing 362 patients were suitable for meta-analysis (EBML II 2-3).
Follow-up time ranged from 1 to 298 months, with a mean follow-up of 47 months.
Six studies showed no difference in VHI between treatment arms; two favored radio-
therapy over surgery (one of which reported transmuscular cordectomy for all surgical
patients); and none favored surgery. The meta-analysis showed no significant differ-
ence in posttreatment VHI between radiotherapy and surgery (mean difference, –5.52;
95 % confidence interval, –11.40, 0.36; heterogeneity I2 = 61 %, p = 0.01) [32].
Ultimate Larynx Preservation
In their review of the literature Yoo et al. [31] found ten studies that provided infor-
mation regarding ultimate laryngeal preservation. Interestingly, the rate of laryngeal
preservation ranged between 77 and 100 %. In five of these studies the rate of larynx
preservation was significantly higher in patients treated with endolaryngeal surgery.
However, the rates were similar in the other five studies.
The existing evidence indicates that the possibility of cure for the patients
presented here, as well as other patients with T1 and T2 tumors of the larynx, ranges
between 80 and 90 % regardless of the treatment modality used. The choice of treat-
ment modality then depends on the anticipated voice outcome, the patient’s wishes
which are often tied to the patient’s occupation, reliability of follow-up, and the
patient’s general medical condition. Consequently, the patient who is a singer, a trial
attorney, a preacher, or a teacher, for whom frequent and often prolonged use of
their voice is essential for their livelihood, may prefer to be treated with radiation.
Likewise, a patient whose general condition is such that precludes safe general
anesthesia would be better treated with radiation. On the other hand, someone for
whom potential minor changes in the quality of their voice may not be greatly
impactful, and wish to be treated more expeditiously, may elect to be treated with
endolaryngeal surgery.
Resection Margins
How Wide a Margin of Normal Tissue Should Be Resected Around the Tumor
in Endolaryngeal Surgery? Should Frozen Section Examination of the Margins
Be Used Routinely?
6 Larynx Cancer 93
The margins of resection around laryngeal tumors removed endoscopically, with or

without the laser, are frequently narrow because of the need to spare tissue to pre-
serve function. In one prospective study, the mean size of margins ranged between
2.45 and 2.64 mm [33]. In addition, histopathological evaluation of the margins may
be challenging because of the size of the specimen, difficult orientation of it, and the
presence of charring artifact. It should be noted, however, that a prospective ran-
domized blinded study (EBML I) of 45 patients with glottic cancer undergoing laser
resection showed that laser excision is associated with a greater degree of artifact in
the margins than steel instrument excision, but was not associated with a higher rate
of uninterpretability [33].
Enigmatically, the large number of margins that are positive or equivocal on
histopatholoy does not seem to result in a corresponding large number of recur-
rences. For instance, in a cohort of 64 patients treated at one institution [34], 24
(37.5 %) of them had positive margins. Interestingly, the overall 5-year survival was
95 % in the patients who had negative margins and 100 % in those with positive
margins. Similarly, the 5-year recurrence-free survival was 91.7 % when the mar-
gins were negative and 95 % when they were positive. These differences were not
statistically significant. Other investigators have previously reported that positive
margins did not affect local control; however, no distinction was made between
superficial and deep margins [35]. In a study of a large number of patients, Peretti
et al. [36] addressed the issue of superficial (mucosal) vs. deep margin involvement.
They reviewed retrospectively 595 patients with larynx cancer removed with tran-
soral laser surgery. With a minimum follow-up of 24 months and a mean follow-up,
84 months, the 5-year local control with laser alone was 94.2 % when the margins
were negative, 93.2 % when the margins were positive “superficially,” and 84.9 %
when the deep margin was positive.
Perhaps the best available evidence regarding margins and the implications of
their status was provided by the group of Wolfgang Steiner, a prolific proponent
of transoral laser surgery [37]. In the largest study of patients treated with tran-
soral laser surgery to date (EBML II-2), these authors analyzed the impact of
margin status on locoregional control of tumor in a cohort of 1426 patients, which
included 846 patients with larynx cancer. Assessment of the margins was done by
histopathology on permanent sections. If these revealed a positive or an uncertain
margin, re-resection in a second operative session was performed. If necessary,
this procedure was repeated until there was no more evidence of tumor in the
specimen. Margins of resection were defined as positive if they were found to be
infiltrated by tumor and uncertain if the pathologist was unable to judge them
precisely. Postoperative radiotherapy, which was prescribed among other reasons
for incomplete removal of the primary tumor, was used in only 8 % (72 of 852) of
the patients with larynx carcinoma. In 256 (30 %), surgical margins were found to
be positive or uncertain indicating the need for revision; in one case, up to four
operations were necessary to remove the tumor completely. Patients with clear
margins from the beginning and those in whom revision specimens were found to
be tumor free had a 5-year locoregional control rate of 78.4 %. On the other hand
94 J.E. Medina
patients in whom residual tumor was detected in revision specimens, the locore-
gional control (51.5 %) was significantly lower (p = 0.0008). Others have reported
similar observations [38, 39].
The reliability of frozen section examination of the margins in assessing margins
of resection has been demonstrated by Remacle et al. [40]. In a study of 97 consecutive
patients undergoing transoral laser cordectomy, they found that the results of frozen
section correlated with the permanent section evaluation in 94 % of the cases; the
negative predictive value of frozen section was 95 %.
Thus, it appears that margins can and should be assessed by frozen section, spar-
ing the patient the inconvenience and expense of additional operations. Positive
margins should be pursued until clear, keeping in mind that those patients are at
higher risk of local recurrence and should be watched accordingly. If frozen section
is not available and margins are assessed on permanent sections, a patient with
equivocal margins or superficially positive may be observed closely, while patient
with infiltrating tumor in the margins should undergo additional resection. The role
of postoperative radiation in these cases has not been studied methodically.
T3, T4 Tumors with Minimal Cartilage Invasion

Clinical Situation: 60-year-old female presents with hoarseness, left soreness of
throat, and left otalgia. Exam reveals a bulky lesion of the left vocal cord, which
appears fixed (Fig. 6.5).
Treatment options in this case are surgery and combinations of radiation and
chemotherapy.
Fig. 6.5 Axial contrast CT

showing a large infiltrating
glottis lesion with
extensive invasion of the
paraglottic space and
possible invasion of the
inner aspect of the thyroid
cartilage
6 Larynx Cancer 95
Surgery
Supracricoid Laryngectomy
It is an alternative to total laryngectomy for large T2, T3, and selected T4 larynx
cancers, particularly in areas of the world where the cost of other alternatives is
prohibitive. The operation consists of the resection of the vocal cords, the false
cords, the aryepiglottic folds, the epiglottis, the part of the subglottis up to the upper
border of the cricoid cartilage, the thyroid cartilage, and the contents of the preglot-
tic and paraglottic spaces. The resection may include one arytenoid but must preserve
the hyoid bone, one arytenoid, and the cricoid cartilage. Depending on whether or not
there is a remnant of the epiglottis for closure, there are two forms of supracricoid
partial laryngectomy: cricohyoidoepiglottopexy (CHEP) and cricohyoidopexy.
Supracricoid laryngectomy is contraindicated in cases with fixation of the ary-
tenoid secondary to cricoarytenoid joint fixation, subglottic extension to the level
of the cricoid or direct invasion of the cricoid, involvement of the posterior com-
missure, and involvement of the outer perichondrium of the thyroid cartilage or
extralaryngeal spread.
The outcomes reported until 2012 have been summarized by Page et al. [41]. The
5-year actuarial survival rates for all stages (T1–T4) range from 68 to 95 % and
actuarial local control rates range from 83 to 98.04 %. Laryngeal preservation was
attained ultimately in 92 % of the cases [42].
Two studies, however, have reported results in patients with advanced T3 and T4
tumors. Lima et al. [43] reviewed retrospectively 43 patients with T3/T4 glottic
squamous cell carcinoma who underwent supracricoid laryngectomy with cricohy-
oidoepiglottopexy. The 5-year disease-specific survival and 5-year relapse-free survival
rates were 78 % and 83 %, respectively. Cartilage invasion was present in 11 cases.
The average length of hospital stay was 5.7 days. The mean time to discontinue
enteral feeding tube was 33.8 days, and the mean time for tracheotomy decannula-
tion was 29.6 days. Overall, normal swallowing was achieved in 74.4 % of patients.
Eleven patients (25.8 %) had complications. The main major complication was
laryngeal stenosis. Dufour et al. studied retrospectively 118 patients with larynx
cancer staged T3 N0–N3 treated with this operation. The 5-year actuarial local
control estimate was 91.4 % and the overall laryngeal preservation rate was 89.8 %.
It should be noted that “most” of their patients received preoperative induction che-
motherapy [44]. The major causes of death after supracricoid laryngectomy are
regional lymph node recurrence and second primary outside the head and neck.
Although the vocal cords are resected, speech and swallowing are maintained by
preserving a cricoarytenoid unit. Restoration of swallowing may require intensive
rehabilitation for several weeks, but eventually 80 and 90 % of patients recover
swallowing function, usually within 1 year [42]. Swallowing outcomes on a series
of 457 patients who underwent supracricoid laryngectomy have been reported by
Benito et al. [45]. Normal swallowing without aspiration was attained in 58.9 % of
the patients, subclinical grade 1 aspiration in 19 %, and severe aspiration in 22.1 %.
They found that the patients most likely to experience severe aspiration were over
70 years old and underwent partial or total arytenoid resection. Management of
96 J.E. Medina
aspiration required a temporary gastrostomy in 34 % of the cases, a permanent

gastrostomy in 1.6 %, and a completion laryngectomy in 3.7 % of the patients.
Total Laryngectomy
Currently, this operation is done rarely for T3 tumors, mainly when the patient is not eli-
gible for chemotherapy or partial laryngeal surgery due to comorbidities. In the Department
of Veterans Affairs (VA) Laryngeal Cancer Group study published in 1991 [46], the sur-
vival of patients with laryngeal cancer mainly staged T3 was 68 % at 2 years.
Radiation and Chemotherapy
Combined regimens of chemotherapy and radiotherapy (chemoradiotherapy) are

increasingly used as the primary treatment of large T2, T3, and selected T4 (without
cartilage “penetration” or base of the tongue extension <1 cm) squamous cell carci-
nomas of the larynx. This is the result of the following key prospective randomized
multi-institutional studies:
The Department of Veterans Affairs (VA) Laryngeal Cancer Group study pub-
lished in 1991 [46]: It involved patients with laryngeal cancer for whom surgical
treatment would necessitate a total laryngectomy. It compared total laryngectomy
and induction chemotherapy with cisplatin and 5-fluorouracil followed by radio-
therapy in responding patients. There was no survival advantage for either regimen
(68 % at 2 years in both groups); however, the larynx was preserved in 64 % of the
surviving patients treated with induction chemotherapy followed by radiotherapy.
Interestingly, more local failures occurred in the induction chemotherapy arm,
whereas more systemic metastases occurred in the laryngectomy arm.
The Radiation Therapy Oncology Group (RTOG) 91-11 trial compared the fol-
lowing three radiotherapy-based treatments as alternatives to total laryngectomy in
patients with stage III or IV laryngeal squamous cell carcinoma without significant
invasion of the tongue base or gross destruction of cartilage.
1. Induction chemotherapy with cisplatin and 5-fluorouracil followed by radiother-
apy in responders (as in the VA study)
2. Concomitant platinum-based chemoradiotherapy
3. Radiotherapy alone
In the initial report, published in 2003 [47], overall survival was almost identical
in the three arms. However, concurrent chemoradiation therapy resulted in signifi-
cantly better local-regional control and larynx preservation (EBML I). In the long-
term report of this study, published in 2012, the latter finding was confirmed [48].
Overall survival did not differ significantly, although there was a possibility of
worse outcome with concomitant relative to induction chemotherapy. These results
are summarized in Table 6.2. Deaths not attributed to larynx cancer or treatment
were higher with concomitant chemotherapy (30.8 % vs. 20.8 % with induction che-
motherapy and 16.9 % with RT alone).
6
Larynx Cancer
Table 6.2 Summary of the results of the Radiation Therapy Oncology Group (RTOG) 91-11 trial
Initial report: 2-year follow-up Long-term results: 10-year follow-up
Induction Concurrent Radiation alone Induction Concurrent Radiation alone
chemotherapy (%) chemoradiation (%) (%) chemotherapy (%) chemoradiation (%) (%)
Overall survival 76 74 75 38 27.5 31.5
Locoregional control 61 78 56 48.9 65.3 47.2
Larynx preservation 75 88 70 67.5 81.7 63.8
97
98 J.E. Medina
In addition, at least two meta-analyses of randomized trials have been published

recently and, unfortunately, they show conflicting results. Blanchard et al. [49] ana-
lyzed 87 randomized trials published between 1965 and 2000. Patients were divided
into four categories according to tumor site: oral cavity, oropharynx, hypopharynx,
and larynx. Individual patient data of 16,192 patients were analyzed, with a median
follow-up of 5.6 years. The benefit of the addition of chemotherapy is consistent in
all tumor sites, with hazard ratios between 0.87 and 0.88 (p-value of interac-
tion = 0.99). The benefit of chemotherapy was higher for concomitant administra-
tion for all tumor sites, but the interaction test between chemotherapy timing and
treatment effect was only significant for oropharyngeal (p < 0.0001) and laryngeal
tumors (p = 0.05). The 5-year absolute benefit associated with the concomitant che-
motherapy is 5.4 % for larynx cancer.
Currently, evidence-based treatment guidelines for larynx cancer, staged T2N+,
and T3 tumors that would require laryngectomy and selected low-volume T4
tumors, such as those with minimal cartilage invasion and base of the tongue exten-
sion of >1 cm, recommend concomitant cisplatin and radiation therapy (EBML 1)
[50]. For patients who are not good candidates for cisplatin, the substitution of
carboplatin or cetuximab concurrent with RT is an accepted best practice in the
absence of comparative data [51].
While this is the standard of care at this time, clinicians should keep in mind that
current larynx preservation regimens are not yet ideal and free of controversy. The
following issues call for the judicious prescription of these regimens:
(a) A recent meta-analysis [52] evaluated overall survival (OS), disease-free sur-
vival (DFS), and laryngectomy-free survival (LFS) for three different larynx-
preserving treatments and laryngectomy in patients with advanced (stage III
and IV) laryngeal cancer. Ten studies were included in this meta-analysis which
covered 2013 patients. Interestingly, radiation alone had the highest OS
(71.6 %), DFS (57.8 %), and LFS (79 %) rates. Comparison between the differ-
ent treatments revealed the following findings:
OS was similar between:
• Laryngectomy followed by radiation vs. induction chemotherapy followed
by radiation
• Induction chemotherapy followed by radiation vs. radiation alone
DFS was significantly higher:
• For laryngectomy followed by radiation vs. induction chemotherapy fol-
lowed by radiation.
DFS was similar between:
• Concomitant chemotherapy vs. induction chemotherapy.
(b) Morbidity: There is no question that the combinations of radiation and chemo-
therapy result in more severe mucositis during treatment, which causes pain,
6 Larynx Cancer 99
inability to swallow, and weight loss. As a result, many clinicians recommend

PEG tube placement prior to the start of treatment.
There is a high prevalence of dysphagia after chemoradiotherapy for laryngeal
and pharyngeal cancers [53]. In the 10-year report of the RTOG 91-11 trial [48],
swallowing difficulty classified as “can only swallow soft foods” or worse was
highest in the concurrent chemotherapy group (17–24 %) compared to the induc-
tion chemotherapy group (13–14 %) and the radiation-alone group (10–17 %).
However, the presence of some speech impairment was similar in the three
groups. In the VA trial population Hillman et al. [54] found that, at 24 months,
technician-assessed intelligibility scores from audio recordings were 90.8 % for
the chemoradiation group and 84.9 % for the surgery and RT group. A 24-item
patient-assessed communication profile showed a similar 5 % point spread of
scores between groups. This minor difference disappeared in patients that were
evaluated 10 or more years later [55].
In a recent review of morbidity related to swallowing associated with chemo-
radiotherapy for larynx cancer Hutcheson and Lewin [53] found that pharyngo-
esophageal stricture has been reported in between 12 and 37 % of the patients,
aspiration in 24 and 31 %, and feeding tube dependence in <10 % of patients at
1 year and <5 % at 2 years.
(c) In the 10-year report of the RTOG 91-11 [48], deaths not attributed to larynx
cancer were higher in the concomitant chemoradiation group at 30.8 % (20.8 %
among the induction chemotherapy arm and 16.9 % among the radiation-only
arm). While the exact cause of the increased mortality is unknown, the investiga-
tors speculate that “unrecognized or under-reported late toxicity affecting swal-
lowing function could have contributed to some of the non–cancer-related deaths.”
T4 Larynx Cancer (Fig. 6.3b)
Currently, there is no level I evidence that supports the use of organ-preservation

regimens for T4 larynx cancer patients. A review of the literature of all studies that
reported overall survival by treatment modality in T4 larynx cancers was published
by Francis et al. in 2014 [56]. The review included only studies published in English
or French. Studies that did not report separate data for T4 tumors or did not report
overall survival by treatment modality were excluded. Twenty-four studies were
identified that met these criteria. All the studies were retrospective and no random-
ized controlled trials were identified. The data in this literature review, summarized
in Table 6.3, does suggest that the results with surgery may be slightly better; how-
ever it is not possible to draw conclusions regarding the superiority of one of the
treatment modalities, the main reason being the heterogeneity of the studies in terms
of inclusion and exclusion criteria, laryngeal subsite, neck staging, and treatment
protocols. Until more definitive data becomes available, the NCCN Clinical Practice
Guidelines [50] recommend total laryngectomy for T4 tumors with chemoradiation
protocols reserved for patients that decline surgery.
100 J.E. Medina
Table 6.3 T4 Larynx cancer: treatment outcomes by modality

Overall survival
Treatment modality 2 years 5 years
Radiation therapy 12–21 % (16.6 %) 0–75 % (38.2 %)
Chemoradiation <30–65 % (57.1 %) 16–50.4 % (43.5 %)
Surgery 30–100 % (68.2 %) 10–81 % (46.0 %)
Overall (56.4 %) (42.9 %)
*The number of patients in each treatment modality ranged from 10 to 79
The N0 Neck
Can the Neck Be Observed and Treated Only If Metastases Become

Apparent?
In a study by Gallo et al. [57], the efficacy of watching the neck and treating it only
when metastases become clinically apparent was found to be similar to that of elec-
tive treatment of the neck in patients with cancer of the larynx. In this study, from a
population of 1808 patients with cancer of the larynx treated at a single institution,
two groups of patients were selected for comparison. One group consisted of 76
patients who had a clinically N0 neck, underwent elective neck dissection, and were
found to have histologically positive nodes. The other group consisted of 96 patients
who were initially staged N0, but subsequently developed lymph node metastases
and underwent therapeutic neck dissection. Postoperative radiation to the neck was
given to 11 % of the patients in the first group and to 20.8 % in the second group
(p = 0.178). The criteria used to determine when patients were selected for one
group or the other was not established a priori. However, the authors state that
patients were “usually” selected to undergo elective neck dissection when they had
an advanced tumor (T3–T4); had a fat, short, or muscular neck that was not easy to
evaluate clinically; and had a low educational level and when poor follow-up was
anticipated. After a minimum follow-up of 5 years, they found no statistically sig-
nificant difference between the two groups of patients in overall, determinant, and
actuarial survival rates. This is surprising since patients who underwent delayed
therapeutic neck dissection had a significantly higher incidence of distant metasta-
ses, multiple positive nodes, and extracapsular tumor spread. This brings up the
possibility that elective treatment of the neck, in the absence of nodal metastases
(pN0), may affect adversely the patient’s outcome. To test this hypothesis, Sarno
et al. [58] reviewed 749 laryngeal cancer patients staged N0, of which 245 received
elective neck dissection and 504 were observed. They found no significant differ-
ences in postoperative complications, local or distant failure, or disease-free or
overall actuarial survival between the two groups, indicating that the treatment of
the neck did not have an adverse effect on prognosis [58]. Other retrospective
6 Larynx Cancer 101
studies have found that elective neck dissection decreases the neck recurrence rates
significantly in patients treated for N0 supraglottic carcinoma [59].
In a recent review of the literature, Rodrigo et al. [60] describe the results of
seven retrospective studies that show that elective neck dissection in patients with
supraglottic cancer does not seem to be superior to observation of the neck and
therapeutic neck dissection in terms of control of the disease in the neck and sur-
vival. An additional retrospective study published subsequently showed similar
results [61].
Self-examination by the patient and reliable follow-up are essential for watchful
waiting to succeed in the management of the N0 neck. Unfortunately, a significant
number of the patients who do not undergo elective neck dissection cannot be
salvaged later, when they present with palpable metastases, because the disease is
too far advanced. In a review of 122 patients with T3–T4N0 cancers of the larynx
that were treated by total laryngectomy and observation of the neck at the University
of Hong Kong [62], 36 % of the patients who later presented with palpable metasta-
ses had inoperable disease, amenable to palliative treatment only. Furthermore, of
the patients that were operable, 42 % eventually died of a neck recurrence. These
observations, in combination with the idiosyncrasies of character and social back-
ground of many larynx cancer patients, are the reason why most head and neck
surgeons prefer to treat the neck electively, even though the impact of this decision
on patient survival remains controversial.
An alternative to this all or none approach has been offered by van den Brekel
et al. [63]. Using ultrasound examination of the neck and fine-needle aspiration
biopsy, dissection is performed only when the nodes are cytologically positive.
While this approach is clearly a step in the right direction, the reported sensitivity of
it is only between 44 and 73 %. Furthermore, in a study of 92 patients who were N0
and cytologically negative, who were followed for 1–3 years, 19 (21 %) subse-
quently developed a neck node metastasis. Six of these 19 patients (32 %) died of
distant metastases or locoregional recurrence [64].
Another alternative has been advocated by the surgeons at the Gustave Roussy
Institute. It consists of performing intraoperative frozen sections of the lymph nodes
in level II. If the presence of metastasis is demonstrated, neck dissection is per-
formed [65].
Sentinel Lymph Node Biopsy

Is It Feasible, Is It Effective, Is It Practical?
Several prospective studies have demonstrated the feasibility of SLN identification

and biopsy in small cohorts of patients with larynx cancer. In some studies the
radiotracer was endoscopically injected around the tumor at the time of surgery.
Lymphoscintigraphy was not performed and the sentinel nodes were identified
intraoperatively or ex vivo in the neck dissection specimen with a gammaprobe.
102 J.E. Medina
Histopathological examination of the neck dissection specimen served as the gold

standard [66]. In one such study of 19 patients (13 patients with untreated necks and
6 with prior neck treatment), identification of the sentinel node(s) was successful in
68.4 % (13/19) of patients overall, and significantly higher in patients with untreated
necks (92.3 % vs. 16.7 %, p < 0.01) [67]. In other similar studies, metastases in sen-
tinel nodes were identified with a sensitivity of 100 % and a specificity of 78 %.
Only one study addressed directly the issue of skip metastasis, that is, metastases in
non-SNs while the SNs were negative; interestingly, no skip metastases were identi-
fied [68]. Other studies have demonstrated the feasibility of injecting the radiotracer
endoscopically using topical anesthesia [69], as well as the reliability of examining
the SLNs using frozen sections, which yielded a false-negative rate of 6.4 % [70].
The existing literature shows that the technique of sentinel lymph node biopsy
(SLNB) is feasible in larynx cancer patients. It also suggests that successful identi-
fication of the SLN depends on the ability to expose the tumor adequately for injec-
tion of the radiotracer, particularly caudal to the tumor, and the ability to avoid the
shine-through of radioactivity from the peritumoral injection sites to levels II and III
in the neck, where the SLN is most likely to be found; it also appears to depend on
whether or not the neck has been previously treated. What is lacking is proof of the
utility of SLNB in appropriate patients with larynx cancers. This would require a
study of a large number of patients with supraglottic cancer staged T1 and T2,
whose primary tumor can be excised transorally, who undergo SLNB using a stan-
dardized technique, and in whom the results of the SLNB are used either to limit the
extent of the neck dissection, as it has been suggested by Werner et al. [66], or to
decide whether or not the neck nodes will be treated electively.
Selective vs. Modified Radical Neck Dissection
Why Is Selective Neck Dissection II–IV the Elective Operation of Choice

for Larynx Cancer?
Evidence indicates that, depending on whether the tumor involves one or both sides
of the larynx, unilateral or bilateral selective neck dissection of levels II, III, and IV
is the appropiate operation. A multi-institutional prospective, randomized study
comparing selective neck dissection (levels II–IV) with modified radical neck dis-
section in patients with laryngeal cancer was carried out by the Brazilian Head and
Neck Cancer Study Group [71]. This study included 132 patients with previously
untreated T2 to T4 N0 M0 supraglottic and transglottic squamous cell carcinoma.
Seventy-one patients were treated with modified radical neck dissections (13 bilat-
eral), and 61 had selective neck dissections (II–IV), 18 of them bilateral. There were
four ipsilateral neck recurrences in the modified radical neck dissection group and
two in the selective neck dissection group. The 5-year actuarial survival rate was
72.3 % in the modified radical neck dissection group and 62.4 % in the selective
neck dissection group (log-rank test, p = 0.312) (EBML I).
6 Larynx Cancer 103
Several retrospective studies have also demonstrated the effectiveness of

selective neck dissection, which is not significantly different than that of the radical
neck dissection and modified radical neck dissection [72].
Should Lymph Nodes in Level IIb and Level IV Be Included Routinely?
The need to include sublevel IIB and level IV in every patient undergoing elective
SND for laryngeal cancer has recently been questioned because the prevalence of
metastases to the nodes in these levels is low (0–2.3 %) [73, 74]. However, outcome
studies are needed to ascertain that not dissecting these node levels will not have a
negative effect on regional control of the disease.
The N+ Neck
Ipsilateral or bilateral neck dissection: Adequate removal of the tumor in the neck
nodes may require a radical or modified radical neck dissection. In patients with N1
diseases in whom the node is located in level 2 only, a selective neck dissection of
levels II, III, and IV may be appropriate.
Decisions Regarding Adjuvant Postoperative Therapy
Postoperative radiation: When pathology reveals multiple positive nodes or positive

nodes at multiple levels [75, 76] the ideal radiation dose to the neck is 5600 and
6300 cGY to areas of the neck where ECS was present [77]. Postoperative chemo-
radiation is indicated when pathology reveals extracapsular spread (ECS) of tumor
of positive margins. In patients with high-risk resected squamous cell carcinoma of
the larynx, several phase III trials (EBML I) have shown that the addition of
cisplatin-based chemotherapy to radiotherapy can improve locoregional control,
disease-free survival, or survival, compared to postoperative radiotherapy alone
[78–82]. While the definition of high-risk pathological features was not uniform in
these studies, a subsequent analysis of two of these studies suggested that the addi-
tion of cisplatin to postoperative radiotherapy was most beneficial when extracapsu-
lar spread or positive margins were present [79]. Furthermore, two meta-analyses
that included jointly 87 trials with several thousand patients with SCCHN have
shown that the addition of chemotherapy to locoregional treatment improves sur-
vival at 5 years in patients with tumors of the larynx.
104 J.E. Medina
Management of the N+ Neck When the Primary Cancer Is Treated

with Radiation with or without Chemotherapy
The management of patients treated with “organ-preservation” strategies using radia-

tion and, more recently, combinations of radiation and chemotherapy, who present
with clinically obvious lymph node metastases, particularly those with advanced
metastasis to the neck (N2–N3), is evolving and remains somewhat controversial.
The first controversy is whether or not a planned neck dissection should be per-
formed, irrespective of the response of the cancer in the neck to the treatment with
radiation or chemoradiation. Some clinicians argue that a neck dissection should be
carried out as part of the treatment plan, irrespective of the response of the cancer in
the neck, because the clinical and pathological responses of the tumor in the neck
correlate poorly with each other. In a study by Brizel et al. [83], a planned neck dis-
section appeared to confer a disease-free survival and overall survival advantage in
patients with N2–N3 disease undergoing chemoradiation, and had acceptably low
morbidity. This was a retrospective study (EBML II-3) of a cohort of 108 patients
with advanced squamous carcinoma of the head and neck, who presented with
lymph node metastasis and were treated with hyperfractionated radiotherapy and
concurrent cisplatinum and 5-fluorouracil. A “modified neck dissection” was per-
formed in 65 patients while 29 patients did not undergo neck dissection because of
“physician and or patient preference.” The 4-year disease-free survival was 70 % for
patients with N1 disease, irrespective of the clinical response or whether a neck dis-
section was performed. For patients with N2–N3 disease who had a complete clini-
cal response to chemoradiation, the 4-year disease-free survival rate was 75 % for
those who had a neck dissection and 53 % for those who did not. This difference
was not statistically significant (p = 0.08). However, the 4-year overall survival rate
was significantly better (77 % vs. 50 %) for the group treated with neck dissection
(p = 0.04). These authors and others have suggested that a planned neck dissection
be considered for all patients with N2 and N3 disease [83, 84].
Other clinicians argue that it is not necessary to perform a “planned” neck dis-
section when the cancer in the neck undergoes a complete response to the treatment
[85, 86], because less than one-third of patients with clinically positive nodes before
therapy have histological evidence of metastases at neck dissection [87], even when
there is residual clinical or radiological “adenopathy” in the neck after completion
of (chemo)radiation [88, 89]. Furthermore, when the cancer in the neck undergoes
a complete response to the treatment, the probability of an isolated recurrence in the
neck is low (0–11 %); therefore the patients may simply be observed [85, 90–92].
The controversy over whether or not a PND is needed is in large measure due to
the inability to determine, preoperatively, when a complete clinical response is asso-
ciated with the presence or absence of viable tumor. PET scanning has been found
useful in identifying the subset of patients who need a neck dissection, since this
imaging modality has been shown to be more accurate than others in the evaluation
of patients following treatment [93]. However, the timing of posttreatment PET
scanning appears to be important. Several studies have shown that a PET scan
obtained 1 month after completion of treatment is often inaccurate [94, 95]. In con-
6 Larynx Cancer 105
trast, a PET scan done 12 weeks after completion of treatment with radiation or
chemoradiation may be more useful [96]. Porcedu et al. [97] evaluated the utility of
PET imaging in 39 patients with N+ neck who achieved a complete response at the
primary site but had a residual mass in the neck, 8 weeks or more after definitive
(chemo)radiotherapy. The PET scan was performed at a median of 12 weeks (range,
8–32 weeks) after treatment. Interestingly, the PET scan showed no metabolic activ-
ity in the residual mass in 32 patients. Five of these patients had a neck dissection
and were all pathologically negative. The remaining 27 patients were observed for
a median of 34 months (range 16–86 months), and only 1 of them had a locore-
gional recurrence. Thus, the negative predictive value of PET for viable disease in a
residual anatomic abnormality in the neck was 97 %. These authors concluded that
a neck dissection is not necessary in patients who have achieved a complete response
at the primary site but have a residual abnormality in the neck that is PET negative
approximately 12 weeks after treatment, and that these patients can be observed
safely. Others have reported similar results [98]. Recently, Corry et al. [99] reviewed
their experience with N2/N3 disease following CRT in 102 patients. Of the 28
patients in whom there was a CR within the primary and a PR in the neck, 11
patients demonstrated resolution of their adenopathy with continued observation, 1
was diagnosed with metastatic cancer prior to any further therapy, and 16 patients
had a neck dissection of which 9/16 (65 %) were pathologically negative. In another
study, patients with a clinical complete response to chemoradiation who were
observed rather than having a neck dissection demonstrated a regional failure rate
of 3–8 %, and if negative PET imaging was included as part of the definition of a
complete response, the regional failure rate decreased to 0–3 % [100]. Thus, it
appears from this information that a decision to perform a neck dissection based on
a PET-CT obtained at least 12 weeks after completion of chemoradiation is an
evidence-based alternative to a “routine” planned neck dissection [100].
The second dilemma regarding “planned” neck dissections is the extent of the
operation. Traditionally, surgeons performed comprehensive neck dissections
(levels I–V) with or without preservation of non-lymphatic structures [101].
Recently, however, surgeons have reported performing selective neck dissections
with recurrence rates below 4 % [102]. Robbins et al. performed 33 selective neck
dissections in patients treated with targeted intra-arterial high-dose cisplatin infu-
sions combined with radiation therapy (RADPLAT) [91, 102]. There was only one
recurrence in the neck. Stenson et al. reported the results in 69 patients who had
planned neck dissections after various concomitant chemoradiation protocols [103].
The majority of them (56/69) underwent a selective neck dissection and only one
patient had a recurrence in the neck. These studies suggest that selective neck dis-
section may be an appropriate option for some patients with an N+ neck who are
treated with organ-preservation regimens (EBML II-3).
Robbins et al. in 2005 reported the results of 106 neck dissections performed in
84 patients with advanced N-stage cancer (N2–N3) that were treated with the
RADPLAT protocol [104]. Fourteen neck dissections were radical or modified radi-
cal, 81 were selective, and 11 were dissections of levels II and III and were labeled
as “superselective neck dissections” (SSND). Interestingly, there were no recur-
106 J.E. Medina
rences in the neck in the group that underwent SSND. The authors outlined the
indications for the different types of neck dissection as follows: in general, a radical
or modified radical neck dissection was performed in patients in whom the residual
lymphadenopathy involved multiple levels, a selective neck dissection was per-
formed when the residual cancer was confined to two levels involving the lymph
node groups at greatest risk, and an SSND was performed when the residual lymph-
adenopathy was confined to one level.
Vasan et al., at our institution, investigated the feasibility of performing a “single-
level dissection.” To that end they studied a cohort of 51 patients, treated between
January 1999 and March 2005, who underwent a total of 55 “planned” neck dissec-
tions for clinically or radiologically apparent residual cancer in the neck, after defin-
itive treatment of the primary tumor and neck with radiation therapy alone or with
chemotherapy [88]. The primary cancer was in the tonsil in 20 (39 %) patients, the
base of the tongue in 12 (23 %), supraglottic larynx in 10 (20 %), hypopharynx in 4
(8 %), faucial arch in 3 (6 %), and “unknown” in 2 (4 %). The neck was staged N1 in
19 (38 %) patients, N2A in 8 (16 %), N2B in 10 (20 %), N2C in 6 (12 %), and N3 in
7 (14 %). All patients were treated with radiation therapy with curative intent. The
mean radiation dose was 7077 and 5814 cGy to the primary cancer and neck, respec-
tively. Twelve patients also received chemotherapy. The neck dissections performed
included lymph node levels II–IV in 32 (58 %) of the cases, II–III in 16 (29 %), I–IV
in 4 (7.1 %), and 1 each of I–IV, II–V, and II only. In 19 dissections (34 %), non-
lymphatic structures were removed, including the internal jugular vein (IJV)
(19/34 %), a portion or all of the sternocleidomastoid muscle (SCM) (14/25 %), the
digastric (5/9 %), and the XI cranial nerve (4/7 %). Interestingly, Robbins also
reported the need to remove one or more of these non-lymphatic structures in 24 %
of “planned” selective neck dissections [91, 102]. The pathologists found histologi-
cally “viable-looking” cancer in one or more lymph nodes in 15 of the 55 neck dis-
section specimens; thus, the yield of histologically positive nodes was 27.2 %. In the
analysis of the distribution of the positive nodes, five patients had clinical or radio-
logical evidence of metastases of one or more nodes in level II only; in all of them
(5/5) histologically positive lymph nodes were found only in level II. Eight patients
had clinical/radiological evidence of metastases in one or more nodes in levels II
and III (1 patient also had a node in level V); histologically positive nodes were
found in level II in one instance, in level III in four, and in levels II, III, and IV in
three. Two patients had clinically/radiologically positive nodes in levels I and II;
histologically positive nodes were found in levels I and II in one of them and in level
I and III in the other. Over a mean follow-up time of 25.9 months, there were only
two recurrences in the neck (4 %).
These findings confirm the effectiveness of selective neck dissection in the man-
agement of residual cancer in the neck. In addition, they suggest that it may be
feasible to perform a single-level dissection in patients whose cancer is confined to
level II nodes, before, during, and after treatment with radiation with or without
chemotherapy. Boyd et al. [105] noted a predictable pattern of residual metastases
following irradiation and suggested that a lateral (II–IV) neck dissection may be
appropriate in the majority of patients. In this study, of nine positive specimens, six
6 Larynx Cancer 107
revealed malignant cells in a single nodal echelon. Obviously such an approach

must be investigated further in prospective studies.
More recently investigators have used CT scans of the neck following chemoradia-
tion to determine the extent of neck dissection. Goguen et al. and Yeung et al. noted that
the NPV for CT for the posttreatment neck was 95 % [106, 107]. They noted that an
SND or superselective neck dissection guided by posttreatment CT would have cap-
tured all residual cancer in 95 % and 93 % of the cases, respectively.
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106. Goguen LA, Chapuy CI, Sher DJ, et al. Utilizing computed tomography as a road map for
designing selective and superselective neck dissection after chemoradiotherapy. Otolaryngol
Head Neck Surg. 2010;143:367–74.
107. Yeung AR, Liauw SL, Amdur RJ, et al. Lymph node-positive head and neck cancer treated
with definitive radiotherapy. Cancer. 2008;112:1076–82.
Index
A D
Accelerated radiotherapy with carbogen Decision making, 59
breathing and nicotinamide NPC (see Nasopharyngeal carcinoma (NPC))
(ARCON), 88 Decision making, hypopharynx
acceleration, radiotherapy, 72
adjuvant therapy, 78–79
B evidence, 71
Bioradiotherapy (BRT), 70 HPHL, 73
BRT. See Bioradiotherapy (BRT) lymph node levels, neck
level IB, 74
level IIB, 75
C level V, 74
Carcinoma, 3, 27–28, 51, 65 N+ Neck, 74
glottic, 83–85 N0 side, 73–74
hypopharynx (see Hypopharynx cancer) retropharyngeal and paratracheal nodes,
NPC (see Nasopharyngeal carcinoma 75–76
(NPC)) organ preservation
OPC (see Oropharyngeal cancer (OPC)) cetuximab, 72
oral cavity (see Oral cavity cancer) CRT and SRT, 71
supraglottic, 83, 84 CT (platinum and 5FU), 70
Chemoradiation (CRT) ICT, 69, 70
and BRT, 70 OS rate, 69
cisplatin and cetuximab, 38, 39 TPF and PF, 70
dysphagia, 72 pyriform sinus, squamous cell
fibrosis, 58 carcinoma, 69
induction chemotherapy, 38, 57 reconstruction
lymph nodes, 59 free flaps, 77, 78
residual fibrotic tissue, 58 regional flaps, 76–77
and SRT, 71 total laryngectomy, 76
stage III and IV oropharyngeal cancers, surgical management, 72
37, 38 surgical options, 72
toxic deaths, 71 TPL, 73
tracheostomy, 71 transoral resection, 68–69
CRT. See Chemoradiation (CRT) Docetaxel plus cisplatin and fluorouracil
Cytotoxic T lymphocyte (CTL), 61 (TPF), 70

DOI 10.1007/978-3-319-18630-6
114 Index
E H
EBM. See Evidence based medicine (EBM) Hemilaryngectomy (HPHL), 73
EBV. See Epstein–Barr Virus (EBV) HPHL. See Hemilaryngectomy (HPHL)
Epstein–Barr Virus (EBV), 54–55, 61 Human papilloma virus (HPV)
Esophagoscopy, 67–68 behavioral implications, 32
Evidence based medicine (EBM) cetuximab, 31
classification, 1 chemoradiation, 31
decision making, 1 CT/MRI scan, 33
definition, 1 E6 and E7 oncoprotein mRNA expression, 29
levels, 1 malignant transformation, 28
Evidence-based decisions, 3–13, 27–34 NPC, 54
OPC (see Oropharyngeal cancer (OPC)) open surgery, 31
oral cavity (see Oral cavity cancer) P16 IHC, 30
Evidence-based decisions, larynx cancer prognostic implications, smoking status,
adjuvant postoperative therapy 30, 31
lymph nodes, 106 radiotherapy, 31
organ-preservation, 104 side effects, cisplatin, 31
PET scanning, 104, 105 tonsil cancer, 28, 29
planned neck dissection, 104 TORS, 41–42
radiation dose, 103 viral product, 29
selective neck dissection, 106 Hypopharyngectomy, 77
single-level dissection, 106 Hypopharynx cancer
SSND, 106 CT/MRI scan, 66
N+ Neck, 103 decisions (see Decision making,
N0 Neck, 100–101 hypopharynx)
odynophagia, 90 endoscopy, 65
primary tumor, 90–91 esophagoscopy, 67–68
radiation and chemotherapy PET/CT, 66–67
benefit, 98 pharyngolaryngoscopy, 67–68
overall survival, 96 pyriform sinus, 65, 66
prescription, 98, 99 thyroid cartilage invasion, 65
RTOG 91-11 trial, 96, 97
total laryngectomy, 96
treatments, 96 I
resection margins ICT. See Induction chemotherapy (ICT)
evaluation, 93 Induction chemotherapy (ICT), 69, 70
frozen section examination, 94 Intensity-modulated radiation therapy (IMRT),
patient survival, 93 56, 72
postoperative radiotherapy, 93
T3, T4 tumors, 94
transoral laser surgery, 93 L
SLNB, 101–103 Larynx cancer
supracricoid laryngectomy, 95–96 axial contrast CT scans, 85, 86
T4 larynx cancer, 99–100 decisions (see Evidence-based decisions,
total laryngectomy, 96 larynx cancer)
tumor stage (T1 and T2 ) glottic carcinoma, 83–85
larynx preservation, 92 panendoscopy, 89–90
local control and survival, 91 supraglottic carcinoma, 83, 84
voice quality, 92 thyroid cartilage invasion
vocal cord, 90 bone formation, 87
CT and MRI, 87
diagnostic value, 86
G MRI accuracy, 87
Glottic carcinoma, 83–85 osteolysis, 87
Index 115
predictive value, 87 postoperative radiation

sclerosis, 86 and chemotherapy, 21
tumor erosion, 85, 86 dose, 20–21
tumor volume and prognosis, 88 indications, 19–20
ultrasound, CT and MRI scan, 88 timing, 20
prevalence, esophageal cancer, 10
resection margins
N frozen section examination, 15
Nasopharyngeal carcinoma (NPC) normal tissue, 14–15
biomarkers, 55 selective neck dissection, 16, 18
CT and MRI, 53 SLNB (see Sentinel lymph node biopsy
EBV, 54 (SLNB))
evidence, lymph node metastasis, 58 squamous cell carcinoma, staged T2N0, 3,
fiber-optic examination, 52 13, 14
HPV, 54 surgery vs. radiation, 13–14
lymph node, CRT, 59 ultrasound and CT/MRI scan, neck,
MRI imaging, 58 10–12
N0 neck, 58, 59 US-FNAB, 12
neck irradiation, 59 Oropharyngeal cancer (OPC)
OME, 55 chemoradiation, 37–39
PET scan, 53 CT/MRI scan, 33–34
primary tumor E6 and E7 oncoprotein mRNA
IMRT, 56 expression, 29
induction chemotherapy, 57 HPV (see Human papilloma virus (HPV))
recurrence, primary site, 60 hyperfractionated/accelerated
right lateral wall, 51, 52 radiotherapy, 37
targeted therapy, 60 incidence, 27
Nasopharynx. See Nasopharyngeal carcinoma left tonsil, 34, 35
(NPC) lymph node metastases, 42, 43
NPC. See Nasopharyngeal carcinoma lymphoid tissue, 42
(NPC) N+ neck management, 44
neck dissection, 44
open surgery, 34–36
O panendoscopy, 33
OME. See Otitis media with effusion PET scanning, 44
(OME) prevalence, 28
Oral cavity cancer radiation therapy, 36–37
brachytherapy and surgery, 11 right tonsil, 34, 35
lymph nodes, level IIb and IV, 18–19 RPM, 43
mandibular invasion smokers, 31–32
alveolar ridge, 8 tonsil and BOT, 35, 36
bone scintigraphy, 7–9 tonsillar fossa, 28
CT scan, 9 transoral surgery, 39–42
marginal mandibulectomy, 6, 7 Oropharynx. See Oropharyngeal cancer (OPC)
median sensitivity and specificity, OS. See Overall survival (OS)
4, 6 Otitis media with effusion (OME), 55, 56
optimal imaging modality, 3 Overall survival (OS), 69
orthopantogram, 6, 7
segmental mandibulectomy, 7
sensitivity and specificity, imaging P
modalities, 4, 5 Panendoscopy, 68, 89–90
signs, 4 Pharyngogastric anastomosis, 77
panendoscopy, 9–10 Post-transplantation lymphoproliferative
PET scan, 12–13 disease (PTLD), 61
116 Index
R T
Retropharyngeal lymph node (RPLN), 75 TLM. See Transoral laser microsurgery (TLM)
Retropharyngeal lymph node metastases TORS. See Transoral robot-assisted surgery
(RPM), 43 (TORS)
RPM. See Retropharyngeal lymph node Total pharyngolaryngectomy (TPL), 73
metastases (RPM) TPF. See Docetaxel plus cisplatin and
fluorouracil (TPF)
TPL. See Total pharyngolaryngectomy (TPL)
S Transoral laser microsurgery (TLM), 39, 40, 68
Sentinel lymph node biopsy (SLNB) Transoral robot-assisted surgery (TORS)
description, 17 Da Vinci surgical system, 39
feasibility, 101 FDA approval, 39
level IIb and IV, 103 frozen section, margins, 40
lymphoscintigraphy, 17, 101 HPV, 41–42
N0 neck, 17 neck dissection and adjuvant therapy, 40
NPV, 17, 18 tracheostomy and gastrostomy, 40
radioactivity, 102 Transoral surgery, OPC
selective vs. modified radical neck margins, 40–41
dissection, 102–103 TLM, 39, 40
SLNB. See Sentinel lymph node biopsy TORS (see Transoral robot-assisted
(SLNB) surgery (TORS))
SRT. See Surgery plus radiation
(SRT)
SSND. See Superselective neck dissections U
(SSND) US Preventative Services Task Force (USPSTF), 1
Superselective neck dissections (SSND), US-FNAB. See US-guided fine- needle
105, 107 aspiration cytology (US-FNAB)
Supraglottic carcinoma, 83, 84 US-guided fine-needle aspiration cytology
Surgery plus radiation (SRT), 71 (US-FNAB), 12

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Cancer of the

Cancer of the Oral Cavity,

ISBN 978-3-319-18629-0 ISBN 978-3-319-18630-6 (eBook)

Library of Congress Control Number: 2016948221

© Springer International Publishing Switzerland 2016

Printed on acid-free paper

This Springer imprint is published by Springer Nature

The pursuit of knowledge is one of the fundamental pillars of medical professional-

Oklahoma City, OK, USA Jesus E. Medina

Index ................................................................................................................. 113

Evidence-based medicine (EBM) can be deﬁned as the application of best available

N.R. Vasan, M.D. (*)

© Springer International Publishing Switzerland 2016 1

1. Timmermans S. Health Aff (Millwood). 2005;24(1):18–28.

Jesus E. Medina, Nilesh R. Vasan, and Anthony Alleman

Decisions in Clinical Evaluation

What Is the Best Method to Assess Mandibular Invasion?

Accurate determination of the presence and extent of invasion of the mandible is

J.E. Medina, M.D. (*) • N.R. Vasan, M.D.

© Springer International Publishing Switzerland 2016 3

Table 2.2 Detection of Sensitivity Speciﬁcity

Should the Patient Undergo Panendoscopy?

Panendoscopy or triple endoscopy, consisting of laryngoscopy, bronchoscopy, and

an esophagoscopy is not warranted in patients with cancer of the oral cavity. In a

Should an Ultrasound, CT, or MRI Scan of the Neck Be Obtained?

Examination of the neck by palpation is not uniformly reliable. It is commonly

In an attempt to overcome the lack of sensitivity of morphologic imaging criteria,

evaluation of the N0 neck since it enabled sampling of lymph nodes as small as

Should a PET Scan or a PET/CT Be Obtained in This Patient?

Positron Emission Tomography

Prospective studies using 18 ﬂuorodeoxyglucose positron emission tomography

Decisions Regarding the Primary Tumor

Surgery vs. Radiation (Why Is Surgery the Best Treatment Modality?)

Fig. 2.8 Clinical

Table 2.4 Comparison of results with brachytherapy and surgery

Table 2.5 Cancer of the Local control (%)

carcinoma. To that end, 50 glossectomy specimens of squamous cell carcinoma of

Should Frozen Section Examination of the Margins Be Used Routinely?

Clinical assessment of the presence of microscopic tumor at the resection margins

What Are the Implications of Having Initially Positive Margins on Frozen

When tumor is present in the resection margins on frozen section (microscopic

Two recent studies address the prognostic impact of intraoperative microscopic

Decisions Regarding the Neck

Observation: Can the Neck Be Observed and Treated Only If Metastases

Sentinel Lymph Node Biopsy

Is it Feasible, Is It Effective, Is It Practical?

Selective vs. Modified Radical Neck Dissection

Why Is Selective Neck Dissection the Operation of Choice?

Should Lymph Nodes in Level IV Be Included Routinely?

Decisions Regarding Adjuvant Therapy

What Are the Indications Supported by Evidence?

of conventionally fractionated postoperative radiation in patients with advanced

What Is the Ideal Timing of Radiation?

Timing of the initiation of radiotherapy is important; delays beyond 6 weeks may

What Is the Ideal Dose of Radiation?

Postoperative Chemotherapy and Radiation

What Are Indications Supported by Evidence?

Nilesh R. Vasan, Jesus E. Medina, and Anthony Alleman

Decisions in Clinical Evaluation

A 39-year-old man presents with a recently diagnosed squamous cell carcinoma of

Should Oropharyngeal Carcinomas Be Tested for HPV?

N.R. Vasan, M.D. (*) • J.E. Medina, M.D.

© Springer International Publishing Switzerland 2016 27