Updates in Adjuvant Therapy in Pancreatic Cancer

Joshua Richter, Muhammad Wasif Saif
Yale University School of Medicine, New Haven, CT, USA
Summary
Pancreatic cancer represents the 4th leading cause of cancer deaths in the United States. Surgical resection remains the only potential
curative approach. However, given the notion of a high recurrence rate, adjuvant therapy is needed to offset this risk. The 2010
American Society of Oncology Gastrointestinal Cancers Symposium offered new insights into optimized approaches towards
adjuvant therapy of pancreatic cancer. Abstracts focusing on the role of targeted therapy utilizing erlotinib or GI-4000 in
combination with gemcitabine (Abstracts #224 and #229) were presented. Subbiah, et al. presented a retrospective analysis
comparing systemic chemotherapy versus chemoradiotherapy (Abstract #230) in the adjuvant setting. In addition, a data driven
prediction tool to help predict which patients would be able to complete a course of adjuvant therapy in order to select out those who
may alternative approaches (Abstract #236) was also presented. The authors summarize these findings presented at the 2010 ASCO
Gastrointestinal Cancers Symposium, January 22-24, 2010, Orlando, FL, USA.
Introduction
The American Cancer Society estimated that
approximately 42,470 new cases of pancreatic cancer
were diagnosed in the United States in 2009 with
35,240 deaths [1]. Of these new cases only 15-20% of
these are classified as resectable disease; with only
one-fifth of those patients surviving 5 years [2]. There
continues to be a need for improvement in adjuvant
therapy for those patients who are candidates for initial
surgical resection. Results from the Charité Onkologie
(CONKO-001) trial have shown that adjuvant
chemotherapy with gemcitabine confers about a 6-
month improvement in median disease-free survival in
patients with R0 and R1 resections. However; there
was no statistically significant improvement in overall
survival between the gemcitabine and the observation
groups [3]. This paper summarizes the recent work
presented at the 2010 Gastric Cancers Symposium
regarding advances in the adjuvant treatment setting of
pancreatic cancer (Table 1).
Update in Adjuvant Treatment in Pancreatic
Cancer
Abstract #224: Phase II trial of adjuvant gemcitabine
and erlotinib for resected pancreatic cancer [4]
Gemcitabine has emerged as a popular chemo-
therapeutic agent in the treatment of pancreatic cancer.
In the metastatic setting the addition of erlotinib to
Key words Chemotherapy, Adjuvant; Combined Modality
Therapy; erlotinib; gemcitabine; Pancreatic Neoplasms
Abbreviations CONKO: Charité Onkologie; EORTC: European
Organization for Research and Treatment of Cancer; MUC-1:
mucin 1; NCCN: National Comprehensive Cancer Network;
VACCR: Veterans Affairs Central Cancer Registry
Correspondence Muhammad Wasif Saif
Yale Cancer Center, Yale University School of Medicine, 100
Church Street South, P.O. Box 9740, New Haven, CT 06536-0740
USA
Phone: +1-203.737.1569; Fax: +1-203.785.3788
E-mail: wasif.saif@yale.edu
Document URL http://www.joplink.net/prev/201003/17.html
Table 1. 2010 ASCO Gastrointestinal Cancers Symposium: adjuvant treatment in pancreatic cancer abstracts.
Abstract
Title
Number of
patients
Study type
#224
Bao PQ, et al. [4]
Phase II trial of adjuvant gemcitabine and erlotinib for resected pancreatic cancer
25
Prospective
Phase II
#229
Richards DA, et al. [6]
A randomized phase II adjuvant trial of resected patients with ras mutation bearing
pancreas cancer treated with GI-4000 and gemcitabine or gemcitabine alone: A safety
analysis of the first 100 treated patients
100
Prospective
Phase II
#230
Subbiah S, et al. [8]
Adjuvant chemotherapy versus chemoradiation therapy in resectable pancreatic cancer:
Retrospective analysis from the VA Central Cancer Registry (VACCR) database
742
Retrospective
#236
Smith JK, et al. [12]
Adjuvant therapy for resectable pancreatic cancer: A simple prediction rule
3,043
Retrospective

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gemcitabine has yielded a small but significant
improvement in median overall survival [5]. The
authors of this abstract have conducted a phase II
prospective trial to evaluate the role of this
combination in the adjuvant setting.
Twenty-five patients with margin-negative resections
were treated with gemcitabine 1,500 mg/mbiweekly
for four months with concomitant erlotinib 150 mg
daily for a total of 12 months. Therapy was to be
initiated within 10 weeks of surgery. The primary
endpoint of the study was to evaluate the effect of
therapy on time to radiographic recurrence. The patient
characteristics are reported in Table 2.
Fourteen of the 25 patients (56.0%) experienced
recurrence of disease. Of those 14 patients:
• 9 recurred during treatment;
• 4 recurred after completing the planned course of
therapy; and
• 1 recurred after being taken off protocol.
The recurrence free survival was 21.5 months (95%
confidence interval: 7.6-24.5 months). Although the
median overall survival was not reached; the estimated
1- and 2-year overall survival was 82% and 61%,
respectively.
Overall, the combination of the two agents was
tolerated moderately well with approximately 1/3 of
patients requiring a dose reduction and/or dose holding
of one or both drugs during treatment.
Abstract # 229: A randomized phase II adjuvant trial of
resected patients with ras mutation bearing pancreas
cancer treated with GI-4000 and gemcitabine or
gemcitabine alone: A safety analysis of the first 100
treated patients [6]
K-ras oncogene mutations have been identified in up to
95% of pancreatic cancers, implying their critical role
in their molecular pathogenesis. Various studies have
identified a wide prevalence and location of these
mutations; however several loci (such as codon 12)
may be associated with a particular tendency towards
oncogenesis [7]. To further exploit this target the
authors of this article have utilized GI-4000 which is a
yeast-based (Saccharomyces cerevisiae) vaccine
system that is designed to stimulate “killer” T cells in
the immune system to find and destroy diseased cells.
They have combined this novel agent with gemcitabine
as an adjuvant treatment strategy for patients with
resected pancreatic cancer. Their study focused on the
safety analysis of this regimen. The patient
characteristics are reported in Table 3.
Eligibility requirements for the study include patients
with an R0 or R1 resection of a pancreatic neoplasm
which contained a K-ras oncogene mutation associated
with one of the mutants expressed in GI-4000. After
successful pancreas cancer surgery, patient tumor
specimens were assessed by DNA sequencing to
identify whether the tumor contains a K-ras mutation
contained in GI-4000. All patients received treatment
with 6 cycles of gemcitabine 1,000 mg/mweekly x3
out of 4 week cycle. Patients were randomized to GI-
4000 or placebo to be administered weekly x3 prior to
chemotherapy, monthly concomitantly with chemo-
therapy and monthly thereafter until death, recurrence
or termination of therapy due to intolerance.
The median exposure to GI-4000 was 11 doses in this
cohort. The safety data revealed 35 deaths and 2
discontinuations secondary to adverse events. Major
serious adverse events included intra-abdominal
abscess and intestinal obstruction. More common
adverse events included fatigue, abdominal pain,
anemia and neutropenia. Based on this initial safety
analysis with acceptable adverse events the cohort has
been expanded to 200 patients.
Abstract # 230: Adjuvant chemotherapy versus
chemoradiation therapy in resectable pancreatic
cancer: Retrospective analysis from the VA Central
Cancer Registry (VACCR) database [8]
There is no universally accepted standard approach to
treat patients with pancreatic cancer in the adjuvant
setting. This controversy derives from several studies,
each fraught with its own limitations. Standards of care
also vary depending on which side of the Atlantic you
are on: chemo-radiotherapy followed by chemotherapy
is considered the optimal therapy in North America
(Gastrointestinal Tumor Study Group: GITSG;
European Organization for Research and Treatment of
Cancer: EORTC; Radiation Therapy Oncology Group;
RTOG 9704) while chemotherapy alone is the current
standard in Europe (European Study Group for
Pancreatic Cancer: ESPAC-1, ESPAC-3; CONKO).
The EORTC utilized a 5-fluorouracil based
chemoradiotherapy strategy and found an improvement
in median survival from 19 to 24.5 months; however
this was not statistically significant (P=0.208) [9]. The
ESPAC-1 trial by Neoptolemos et al. actually found a
Table 2. Patient characteristics: Abstract #224 [4].
Number of patients accrued
25
Age (years; median, range)
66 (34-81)
Surgery:
- Pancreaticoduodenectomy
- Distal pancreatectomy
20 (80%)
5 (20%)
Nodal status:
- Node positive
- Node negative
16 (64%)
9 (36%)
Time to treatment (days; median, range)
62 (34-70)
Follow-up (months; median, range)
13.1 (7.3-23.5)
 
Table 3. Patient characteristics: Abstract #229 [6].
Number of patients accrued
100
Age (years; median)
61
Sex:
Male
- Female
60%
40%
Resection:
- R0
- R1
77%
23%

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146
detriment to survival in the chemoradiotherapy arm
[10]. As there still remains some controversy; the
National Comprehensive Cancer Network (NCCN)
guidelines for the management of pancreatic cancer
still allow for the use of adjuvant chemoradiotherapy
[11].
In an effort to further elucidate this question, the
authors of this paper analyzed retrospective data from
the Veterans Affairs Central Cancer Registry
(VACCR) database regarding patients with resected
pancreatic cancer. The treatment modalities are
reported in Table 4.
The cohort for this study was collected from patients in
the VACCR database from 1995-2007. The majority of
patients received either no adjuvant therapy or
treatment with chemoradiotherapy. Both the
chemotherapy and the chemoradiotherapy arms yielded
an improvement in median survival when compared to
those who received either no adjuvant therapy or
radiation alone. The radiotherapy alone arm yielded the
lowest median survival.
A multivariate analysis was conducted to evaluate the
effect of differing factors on the survival statistic. The
statistically significant results are displayed in Table 5.
The chemotherapy arm was associated with a superior
overall survival at 1 year at 63%. However, the
chemoradiotherapy arm showed superior overall
survival at the 1, 3 and 5 year marks with 72%, 28%,
and 19%, respectively. The data suggest a benefit to
treating pancreatic cancer with adjuvant therapy;
however further prospective studies are needed to tease
out exactly what approach is best for each individual
patient.
Abstract # 236: Adjuvant therapy for resectable
pancreatic cancer: A simple prediction rule [12]
Despite adequate R0/R1 resections for pancreatic
cancer there remains a high recurrence rate in patients
with macroscopically completely resected tumors.
Although the optimal adjuvant therapy is not clearly
defined; what is clear is that there is a need for therapy
beyond surgical resection. Although regimens such as
gemcitabine monotherapy are generally well tolerated,
there are a substantial number of patients, for one
reason or another, who will be unable to complete a
course of adjuvant chemotherapy. If at presentation
(upfront/prior to surgery) we knew which patients
would be unable to complete adjuvant therapy we
would need to do something else to reduce this risk.
The authors of this abstract sought to create a
prediction model to help define that subset.
Patients were identified through the Surveillance,
Epidemiology, and End Result (SEER) and Medicare
linked databases and selected out for age less than 65
years with pancreatic cancer resection between 1991
and 2007.
Of the 3,043 patients identified using this tool 80%
were used to generate the data and the remaining 20%
were used to validate it. The prediction tool takes into
account a variety of factors including age, sex, surgery
type, as well as comorbidities as calculated by the
Charlson comorbidity score. The prediction tool
generated a c statistic of 0.62 for the validation set,
which translates into a fair predictive value. This tool
can help predict those who may not be able to complete
a significant course of adjuvant therapy and who
should be selected out for alternative approaches for
tumor recurrence risk reduction.
Discussion
The optimal adjuvant approach for patients with
resected pancreatic cancer remains elusive. The NCCN
guidelines offer a variety of approaches including
systemic chemotherapy with agents such as
gemcitabine, 5-fluorouracil, capecitabine or
gemcitabine followed by 5-fluorouracil based
chemoradiotherapy [11]. The NCCN maintains that the
best management for any cancer patient is enrollment
in a clinical trial.
Intensive research is currently being conducted looking
at vaccine strategies in a variety of solid and liquid
tumors. Several groups have been evaluating the role of
a mucin 1 (MUC-1) based vaccine in the adjuvant
setting [13, 14]. MUC-1 is a tumor associated antigen
which has been shown to be overexpressed in
pancreatic adenocarcinoma. This vaccine approach
focuses on the induction of an endogenous T-cell
response which may confer a role in both the active
therapeutic as well as the preventative setting. It
represents an ideal approach in the adjuvant setting
where the patient is either disease free or possesses
minimal residual disease.
While these approaches offer some degree of benefit,
as we enter into an age of “personalized medicine” we
need to push the mantra of “the right approach for the
right patient!”. A certain approach in a K-ras mutated
patient may not be correct in the age-matched K-ras
wild type. In the R0 resection setting cure is the goal
and we can do better still. It is also important to
underline the importance on developing as well as
considering neoadjuvant therapy (chemo-radiotherapy
or chemotherapy) in this setting. This approach can
lead to improved survival, down-staging marginal
lesions, sparing patients with rapidly progressive
disease unnecessary surgery, and eliminate potential
Table 5. Multivariate analysis of individual variables' effect on
survival: Abstract #230 [8]
Negative effect
No effect
Advanced age
Number of positive lymph nodes
Poorly differentiated tumor
Race
Sex
Smoking history
Number of examined lymph nodes
Table 4. Treatment modalities: Abstract #230 [8].
Number of patients
742
Adjuvant therapy:
- None
- Chemoradiotherapy
- Chemotherapy
- Radiotherapy
57%
28%
11%
4%

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treatment delays that may be associated with adjuvant
therapy [15].
Conflict of interest The authors have no potential
conflicts of interest
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