2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

an OS benefit with radiation therapy against a backbone of
gemcitabine.
Further Evidence of Delaying Radiation Therapy
Investigators at the University of California, San Francisco
(UCSF), seeking to optimize systemic control, performed
a phase II study of fixed-dose rate gemcitabine in
combination with cisplatin for six cycles, followed by chemoradiation
therapy. 9 The gemcitabine was given at 1,000
mg/m 2 infused at 10 mg/m 2 /minute followed by cisplatin (20
mg/m 2 ) administered on days 1 and 15 of a 28-day cycle.
Patients initiated chemoradiation therapy 2 to 6 weeks after
completing six cycles of chemotherapy. Radiation was delivered
to a standard 50.4 Gy with continuous infusion 5-FU.
Of the 25 patients enrolled on the study, eight (28%)
developed disease progression while receiving chemotherapy
between two and 4.5 treatment cycles (median three cycles),
consistent with the rate of metastatic progression seen in
the GERCOR study. Thirteen patients (56%) proceeded to
the chemoradiation phase. The median OS for the entire
cohort was 13.5 months, with a median time to progression
(TTP) of 10.5 months.
The patterns of treatment failure were informative for the
selection that occurs with upfront chemotherapy. Seven of
the eight patients who had progressive disease during chemotherapy
had metastatic disease. In contrast, six of the 12
patients who received all six cycles of chemotherapy and
chemoradiation developed local progression, rather than
metastatic progression. This study suggests that delayed
radiation therapy enriches the group of patients receiving
radiation for those with more localized biology.
Investigators at Massachusetts General Hospital (MGH)
also compared upfront chemoradiation therapy with delayed
chemoradiation therapy. At MGH, patients with LAPC were
historically treated with early chemoradiation therapy.
With the publication of the GERCOR study in 2007, a
gradual shift to delayed chemoradiation therapy occurred.
In a retrospective analysis, investigators compared patients
who received chemotherapy before chemoradiation therapy
with those who started with chemoradiation therapy to
determine the relative outcomes associated with patient
selection based on the timing of chemoradiation treatment.
10
In this study, 70 consecutive patients with unresectable
(46 patients) or borderline resectable (24 patients) LAPC
were treated with chemoradiation from 2005 to 2009. Patients
typically received 50.4 Gy of radiation in 28 fractions
(91%) with concurrent 5-FU (84%) or capecitabine (14%).
Forty patients received chemoradiation alone, and 30 patients
received a median of 4 months of chemotherapy before
chemoradiation, typically gemcitabine (93%). All patients
without progression after chemotherapy were offered
chemoradiation.
Fifty-three percent of the patients in the early chemoradiation
group compared with 83% in the delayed chemoradiation
group had categorically unresectable tumors at
diagnosis. Median OS for the early and delayed chemoradiation
groups was 12.4 months and 18.7 months, respectively
(p � 0.02). Median PFS for early compared with delayed
chemoradiation was 6.7 months and 11.4 months, respectively
(p � 0.02). On multivariate analysis, administration
of chemotherapy before chemoradiation (adjusted hazard
240
HONG, WO, AND KWAK
ratio [AHR] � 0.49; 95% CI, 0.28 to 0.87; p � 0.02) and
surgical resection (AHR � 0.38; 95% CI, 0.17 to 0.85; p �
0.02) were associated with increased OS.
These studies are representative of the paradigm shift
that has occurred at many institutions over the past 5 years.
The use of upfront chemotherapy represents a way to
identify patients more likely to benefit from chemoradiation
treatment.
A Marker for Different Biologies: DPC4 Status
Although clinical evidence has suggested that upfront
chemotherapy could help identify patients more likely to
benefit from chemoradiation, a biomarker predictive of clinical
course had yet to be identified. To this end, investigators
at Johns Hopkins University evaluated 76 patients who had
consented to participate in their rapid autopsy program. 11
Patients were grouped according to death with widely metastatic
disease or death with locally progressive disease.
Grouping was correlated with KRAS and TP53 mutations
and DPC4 (which stands for Deleted in Pancreatic Cancer,
locus 4) status.
Of the 76 patients, 9 had no metastases at the time of
death, 13 had 10 metastases or fewer, 26 had 11 to 99
metastases, and 26 patients had more than 100 metastases.
Investigators found a striking correlation between DPC4
status and patterns of treatment failure. Generally, patients
with DPC4 loss had widespread disease, whereas patients
with intact DPC4 were more likely to have locally destructive
disease (p � 0.007).
This study highlights two major points. First, almost 30%
of patients died with either no metastases or fewer than 10
metastases, highlighting that a substantial number of patients
succumb to locally destructive disease rather than
metastatic disease. Second, intact DPC4 presence as assayed
by immunohistochemistry may identify a subgroup of
tumors that are destined to be locally destructive as opposed
to widely metastatic. Because this finding may have implications
for the relative roles of chemotherapy and radiation
therapy, the Radiation Therapy Oncology Group (RTOG)
has proposed a study in which systemic chemotherapy with
a combination of 5-FU, oxaliplatin, irinotecan, and leucovorin
(FOLFIRINOX) will be studied in patients with loss of
DPC4 and radiation dose escalation will be studied in
patients with intact DPC4.
Current Recommendations and Future Directions
The evidence that LAPC represents a heterogeneous
group has been mounting. Although the majority of patients
will succumb to metastatic disease, there appears to be a
group of patients that has more locally destructive disease.
Currently, the use of chemotherapy before radiation therapy
has the advantages of early treatment of micrometastatic
disease and better selection of patients who may benefit
from chemoradiation therapy. Efforts are currently ongoing
to further clarify the timing of radiation for LAPC. At this
writing, the LAP 07 study is evaluating the role of radiation
therapy in this very manner (Fig. 1). Led by GERCOR, LAP
07 is evaluating chemoradiation therapy after four cycles of
chemotherapy compared with two more cycles of chemotherapy.
This trial involving 902 patients will hopefully provide
a definitive answer to the role of delayed chemoradiation.
In the future, the use of biomarkers, such as DPC4, may