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Controversies in Adjuvant Therapy for
Pancreatic Cancer
Parag Sanghvi M.D.Tasha McDonald M.D.
Department of Radiation MedicineOHSU
Median Survival of Patients With Pancreatic Cancer
Localized/ Resectable 15-19 months 10%10%
Locally Advanced 6-10 months 30%
Metastatic/ Advanced 3-6 months 60%
Adjuvant Therapy
No clear consensus on adjuvant therapy for pancreatic cancerDifference in philosophy between Europe &
North America
Europeans have moved to adjuvant chemotherapy alone
Adjuvant ChemoRT
GITSG (1985)
43 pts randomized into two groupsXRT/bolus 5-FU 5FU X 2 years
vs. ObservationSplit course radiation – total dose
40 GyMedian survival – 20 vs. 11 months2 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 tumors2 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 designPatients randomized to 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 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 monthsR1 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 9704Treatment Paradigm
RTOG 9704 Results
No statistically significant difference in OS between the two arms when all patients analyzedHowever, patients with pancreatic head lesions showed significantly improved survival in the Gemcitabine armMS 36.9 months vs. 20.6 months 3 y OS 32% vs. 21%
RTOG 9704Results
RTOG 9704Results
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 cancer1123 received adjuvant RT1513 did not receive any adjuvant therapy
Median F/U 19 months
Adjuvant Radiation Therapy in Surgically Resected Pancreatic
Cancer: SEER DatabaseMedian 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 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 Median dose 50.4 Gy 98% received concurrent 5FU based
chemotherapy
Mayo Clinic ExperienceResults
Mayo Clinic ExperienceResults
Future Trials – ESPAC 3
Conclusions
Obvious controversies in management of pancreatic cancerAll randomized trials have significant flawsWhat we need (but will not get) is a well designed RCT Our design: 3 arms, no cross-over
Observation Adjuvant chemotherapy (gemcitabine) Adjuvant chemoRT (5-FU with RT to 50.4 Gy followed by
gemcitabine)