EJSO (2005) 31, 158–163

www.ejso.com

Adjuvant chemo-radiotherapy in ampullary cancers

S.S. Sikoraa,*, P. Balachandrana, K. Dimrib, N. Rastogib, A. Kumara,
R. Saxenaa, V.K. Kapoora
a
Department of Surgical Gastroenterology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences,
Lucknow 226014, India
b
Department of Radiotherapy, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow
226014, India

Accepted for publication 9 August 2004

Available online 11 November 2004

KEYWORDS Abstract Purpose. Patterns of failure following surgical treatment of ampullary

Ampullary neoplasm; cancers indicate that up to 45% of patients develop loco-regional recurrence. The
Adjuvant effect of adjuvant chemo-radiotherapy on survival and loco-regional control is not
radiotherapy; yet established in this malignancy.
Pancreatico- Patients and methods. From January 1989 to December 2000, 113 patients
duodenectomy underwent pancreatico-duodenectomy for ampullary cancer. One hundred and four
patients who survived the operation were available for analysis to study the effect of
adjuvant chemo-radiotherapy on survival and loco-regional control. Forty-nine
patients received adjuvant chemo-radiotherapy (median dose 50.4 Gy with con-
current 5-Flurouracil) and long-term outcome in these patients was compared with
those 55 who did not receive adjuvant therapy.
Results. The overall median survival was 30.1 (range 1.6–140.0) months with
actuarial 1, 3 and 5-year survival rates of 79, 43 and 33%, respectively. No significant
difference in median survival (34.6 vs 24.5 months; PZ0.3) and actuarial 5-year
survival rates (38 vs 28%) was seen between those who received and those who did not
receive adjuvant therapy. Adjuvant chemo-radiotherapy did not influence the
survival in high-risk patients (PZ0.84), in various T and N stages and had no impact on
loco-regional recurrence (PZ0.6).
Conclusions. Adjuvant chemo-radiotherapy did not improve the long-term survival
or decrease recurrence rates in patients with ampullary cancers who had undergone
pancreatico-duodenectomy.
q 2004 Elsevier Ltd. All rights reserved.

Introduction

Ampullary cancer is the second most common

* Corresponding author. Tel.: C91 522 2668700/800/900
malignancy of the periampullary region with an
x2435. incidence of 6–20%.1–3 Pancreatico-duodenectomy
E-mail address: sadiqss@sgpgi.ac.in (S.S. Sikora). (PD) is the preferred surgical procedure for
0748-7983/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejso.2004.08.013
Adjuvant treatment in ampullary cancer
ampullary cancers.4,5 With improvement in pre-
operative evaluation and perioperative care, survi-
val after potentially curative PD has improved over
the past several years and post-operative mortality
has decreased from the earlier reported 20 to 0–
5%.1,2 In several reports with large experience of
ampullary cancers, the resectability rates have
ranged from 80 to 100% with 5-year survival rates
of 6–46%.2,4–8
Adjuvant chemo-radiotherapy9,10 or chemother-
apy alone11 has improved long-term control of
disease and survival rates in patients with pancrea-
tic cancer. However, there is limited data to
support its use in ampullary cancer. In this report,
we have evaluated the efficacy of adjuvant therapy
on survival and loco-regional recurrence following
standard PD.
Patients and methods
Between January 1989 and December 2002, 163
patients underwent PD for ampullary cancers in the
Department of Surgical Gastroenterology at the
Sanjay Gandhi Post-Graduate Institute of Medical
Sciences (SGPGIMS), Lucknow—a tertiary care
referral hospital in north India. In order to allow
sufficient follow-up, patients operated until
December 2000 and who survived surgery (nZ104)
were selected for analysis to assess long-term
survival and the efficacy of adjuvant chemo-
radiotherapy.
For the purpose of analysis, ‘high risk’ patients
were defined as those with any one or more of the
following pathological findings: node positive dis-
ease, pancreatic infiltration, poorly differentiated
tumour grade and positive resection margin.
All patients were offered adjuvant chemo-radio-
therapy. Patients who did not receive adjuvant
therapy were those with poor performance status,
those with delay in initiating therapy due to post-
operative complications and those who refused
further therapy.
Adjuvant chemo-radiotherapy
All patients were treated with telecobalt or 10 MV
X-ray photons by three fields (one anterior and two
lateral portals). The treatment volume included the
tumour bed (area marked by surgical clips) and
porta hepatis. A dose of 50.4 Gy was delivered in 28
fractions in 5.5 weeks at 1.8 Gy per fraction.
Isodose curves were generated on a 2-dimensional
treatment planning system and tumour bed and
areas at risk were covered with 95% isodose volume.
159
Chemotherapy consisted of 5-fluorouracil (5-FU)
delivered as bolus injection either in a dose of
325 mg/m2 to a maximum of 500 mg from day 1 to 5
concurrently with radiotherapy and repeated at 4
weekly interval for 6 months post-radiotherapy or in
an alternative schedule of 500 mg of 5-FU as
intravenous bolus weekly during radiotherapy fol-
lowed by 500 mg weekly for 12 cycles.
Toxicity of adjuvant therapy was monitored
using toxicity criteria of the Radiation Therapy
Oncology Group (RTOG) and the European Organiz-
ation for Research and Treatment of Cancer
(EORTC).12
Follow-up
Patient follow-up was completed by outpatient
review or by postal questionnaire and was com-
pleted till June 2003. Patients were followed up
monthly for 6 months, then 3 monthly for 2 years
and at 6 months thereafter. They were assessed for
loco-regional control, distant disease, and disease
free survival. Patients underwent a liver and kidney
function tests and abdominal ultrasound (US) at
regular intervals (6 monthly for the first 2 years,
then annually or when indicated). CT scan of the
abdomen was performed if indicated based on US
examination.
Recurrence was categorized as either loco-
regional or metastatic. Disease relapse was defined
as biopsy-proven disease or radiological evidence of
recurrence. Loco-regional recurrence was defined
as recurrent pancreatic or regional nodal mass.
Metastasis was defined as relapse of disease at a
distant site in the visceral organs or non-regional
lymph nodes.
Staging was done using the American Joint
Committee on Cancer (AJCC) classification.13 End-
point of the study was taken as either death or
recurrent disease (whichever was earlier) at the
last follow-up. Survival analyses were performed by
Kaplan–Meier method. Differences in survival
between subsets were compared using log-rank
test. Statistical comparison between two groups
was done by chi-square test for categorical vari-
ables and independent sample t-test for continuous
variables. Significance was accepted at a P value of
%0.05. Analysis was performed using SPSS for
windows, version 9.0 (SPSS Inc., Chicago, Ill, USA).
Results
One hundred and four patients who underwent PD
for ampullary cancer between January 1989 and
December 2000 were included in this analysis. The
160 S.S. Sikora et al.

mean age of the patients was 50G10 years with a

gender ratio of 3:1 (men:women). Classical PD was
performed in 59 patients, 44 patients had a pylorus
preserving PD and one patient had total pancrea-
tectomy. The median post-operative hospital stay
was 14 (7–112) days.
Forty-nine patients received adjuvant chemo-
radiotherapy. Those who received and those who
did not receive adjuvant therapy were well
matched for age, sex, pre-operative bilirubin,
haemoglobin and pre-operative biliary drainage.
More patients with T3 cancers (74.2 vs 14.5%), node
positive disease (44.9 vs 9.1%) and high-risk patients
(71 vs 24%) received adjuvant chemo-radiotherapy
(Table 1).
Figure 1 Overall survival of patients undergoing pan-
The median survival of this group of patients was creaticoduodenectomy for ampullary cancers (nZ104).
30.1 (1.6–140.0) months with an actuarial 1, 3 and Values in the figure indicate: nZnumber of patients,
5-year survival rates being 79, 43 and 33%, median survival in months (mo), 5-year actuarial survival,
respectively, (Fig. 1). respectively.

Survival analysis months; PZ0.83). Benefit was seen in T3N1 group

Adjuvant therapy had no influence on the overall
survival (24.5 vs 34.6 months). The actuarial 1, 3
and 5-year survival in patients having received or
not received adjuvant therapy was 76, 38 and 28% vs
82, 47 and 38%, respectively (Fig. 2).
Subgroup analyses of patients with lymph nodal
metastasis did not reveal any survival benefit for
adjuvant therapy (median survival 20.3 vs 22.5
(PZ0.03) but only one patient in this group did not
receive adjuvant therapy. Other T, N stages and low
and high-risk groups (Figs. 3 and 4) showed no
beneficial effect of addition of adjuvant therapy
(Table 2).
Recurrence patterns
Thirty-nine (37.5%) patients had recurrent disease

Table 1 Comparison of patients with ampullary cancers who did and those who did not receive adjuvant therapy
Factor Adjuvant therapy (nZ49) No adjuvant therapy (nZ55) P value
Age (years), meanGSD 50G9 49G11 0.87
Sex (M/F) 36/13 40/15 0.93
Jaundice 49 51 0.67
Duration of jaundice (days) (median) 60 60 0.88
Cholangitis 33 27 0.06
Medical risk factors 14 6 0.03
Hemoglobin (gm/l) meanGSD 103G20 112G18 0.09
Serum albumin (gm/l) meanGSD 33G7 33G8 0.87
Serum bilirubin (mmol/l) meanGSD 142G132 109.4G102.6 0.16
Pre-operative biliary drainage 24 31 0.46
T status
T1CT2 26 47 0.00
T3 23 8
Nodal status
N0 27 50 0.00
N1 22 5
Tumour grade
Low (1C2) 41 53 0.65
High (3) 8 2
Risk status
Low risk 14 42 0.00
High risk 35 13
Adjuvant treatment in ampullary cancer 161

Figure 3 Effect of adjuvant chemo-radiotherapy on

Figure 2 Effect of adjuvant chemo-radiotherapy on
survival in patients with high-risk ampullary cancers.
survival in patients with ampullary cancers. Values in the
Values in the figure indicate: nZnumber of patients,
figure indicate: nZnumber of patients, median survival in
median survival in months (mo), 5-year actuarial survival,
months (mo), 5-year actuarial survival, respectively.
respectively. NR, not reached.
(15 loco-regional, 18 metastatic and 6 combined).
The sites of distant metastasis were liver (nZ18),
peritoneal with ascitis (nZ2) and supraclavicular
lymph node, lung, bone and parietal wall in one
patient each. Median interval to relapse was 19.8
months. Patients receiving adjuvant therapy had a
higher incidence of metastatic disease as compared
to the group with no adjuvant therapy (17 patients
vs seven patients: PZ(0.001). Loco-regional con-
trol was not significantly altered by addition of
adjuvant therapy in various T, N groups and risk
strata (Table 3).

Toxicity
Minor acute haematological toxicity (grade-1 and 2)
was seen in (30/49) of patients. Grade 3 toxicity
was seen in (3/49) of patients and in two of these
dose of 5-FU was reduced. Grade-4 toxicity was not
encountered. Minor acute non-haematological tox-
icity (grade-1 and 2) in the form of diarrhoea and
Figure 4 Effect of adjuvant chemo-radiotherapy on
survival in patients with low-risk ampullary cancers.
Values in the figure indicate: nZnumber of patients,
median survival in months (mo), 5-year actuarial survival,
respectively.

Table 2 Effect of adjuvant therapy in T and N categories

Groups Adjuvant therapy No adjuvant therapy Log-rank
n Median survival 5-year AS n Median survival 5-year AS
(mo) (%) (mo) (%)
Overall (nZ104) 49 24.5 28.3 55 34.6 37.8 0.33
(T1CT2) N0 15 54.4 42 43 44.9 43 0.95
(T1CT2) N1 11 22.9 NR 4 22.5 NR 0.69
T3N0 12 30.1 37 7 25.9 NR 0.36
T3N1 11 11.9 NR 1 2.8 NR 0.03
NKve 27 30.7 38.9 50 34.6 39.3 0.99
NCve 22 20.3 NR 5 22.5 NR 0.83
Low-risk 14 54.4 44.9 42 44.9 42.7 0.80
High-risk 35 22.3 22.5 13 25.9 NR 0.89
AS, actuarial survival; NR, not reached.
162
Table 3 Influence of adjuvant chemo-radiotherapy on loco-regional recurrence pattern
Factors Subgroups Adjuvant group
N LR rec
T and N status (T1CT2) N0 15
T3N0 12
(T1CT2) N1 11
T3N1 11
Risk status Low-risk 14
High-risk 35
a
LR rec, loco-regional recurrence.
abdominal cramps, requiring symptomatic treat-
ment was seen in (34/49) of patients. Three
patients had significant toxicity in the form of
subacute intestinal obstruction (nZ1) and severe
diarrhoea (nZ2) requiring hospitalization. Late
morbidity in the form of persistent diarrhoea and
abdominal colic was seen in (20/49) of patients.
Two patients had delayed morbidity in the form of
intestinal obstruction and delayed necrosis of
hepatico-jejunostomy and pancreatico-jejunost-
omy bearing intestinal segment secondary to radio-
therapy—both of which required surgical
treatment.
Discussion
Ampullary cancers are uncommon accounting for
only one third of patients undergoing PD for
malignant biliary obstruction. The 5-year survival
in series reporting large number of patients varies
from 34 to 46%.2,4,5,14,15 In this series, overall
median survival was 30 (1.6–110) months with an
actuarial 1, 3 and 5 year survival rates being 79, 43
and 33%, respectively. The comparatively lower
survival rates could be due to the fact that we
considered either death or recurrence as the
endpoint for survival analysis in our paper, which
might have contributed to this falsely low survival
figure.
Despite a relatively favorable outcome following
resection, 32–44% of patients exhibit relapse of the
disease either local or distant.6,16 The high local
and distant failure in ampullary cancers merits
consideration for adjuvant therapy to prevent loco-
regional and metastatic failure. Nevertheless, the
role of adjuvant therapy in patients with ampullary
cancer is not yet well established. There are no
randomized studies addressing this select group of
patients and the available retrospective series are
small and, therefore, no definite guidelines can be
drawn regarding the role of adjuvant chemo-
radiotherapy.
S.S. Sikora et al.
No adjuvant group P value
a a
N LR rec
4 43 4 0.18
2 7 1 1.0
4 4 1 1.0
4 1 1 0.41
3 42 4 0.35
11 13 3 0.72
Willet et al.16 demonstrated a significant
improvement in loco-regional control and overall
survival with the use of adjuvant 5-FU and radiation
therapy in high-risk patients of ampullary cancer.
They defined high-risk group as those with node
positive disease, pancreatic infiltration, poorly
differentiated grade of tumour and/or positive
resection margin. Lee et al.6 (nZ31) also showed
similar benefit in high-risk patients. Mehta et al.17
in a prospective study reported their experience of
adjuvant chemo-radiotherapy (45 Gy with concur-
rent 5-FU) in 12 patients with ampullary cancer
having ‘high’ risk factors (involved lymph node and
margins, poorly differentiated tumour, tumour
size!2 cm and neurovascular invasion). The
median survival was 34 months with 89% two-year
actuarial survival.
The EORTC trial randomized patients with
pancreatic and periampullary cancer to observation
or adjuvant radiotherapy (40 Gy, split course) and
5-FU chemotherapy after surgery.10 Ninety-three
patients with periampullary carcinoma (these
included distal common bile duct, ampulla of
Vater and duodenal cancers, though the exact
distribution of each of these cancers was not
specified) were randomized to surgery alone (nZ
49) or post-operative adjuvant therapy (nZ44).
This EORTC randomized study did not show any
benefit in terms of progression free and overall
survival with the use of adjuvant chemo-radio-
therapy in periampullary cancers. However, 30% of
patients after randomization in adjuvant chemo-
radiation arm did not actually receive adjuvant
treatment for various reasons.
The role of adjuvant chemotherapy (CT) in
resected ampullary cancers is equivocal. In the MD
Anderson Cancer Center experience of using post-
operative CT for carcinoma of the ampulla of Vater,
17 patients received a variety of CT regimes (5-FU
used in combination with doxorubicin, carmustine,
vincristine sulphate and mitomycin).18 There was
no improvement in overall survival with post-
operative CT. On the contrary, Chan et al.19 in a
Adjuvant treatment in ampullary cancer
retrospective review reported that 13 patients
treated with adjuvant CT had a significantly better
survival rate than 16 patients who underwent
surgical resection alone.
In our analysis, subgroup analyses of patients on
the basis of T and N status and low and high-risk
groups did not show any beneficial effect of
adjuvant therapy. Loco-regional control did not
significantly improve by the addition of adjuvant
therapy in various T, N and risk strata. This may be a
reflection of the more advanced disease in the
group receiving adjuvant therapy. The overall
number of patients with metastasis was quite
small for any subanalysis.
Our study nevertheless is limited by the non-
randomized selection of the patients, retrospective
nature of the analysis, long duration of study
period, and the fact that administration of adjuvant
therapy strategy in ampullary cancers has evolved
during the course of the study period. Based on our
previous reported analysis in periampullary carci-
noma20 wherein benefit was seen with post-oper-
ative chemo-radiotherapy, most patients were
offered adjuvant chemo-radiotherapy especially
those with high-risk factors which is quite clearly
reflected in the distribution of patients in the two
groups. Evidently patients with more advanced
disease and poor prognostic factors more often
received adjuvant therapy.
In conclusion, adjuvant chemo-radiotherapy did
not improve the long-term survival or decrease
recurrence rates in patients with ampullary cancers
who had undergone pancreatico-duodenectomy.
Significantly, irrespective of the risk status of the
disease, adjuvant therapy did not confer any benefit
in recurrence rates or survival. At present as evident
by other studies as well there is no or marginal benefit
of the studied adjuvant therapy regimens in ampul-
lary cancers. Since ampullary cancers constitute
only a small proportion of patients reported under
the periampullary cancers category, large multi-
center randomized control trials are warranted to
define the role of adjuvant therapy in these patients.
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