2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

RADIATION AND PANCREATIC CANCER
Although these results suggest that chemoradiation
should not be used, the study design limits the ability to
interpret the outcome. The choices of chemotherapy agents
and radiation dose were nonstandard and may have compromised
tolerability in the chemoradiation arm. For instance,
although highly emetogenic, cisplatin has not demonstrated
significant activity in pancreatic cancer and the dose of
radiation used was higher than tested in most clinical trials.
Furthermore, this nonstandard regimen was not tested in
phase II trials before its use in this randomized trial. The
toxicity of this regimen led to fewer than half of the patients
receiving 75% of the chemoradiation dose and contributed to
the poor tolerance of subsequent maintenance chemotherapy.
The median total dose of gemcitabine received by
patients in the chemoradiation arm was well below half the
total dose received by patients in the chemotherapy-alone
group.
Despite the flaws, this trial underscores a key lesson: even
when localized in presentation, pancreatic cancer is a
largely systemic disease, and it is important for patients to
receive chemotherapy early in the treatment course.
Does Anyone Benefit from Radiation Therapy?
The GERCOR Study
In the late 1990s through the early 2000s, the Groupe
Coopérateur Multidisciplinaire en Oncologie (GERCOR) ran
a number of phase II and III trials evaluating different
chemotherapy regimens. 7 Following the trend of including
patients with locally advanced disease in chemotherapy
trials but acknowledging the controversial role of radiation
therapy, investigators recommended patients for these trials
who had no progression after 3 months of receiving chemotherapy
and who had ECOG performance status of 2 or
better. However, investigators could also continue chemotherapy
at their discretion. Radiation therapy was delivered
to 45 Gy with a boost to a total dose of 55 Gy with continuous
infusion 5-FU. Computed tomography (CT) planning was
mandated.
In a retrospective analysis of prospective trials, 167 of the
497 patients enrolled on these trials had locally advanced
disease. After 3 months of chemotherapy, 71% of patients
with LAPC did not have progressive disease and had performance
status scores eligible for chemoradiation. Of the
remaining 29% of patients ineligible for chemoradiation, 45
of the 53 patients were ineligible because they had progres-
KEY POINTS
● Most patients with locally advanced pancreatic cancer
will succumb to metastatic disease.
● A subset of patients with more locally aggressive
disease may be identified by the use of upfront
chemotherapy.
● The use of radiation therapy may be beneficial in
patients with nonprogressive disease.
● DPC4 may be a biomarker that can predict biologic
behavior.
● Future directions include improving the evaluation of
new radiation techniques and integrating biologic
therapies.
sive disease. Of the 128 patients eligible for chemoradiation,
72 (56%) patients received chemoradiation and 56 (44%)
patients continued receiving chemotherapy alone. Patients
in both groups were well matched by chemotherapy regimen,
age, performance status, weight loss, and response to
chemotherapy. The median progression-free survival (PFS)
for the chemoradiation and chemotherapy groups were 10.8
months and 7.4 months, respectively (p � 0.005). The
median OS was 15 months for the chemoradiation group and
11.7 months for the chemotherapy group (p � 0.0009).
Because of its retrospective nature, this study was limited
by potential patient selection bias; however, the two treatment
groups were well balanced for performance status, age,
and chemotherapy response. This study suggests that some
patients might benefit from chemoradiation therapy. Although
previous studies have recognized that some patients
have rapidly metastatic disease, this study suggests that an
effective strategy to evaluate which patients have aggressive
systemic biology is to start with systemic chemotherapy and
to move only those patients whose disease does not progress
after several months of chemotherapy to receive chemoradiation.
This study caused a substantial paradigm shift in
the way radiation therapy was timed. Increasingly, institutions
would initiate radiation therapy with chemotherapy,
primarily to identify patients with rapid, early metastatic
progression who would not benefit from aggressive local
therapy.
Further Evidence of the Benefit of Radiation Therapy:
ECOG 4201
During this period, investigators in the United States
were also investigating the role of radiation therapy. Using
a gemcitabine platform, ECOG 4201 directly compared
gemcitabine alone with gemcitabine-based chemoradiation
therapy followed by gemcitabine. 8 The chemotherapy-alone
group received one 7-week induction cycle, followed by five
additional 4-week cycles (3 weeks on, 1 week off). The
chemoradiation arm received 50.4 Gy of radiation as 1.8
Gy/fraction with concurrent gemcitabine (600 mg/m 2 )
weekly during radiation treatment followed by five additional
cycles of gemcitabine. The intended study design
included 316 patients but was closed after enrolling only 74
patients because of slow accrual.
As expected, the radiation arm had greater toxicity, with
41% of patients experiencing grade 4 toxicity compared to
9% in the chemotherapy-alone arm. Despite this, both arms
received a median of three cycles of chemotherapy. Median
survival was improved in the radiation arm (11.1 months vs.
9.2 months, p � 0.017). There was no difference in PFS.
This trial was more straightforward than the FFCD trial
because it directly compared radiation therapy with gemcitabine
to gemcitabine alone. The chemoradiation regimen
demonstrated safety in phase I testing, which in contrast to
the FFCD trial, is reflected in the fact that both arms
received a similar amount of chemotherapy. However, the
small number of patients enrolled in this study limited the
ability to understand the role of radiation therapy. Additionally,
because radiation therapy was used at the beginning
of treatment, issues of timing were not addressed. Finally,
this small study elicited an OS benefit, despite a lack of
difference in PFS. It is unclear why this would be the case,
especially in light of the increased toxicity of the radiation
arm. However, this study was the first study to demonstrate
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