Transcript Controversies in Adjuvant Therapy for Pancreatic Cancer Parag Sanghvi M.D. Tasha McDonald M.D. Department of Radiation Medicine OHSU.

Controversies in
Adjuvant Therapy for
Pancreatic Cancer
Parag Sanghvi M.D.
Tasha McDonald M.D.
Department of Radiation Medicine
OHSU
Median Survival of
Patients With Pancreatic
Cancer
Localized/ Resectable 15-19 months
10%
Locally Advanced
30%
6-10 months
Metastatic/ Advanced 3-6 months
60%
Adjuvant Therapy
No clear consensus on adjuvant therapy
for pancreatic cancer

Difference in philosophy between Europe &
North America
Europeans have moved to adjuvant
chemotherapy alone
Adjuvant ChemoRT
GITSG (1985)
 43
pts randomized into two groups
 XRT/bolus 5-FU  5FU X 2 years
vs. Observation
 Split course radiation – total dose
40 Gy
 Median survival – 20 vs. 11 months
 2 y OS – 43% vs. 18%
EORTC (1999)
Phase III randomized trial
Adjuvant chemoRT vs. observation
Split course RT (40 Gy) with concurrent
5 FU vs. Observation
Median survival 24.5 months vs. 19.0
months (p = 0.21)
2 y OS 41% vs. 51% (p = 0.21)
EORTC (1999)
EORTC (1999)
Criticism is that this study included
patients with ampullary tumors
Improved benefit of adjuvant therapy
seen in patients with pancreatic head
tumors
2 y OS 34 % vs. 26% (p = 0.099)
 MS 17.1 months vs. 12.6 months

ESPAC 1 (2001)
Randomized trial with 2 X 2 factorial design
Patients randomized to
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Chemoradiation
Chemoradiation followed by Chemotherapy
Chemotherapy alone
Observation
Radiation was split course RT (total dose
40Gy; 2 week course)
Chemotherapy was 5FU + Leucovorin
ESPAC 1 (2001)
ESPAC 1 (2001)
ChemoRT vs. No ChemoRT
MS 15.9 months vs. 17.9 months
2 y OS 29% vs. 41% (p = 0.05)
ESPAC 1 (2001)
Chemotherapy vs. No Chemotherapy
MS 20.1 vs. 15.5 months (p = 0.009)
2 y OS 40% vs. 30%
ESPAC 1 (2001)
Criticisms
Split course RT; No central review of RT
Doses ranged from 40-60 Gy;
treatment not uniform or not delivered
in 30% patients
Significant protocol violations in all
arms; cross-over allowed
Newer Trials
CONKO -001 (2007)

Adjuvant chemotherapy vs. observation
RTOG 9704 (ASCO 2006)
CONKO-001 (2007)
Oettle et al. (JAMA)
Randomized Phase III European trial; 368
patients
T1-4 N0-1 M0 pancreatic cancer
R0 or R1 resection
Chemotherapy
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Started 10-42 d after surgery
6 cycles of Gemcitabine q 4 weeks
Each cycle – 3 weekly infusions 1000mg/m2
CONKO-001 (2007)
Results

Median DFS 13.4 months vs. 6.9 months
(p < 0.001)
R0 13.1 months vs. 7.3 months
 R1 15.8 months vs. 5.5 months

OS MS 22.1 vs. 20.2 months (p = 0.06)
 Overall, 83% of all patients had relapses

CONKO-001 (2007)
RTOG 9704 (ASCO 2006)
538 patients enrolled; 442 eligible &
analyzable
T1-T4 N0-1 M0
381 pancreatic head lesions
Patients randomized to pre and post
chemoRT 5FU vs. pre and post
chemoRT gemcitabine
RTOG 9704
Treatment Paradigm
RTOG 9704
Results
No statistically significant difference in
OS between the two arms when all
patients analyzed
However, patients with pancreatic head
lesions showed significantly improved
survival in the Gemcitabine arm
MS 36.9 months vs. 20.6 months
 3 y OS 32% vs. 21%

RTOG 9704
Results
RTOG 9704
Results
No real gains in survival seen in this 1st
RCT with modern doses / treatment
technique compared to historical RCT
with split course lower dose RT
Adjuvant Radiation Therapy in
Surgically Resected Pancreatic
Cancer: SEER Database
1973 - 2003
2636 patients with resectable pancreatic
cancer
1123 received adjuvant RT
 1513 did not receive any adjuvant therapy

Median F/U 19 months
Adjuvant Radiation Therapy in
Surgically Resected Pancreatic
Cancer: SEER Database
Median Survival

Adjuvant RT vs. No RT – 18 months vs. 11 months
(p <0.001)
Cox regression showed HR 0.57 (0.52,0.63;
p<0.01)
Independent statistically significant factors
linked to decreased survival
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African Americans
Moderate & Poorly diff. adenoCA
Age <60
Stage
Mayo Clinic Experience
Retrospective review of 472 consecutively
treated patients with R0 resection
T1-3 N0-1 M0
1975-2005
If adjuvant chemoRT given
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Median dose 50.4 Gy
98% received concurrent 5FU based
chemotherapy
Mayo Clinic Experience
Results
Mayo Clinic Experience
Results
Future Trials – ESPAC 3
Conclusions
Obvious controversies in management of
pancreatic cancer
All randomized trials have significant flaws
What we need (but will not get) is a well
designed RCT

Our design: 3 arms, no cross-over
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Observation
Adjuvant chemotherapy (gemcitabine)
Adjuvant chemoRT (5-FU with RT to 50.4 Gy followed by
gemcitabine)