Controversies in the Adjuvant Treatment

Muhammad Wasif Saif
Yale University School of Medicine. New Haven, CT, USA
Summary
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 (GITSG,
RTOG) while chemotherapy alone is the
current standard in Europe (ESPAC-1,
CONKO). Whether gemcitabine is superior to
5-FU remains to be learnt from the ESPAC-3
study currently on-going in Europe. A number
of important questions have yet to be fully
addressed:
• What is the absolute value of radiotherapy
in this setting?
• How should radiotherapy be delivered, if
at all?
• What should be the time to deliver of
either or both therapeutic modalities in the
adjuvant setting?
• Are there any patients who can benefit
from the combined modality?
• What is the most appropriate
chemotherapeutic agent(s) to administer in the
adjuvant setting?
• Is there any role of integrating the
novel/targeted agents, albeit the negative
studies in the metastatic setting?
• What are the new developments (such as
vaccines, pancreas cancer stem cells, etc.) in
this area?
The author summarizes the evolution of
adjuvant therapy for resected pancreatic
cancer and highlights the controversies that
originate from several studies, each fraught
with its own limitations.
Pancreatic cancer is the fourth most common
malignancy in the United States. The annual
incidence rate is almost identical to the
mortality rate with an estimated incidence of
37,170 new cases diagnosed and 33,370
deaths due to pancreatic cancer in 2007 [1].
Five-year survival rate remains less than 5%
[1]. Poor prognosis had been attributed to
inability to diagnose while tumor is resectable
and its propensity towards early vascular
dissemination and spread to regional lymph
nodes. About 10%-20% of patients have
resectable disease at the time of pancreatic
cancer diagnosis; the curative resection rate is
only 14% and median survival of 15-19
months [2]. The 5-year survival rate following
resection is 25-30% for node-negative disease
and 10% for node-positive cancers [3]. Local
recurrence is usually attributed to the
difficulty of achieving microscopically
disease-free surgical margins, particularly at
the retroperitoneal margin. These outcomes
are improving, likely related to an increased
proportion of patients undergoing operations
at high-volume centers and the increased use
of adjuvant therapies [4]. The high risk of
local and systemic disease recurrence as well
as overall poor prognosis laid down the

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rationale for adjuvant therapy after resection
of pancreatic adenocarcinoma (Table 1).
There is no consensus on what constitutes
'standard' adjuvant therapy. 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; Radiation Therapy Oncology Group:
RTOG) while chemotherapy alone is the
current standard in Europe (European Study
Group for Pancreatic Cancer: ESPAC-1;
Charité Onkologie: CONKO).
Chemo-Radiotherapy
The GITSG trial was the first prospective
randomized trial suggesting survival
advantage with postoperative chemo-radio-
therapy using bolus 5-FU (median survival:
20 months vs. 11 months and 5-year survival:
18% vs. 8%) [5]. However this study was
criticized for poor patient accrual, early
termination, and small patient numbers, and
some maintained that the radiotherapy dose
was suboptimal (some authors advocate 50
Gy as a total effective dose).
Multiple authors have attempted to confirm
its findings. The European Organization of
Research and Treatment of Cancer (EORTC)
compared 5-FU (25 mg/kg/day continuous
infusion for 5 days every 4 weeks) with
concurrent radiotherapy using a split course
(40 Gy) with observation only in patients with
resected pancreatic and periampullary cancer
[6]. Klinkenbijl et al. were able to show a
trend toward benefit in terms of median
survival (24.5 months vs. 19.0 months;
P=0.208) [6]. The subgroup analysis looking
only at pancreatic cancer patients showed a
trend toward benefit in median survival (17.1
months vs. 12.6 months; P=0.099) [6]. This
study too was criticized for suboptimal dose
of radiotherapy and split courses. Lower
radiotherapy dose and split courses that may
have allowed cancer repopulation between
courses thereby under-estimating the benefit
of chemo-radiotherapy (Figure 1).
Although not conclusive, these results showed
a trend toward benefit of adjuvant therapy and
led to the ESPAC-1 trial, the largest reported
randomized study to date investigating the
role of combination chemo-radiotherapy in
pancreatic cancer [7]. This study, in fact, has
sparked a new debate over the role of
radiotherapy in the adjuvant therapy of
pancreatic cancer. ESPAC-1 trial was 2x2
factorial designed study comparing adjuvant
concurrent chemo-radiotherapy (bolus 5-
FU/split course radiotherapy), chemotherapy
alone (5-FU/leucovorin), chemo-radiotherapy
followed by chemotherapy, and observation.
Chemotherapy only arm had statistically
significant benefit over observation arm in
median survival (20.1 months vs. 15.5
months; P=0.009). However, chemo-
radiotherapy arm showed worse median
survival compared with patients who did not
receive chemo-radiotherapy (15.9 months vs.
17.9 months; P=0.05) [6]. Interpretation of
this study is complicated slightly because two
different study designs are used: a 2x2
factorial design and direct head-to-head
comparisons (chemotherapy
vs. no
chemotherapy and chemo-radiotherapy vs. no
chemo-radiotherapy). Eligible patients were
pre-enrolled in one of the above strategies.
The authors then reported their findings for
each of the separate study designs as well as
for the pooled data. Therefore, major criticism
Table 1. Median survival of patients in different stages
of pancreatic cancer.
Stage
Incidence Median survival
Localized/resectable
10%
15-19 months
Locally advanced
30%
6-10 month
Metastatic
60%
3-6 months
Figure 1. EORTC: adjuvant chemo-radiotherapy.

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was made on this study for possible selection
bias as both patients and clinicians were
allowed to select which trial to enter, a
concern of suboptimal radiotherapy, and for
allowing the final radiotherapy dose to be left
to the judgment of the treating physicians.
Moreover, the treatment for patients in the
chemo-radiotherapy group did not include
post-radiotherapy adjuvant chemotherapy,
making direct comparison to the GITSG trial
difficult (Figure 2).
The ESPAC-1 study uses only a 5-FU-based
chemotherapy regimen; and certainly, a
gemcitabine-based approach is the most
logical place to start, which was recently
evaluated in the RTOG 9704 study. RTOG
9704 study randomized 538 resected
pancreatic cancer patients to evaluate benefit
of adding gemcitabine to infusional 5-FU
combined with radiotherapy [8]. One arm
received 5-FU plus radiotherapy and the other
arm was treated with gemcitabine before and
after 5-FU plus radiotherapy. Patients with
pancreatic head tumors (No. 380) showed
benefit in median survival (18.8 months vs.
16.7 months; P=0.047) by the incorporation
of gemcitabine before and after 5-FU plus
radiotherapy. However, there was no
significant difference when pancreatic body
and tail cancers were all included (Figure 3).
Chemotherapy Alone
While benefit of radiation therapy was
inconclusive in randomized trials, Oettle et al.
published the results of CONKO-001 study in
JAMA this year [9]. CONKO-001 study
randomized 368 patients with resected
pancreatic cancer to gemcitabine or
observation for 6 months. Tumor prognostic
characteristics were similar in both arms. This
trial showed statistically significant disease
free survival benefit (13.4 months vs. 6.9
months; P<0.001) of gemcitabine over
observation. Gemcitabine rendered a trend
toward overall benefit (22.1 months vs. 20.2
months; P=0.06). This benefit of
chemotherapy was consistent with the result
from ESPAC-1 trial which showed benefit of
5-FU/leucovorin over no adjuvant therapy in
pancreatic cancer patients (median survival of
19.7 months vs. 14.0 months) who had
complete resection [7] (Figure 4).
The CONKO-001 study has many worth
mentioning points. Gemcitabine, the current
standard of care in first line treatment, has
Figure 2. ESPAC-1: trial design.
Figure 4. CONKO-001: trial design.
Figure 3. RTOG 9704: post operative 5-fluorouracil
vs. gemcitabine as pre- and post-chemo-radiotherapy
for pancreatic cancer.

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clearly showed superiority over 5-FU in
patients with advanced pancreatic cancer,
both in terms of dramatic improvement in
clinical benefit response as well as a modest
improvement in median survival [10].
Therefore, ESPAC-1 (in which 5-FU was the
chemotherapy agent of choice) and the Burris
et al. study both provide a rationale for
choosing gemcitabine arm in CONKO-001
study [7, 10]. CONKO-001 study also re-
confirmed that single-agent chemotherapy
with gemcitabine was generally well-tolerated
in this study and most of the patients were
able to complete the full six cycles of
treatment [9]. On the other hand, the median
disease free survival of patients in the
observation-only was dismal (less than 7
months), underlying the fact in addition to
further improve the adjuvant treatment
regimens, specialized surgeries such as
Whipple’s procedure should preferentially be
carried out at high volume centers by
experienced surgeons, where outcomes are
known to be better [4].
Alternate Adjuvant Therapies
Interferon-alpha
Alternate adjuvant therapies have also been
investigated. Picozzi et al. performed a phase
II trial of an interferon-based chemotherapy
regimen with concomitant post-operative
adjuvant radiotherapy [11]. Forty-three
patients received radiotherapy at a dose of
4,500 to 5,400 cGy (25 fractions over 5
weeks) and three-drug chemotherapy:
continuous infusion 5-FU (200 mg/m
2
daily,
days 1 to 35), weekly intravenous bolus
cisplatin (30 mg/m
2
daily, days 1, 8, 15, 22,
29), and subcutaneous alpha, interferon
(3x10
6
units, days 1 to 35). This chemo-
radiotherapy was followed by continuous
infusion 5-FU (200 mg/m
2
daily, weeks 9 to
14 and 17 to 22). Chemo-radiotherapy was
generally initiated between 6 and 8 weeks
after surgery. At a mean follow-up of 31.9
months, 67% of patients were still alive. The
actuarial overall 1-, 2-, and 5-year survival
rates were 95%, 64%, and 55%, respectively.
Although the potential survival benefit with
this regimen seems promising, but about 70%
of the patients developed moderate to severe
gastrointestinal toxicity. The confirmatory
studies are under way.
Vaccines
The development of pancreatic cancer
vaccines has been the subject of recent
developments in the adjuvant treatment of
pancreatic cancer [12]. Jaffee et al. developed
an irradiated granulocyte/macrophage-colony-
stimulating factor (GM-CSF) transfected
allogeneic whole cell line pancreas
adenocarcinoma
immunotherapy
and
previously reported the results of the first
phase I trial establishing the safety of the
GM-CSF-secreting tumor in patients with
resected pancreatic cancer [13]. Most
recently, their group presented the results of a
phase II study of 60 patients with resected
pancreatic adenocarcinoma administered a
total of five immunotherapy treatments using
two pancreatic cancer cell lines each
delivering 2.5x10
8
cells intradermal [14].
Immunotherapy treatment one was
administered 8 to 10 weeks following surgical
resection. Patients subsequently were treated
with 5-FU continous intravenous infusion
with concurrent radiotherapy. Patients who
were disease-free one month after completion
of chemo-radiotherapy received immuno-
therapy treatment 2-4, each one month apart.
A fifth and final booster immunotherapy
treatment was administered 6 months after
vaccine 4. One- and 2-year survivals are 88%
and 76% respectively. The pancreas cancer
vaccine was well tolerated. Treatment related
side effects included transient vaccine
injection site reactions. While the data is only
preliminary, this study compares very
favorably with the available published data.
Figure 5. ESPAC-3: trial design.

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Pancreatic Cancer Stem Cells
The cancer stem cell hypothesis suggests that
neoplastic clones are maintained exclusively
by a small subset of cells with stem cell
properties within a tumor [15]. There has
been strong evidence to support this theory in
blood, brain, and breast cancers. Pilot studies
are currently under way to study pancreatic
cancer stem cells. The information gained
may lead to new avenues to identify novel
tumor cell markers for diagnostic purposes
and to identify new cellular targets and will
provide a cell population that can be used for
testing new chemotherapeutic agents,
biological modifiers, and immune-based
therapies.
Discussion
Pancreatic cancer remains a dismal disease
with poor prognosis, even after curative
resection and most aggressive combine-
modality approaches. This serves as a
sobering reminder that we need to push the
envelope even further so that in the future, for
patients who undergo resection of pancreatic
cancer with “curative intent”, the curative
intent is fulfilled more frequently than not.
The varying results of these randomized trials
make it difficult to establish a standard of
adjuvant therapy for resected pancreatic
adenocarcinoma. The absolute value of
radiotherapy in this setting remains to be
defined. The question is whether we should
change our practice with regard to how we
treat patients whose pancreatic cancer was
resected based on ESPAC-1 study [7]. The
answer is no - at least not yet. Radiotherapy,
at the very least, serves to decrease the
chances of local recurrence (not examined in
this study), which ultimately may influence
patients' quality of life down the road.
However, a compelling argument can be
made that identification of an effective
systemic
regimen
to
eradicate
micrometastases and reduce the opportunity
for metastasis may not be the most critical
factor in improving these patients' chances for
long-term survival. The ESPAC-1 study uses
only a 5-FU-based chemotherapy regimen;
and certainly, a gemcitabine-based approach
is the most logical place to start, which was
recently evaluated in the RTOG 9704 study
[8]. Sub-group analysis of ESPAC-1
suggested a potential role for chemo-
radiotherapy only in patients with positive
resection margins [7]. The CONKO-001
study did not include radiotherapy as a
component of either study arm, and hence
does not resolve the question of whether
radiotherapy is an essential component of
adjuvant therapy. On the other hand, RTOG
9704 included infusional 5-FU as a
radiosensitizer with concomitant radiotherapy
in both study arms. Although this study
showed RTOG 9704 did suggest superior
results for gemcitabine pre-chemo-
radiotherapy compared with 5-FU, but this
improvement only applied to the subgroup of
patients with tumors in the pancreatic head
(for head: HR=0.79, 95% CI: 0.63-0.99,
P=0.047; for body/tail tumors included:
P=0.2) [8]. While both the CONKO-001 and
RTOG 9704 studies support the use of
gemcitabine as the systemic agent of choice in
the adjuvant setting, the benefit of
radiotherapy remains inconclusive in
randomized trials. Our European colleagues
have already commenced ESPAC-3 (Figure
3), the results of this trial will be important in
underscoring the value of postoperative
adjuvant chemotherapy using the modern
chemotherapy (gemcitabine) versus 5-FU in
the setting of resected pancreatic adeno-
carcinoma [16] (Figure 5).
The story of development of chemotherapy
regimens in the metastatic setting has also a
bleak landscape. For the past 10 years, many
cytotoxic and targeted agents have been pitted
against, or combined with, gemcitabine in
randomized phase III trials. No drug was
shown to be superior to single-agent
gemcitabine or when combined with
gemcitabine, except two combinations:
capecitabine plus gemcitabine vs. gemcitabine
and erlotinib plus gemcitabine vs.
gemcitabine [17]. It is worth mentioning that
the results of these studies of combination
chemotherapy regimens in patients with

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metastatic pancreatic cancer should not be
extrapolated to the adjuvant setting, and
routine use of such combinations
(gemcitabine in combination with erlotinib or
capecitabine, or a platinum compound) should
not be undertaken in the post-operative
adjuvant setting. Mornex et al. presented a
multicenter phase II study of post-operative
adjuvant gemcitabine plus oxaliplatin
chemotherapy followed by chemo-
radiotherapy in patients with pancreatic
carcinoma [18]. Fifty-four patients with
potentially curative resection of pathological-
ly confirmed adenocarcinoma of the pancreas
with negative resection margins (R0) received
gemcitabine 1,000 mg/m
2
i.v. over 100 min
on day1 and oxaliplatin 100 mg/m
2
i.v. over
120 min on day 2 every 2 weeks for 6 cycles
followed 4 weeks after by gemcitabine 100
mg/m
2
i.v. over 30 min combined with
radiotherapy 50 Gy (2 Gy fraction) for 5
weeks. Forty-nine patients received at least
two induction cycles. Forty-six patients (85%)
received the 6 planned induction cycles and
41 patients (76%) completed chemo-
radiotherapy. Gemcitabine plus oxaliplatin in
post-operative adjuvant setting followed by
gemcitabine plus radiotherapy demonstrated
71% of 1-year disease free survival rate with
manageable toxicities. However, such results
have to be validated in big randomized trials.
At the Yale Cancer Center, we generally defer
chemo-radiotherapy until after completion of
chemotherapy. At that point, for fit patients -
particularly those with high-risk features
(large tumors, close or microscopically
positive margins) and no radiological
evidence of recurrent or metastatic disease -
we will consider consolidative chemo-
radiotherapy, typically using capecitabine or
infusional 5-FU. Based on the results of
CONKO-001, a 6-month course of standard-
infusion gemcitabine or a regimen similar to
RTOG 9704 (only in head of pancreas) both
can be considered appropriate options. Both
options yield a median survival of
approximately 20 months. However, in light
of the systemic nature of pancreatic cancer
with high rates of distant recurrence,
delivering systemic treatment (gemcitabine)
as the immediate next step after surgery
before any consideration of radiotherapy is
probably the best strategy (modified RTOG
9704 strategy: gemcitabine upfront followed
by chemo-radiotherapy). Using this approach,
patients who have an early systemic
recurrence are selected out and spared the
morbidity associated with abdominal
radiotherapy. This approach is further
strengthened by the fact that there is always a
possibility of delaying initiation of
chemotherapy by the surgery and then further
delay by the initiation of radiotherapy. In the
EORTC trial, of 110 patients in the treatment
arm, 21 (20%) received no treatment because
of excessive delay due to post-operative
complications [6]. Investigators of ESPAC-1
study also are of the opinion that delay in the
administration of chemotherapy in those
patients undergoing combination chemo-
radiotherapy might explain the inferior
outcome [7]. The true incidence and effect of
delay due to post-operative complications are
unknown. The National Comprehensive
Cancer Network (NCCN) recommends that
investigational options be considered in all
phases of disease management [19].
Additionally, until further data are available,
the NCCN recommends postoperative
radiotherapy, administered at a dose of 45-54
Gy, with concurrent 5-FU with or without
additional chemotherapy (gemcitabine based),
or chemotherapy alone (gemcitabine based)
for all patients after curative resection for
pancreatic cancer, regardless of nodal status.
One way of eliminating potential treatment
delays that may be associated with adjuvant
therapy is to consider neoadjuvant chemo-
radiotherapy or chemotherapy. In addition,
this approach leads to increased survival,
down-staging marginal lesions, and sparing
patients with rapidly progressive disease
unnecessary surgery [20]. Single institution
studies including neoadjuvant chemo-
radiotherapy as well as chemotherapy have
shown promise and provide the framework
for larger controlled trials evaluating the role
of neoadjuvant therapy in the management of
both resectable and marginally resectable
lesions.

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Conclusions
Based on the conflicting results of the studies
mentioned above, what is the best modality of
adjuvant therapy for a patient who has
undergone successful resection for a
pancreatic adenocarcinoma, has recovered
adequately, and now wants to know how he or
she should be treated? The answer is not there
yet but at present a 6-month course of
standard-infusion gemcitabine (CONKO-001)
or a regimen similar to RTOG 9704 (only in
head of pancreas) both can be considered
appropriate options. However, the best
approach will be to enroll the patient on a
clinical trial. Early detection strategies, better
identification of precursor lesions and high-
risk groups, direction of patients to high-
volume centers for surgical and oncologic
expertise, and from ongoing trials designed to
identify active agents (chemotherapeutic,
immunotherapeutic, and other) and implement
their use in appropriate patient groups are
warranted to improve outcome in this
population of patients.
Keywords
capecitabine; Chemotherapy,
Adjuvant;
erlotinib;
Fluorouracil;
gemcitabine;
oxaliplatin;
Pancreatic
Neoplasms; Radiotherapy
Abbreviations CONKO: Charité Onkologie;
EORTC: European Organization of Research
and Treatment of Cancer; ESPAC: European
Study Group for Pancreatic Cancer; GITSG:
Gastrointestinal Tumor Study Group; GM-
CSF: granulocyte/macrophage-colony-stimulating
factor; NCCN: National Comprehensive
Cancer Network; RTOG: Radiation Therapy
Oncology Group
Conflict of interest The author has no
potential conflicts of interest
Correspondence
Muhammad Wasif Saif
Section of Medical Oncology
Yale University School of Medicine
333 Cedar Street; FMP: 116
New Haven, CT 06520
USA
Phone: +1-203.737.1568
Fax: +1-203.785.3788
E-mail: wasif.saif@yale.edu
Document URL: http://www.joplink.net/prev/200709/16.html
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