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

2. Median Survival of Patients With Pancreatic Cancer 10% Localized/ Resectable15-19 months 10% Locally Advanced 6-10 months 30% Metastatic/ Advanced 3-6 months 60%

3. 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

4. Adjuvant ChemoRT

5. 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%

6. 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)

7. EORTC (1999)

8. 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

9. ESPAC 1 (2001) Randomized trial with 2 X 2 factorial design Patients 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

10. ESPAC 1 (2001)

11. ESPAC 1 (2001) ChemoRT vs. No ChemoRT MS 15.9 months vs. 17.9 months 2 y OS 29% vs. 41% (p = 0.05)

12. ESPAC 1 (2001) Chemotherapy vs. No Chemotherapy MS 20.1 vs. 15.5 months (p = 0.009) 2 y OS 40% vs. 30%

13. 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

14. Newer Trials CONKO -001 (2007) Adjuvant chemotherapy vs. observation RTOG 9704 (ASCO 2006)

15. 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

16. 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

17. CONKO-001 (2007)

18. 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

19. RTOG 9704 Treatment Paradigm

20. 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%

21. RTOG 9704 Results

22. No real gains in survival seen in this 1 st RCT with modern doses / treatment technique compared to historical RCT with split course lower dose RT

23. 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

24. 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 African Americans Moderate & Poorly diff. adenoCA Age <60 Stage

25. 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

26. Mayo Clinic Experience Results

28. Future Trials – ESPAC 3

29. 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 Observation Adjuvant chemotherapy (gemcitabine) Adjuvant chemoRT (5-FU with RT to 50.4 Gy followed by gemcitabine)