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Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC

Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC. Adjuvant Therapy: Historical Lack of Consensus. GITSG 1 Survival advantage for chemoradiation followed by 5-FU for 1 year, but Early termination, and Slow accrual (43 patients in 8 years) EORTC 2

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Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC

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  1. Pancreatic CancerAliShamseddine MDProessor of MedicineAUBMC

  2. Adjuvant Therapy: Historical Lack of Consensus • GITSG1 • Survival advantage for chemoradiation followed by 5-FU for 1 year, but • Early termination, and • Slow accrual (43 patients in 8 years) • EORTC2 • No survival benefit for chemoradiation, but no maintenance chemotherapy 1. Kaiser MH, et al. Arch Surg. 1985;120:899-903.2. Klinkenbijl JH. Ann Surg. 1999;230:776-782.

  3. Adjuvant Chemotherapy • Two recent randomized clinical trials demonstrated benefit • ESPAC-11 • N = 289 (4-arm study also evaluating chemoradiation) • Observation vs 5-FU/LV (Mayo) • 5-year survival: 8% vs 21% (P = .009) • CONKO-0012 • N = 368 • Observation vs gemcitabine (Days 1, 8, and 15 of 4-week cycle x 6 months) • Disease-free survival: 6.9 vs 13.4 months • 5-year disease-free survival: 5.5% vs 16.5% 1. Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.2. Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

  4. Adjuvant Chemotherapy:Outcomes CONKO-001: Disease-Free Survival ESPAC-1: Survival 100% 75% 100% 75% 50% Cumulative Disease Free Survival 50% Survival (%) gemcitabine Chemotherapy 25% 25% observation No chemotherapy 0% 0% 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 Months Months Neoptolemos JP, et al. NEJM. 2004;350:1200-1210. Oettle H, et al. J Am Med Assoc. 2007;297:267-277. Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

  5. CONKO-001: Previous Analysis • Previously reported data indicated that the median DFS was 13.4 and 6.9 mos in the gemcitabine and control groups, respectively • Estimated DFS at 3 and 5 yrs was 23.5% and 16.5% in the gemcitabine group and 7.5% and 5.5% in the control group, respectively • Subgroup analyses showed the effect of gemcitabine on DFS was significant in patients with either R0 and R1 resection • No difference in OS between the gemcitabine and control groups Oettle H, et al. JAMA. 2007;297:267-277.

  6. CONKO*-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC) U.P. Neumann P. Neuhaus, H.Riess, S. Post, K. Gellert, K. Ridwelski, H. Schramm, C. Zülke, G. Fahlke, J. Langrehr, H. OettleCharitè - Universitätsmedizin Berlin - Campus Virchow Klinikum;Ruprecht-Karls-Universität, Mannheim; Oskar-Ziethen-Krankenhaus, Berlin; Otto-von-Guericke-Universität, Magdeburg; Wald-Klinikum, Gera; Universität Regensburg, Regensburg; AIO; CAO; Deutsche Krebsgesellschaft e.V. *CHARITÉ ONKOLOGIE:Clinical studies in GI cancers

  7. Disclosure I have Consultant or Advisory Role to disclose: Lilly Oncology Roche Sanofi-Aventis

  8. CONKO-001Study Design and Patient Disposition Resected pancreatic cancer 368 patients enrolled 7/98 - 12/04 Stratification R; T; N 186 pts. for Gemcitabine 182 pts. for Observation 179 eligible* pts. (96%) for Intent-to-Treat Analysis 175 eligible* pts. (96%) for Intent-to-Treat Analysis * 7 excluded Patients: 4 pts. withdrew consent 1 pt. no histologic verification 1 pt. persistent disease after resection 1 pt. another malignant disease * 7 excluded Patients: 4 pts. withdrew consent 3 pts. another malignant disease Date of Analysis: March 2008

  9. CONKO-001 Endpoints • Primary Endpoint • Disease free survival (DFS) • Secondary Endpoint • Overall survival (OS) • Toxicity

  10. CONKO-001 Inclusion Criteria • Histologically proven resected pancreatic carcinoma • Standard operation • No measurable disease • No prior chemo- or radiotherapy • No active infection • Karnofsky performance status  50% • Adequate hematologic, renal and hepatic function • CA 19-9, CEA < 2.5 ULN • Start with adjuvant therapy within 6 weeks after resection • Written informed consent

  11. CONKO-001 Treatment Schedule Randomisation Ultrasound after week 16 CT Scan after week 32 Ultrasound after week 8 Gem Gem Gem Gem Gem Gem Follow up every 8 weeks Obs Obs Obs Obs Obs Obs 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks Gem Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks Obs Observation: d1; q 4 weeks

  12. CONKO-001 Patient Characteristics

  13. CONKO-001 Tumor Characteristics

  14. CONKO-001 Disease Free Survival (DFS) • We already demonstrated safety data and superior DFS for adjuvant treatment with gemcitabine as compared to observation in patients with resected pancreatic cancer.P. Neuhaus et al., ASCO 2005 H. Oettle et al., JAMA 2007

  15. CONKO-001 DFS Date of Analysis: March 2008 Gemcitabine Median: 13.4 months (95% CI. 11.3-15.4)(21.2% censored) Observation Median: 6.9 months (95% CI. 6.2-7.5) (7.4% censored) Log Rank P<0.001(14.4% censored)

  16. CONKO-001 DFS Hazard Ratios DFS (fixed) 95% CI Hazard ratio 95% CI Sub-category R StatusR0 R1 0.59 [0.46, 0.76] 0.33 [0.18, 0.58] Test for heterogeneity: Chi² = 3.54, df = 1 (P = 0.06), I² = 71.7% N stage N- N+ 0.53 [0.34, 0.84] 0.53 [0.41, 0.69] Test for heterogeneity: Chi² = 0.00, df = 1 (P = 0.96), I² = 0% T stageT1-2 T3-4 0.52 [0.27, 1.00] 0.55 [0.43, 0.70] Test for heterogeneity: Chi² = 0.02, df = 1 (P = 0.87), I² = 0% Total (95% CI) 0.55 [0.44, 0.69] 0.2 0.5 1 2 5 Favours gemcitabine Favours control

  17. CONKO-001 Overall Survival (OS) Gemcitabine Median: 22.8 months (95% CI. 18.5-27.2) (23.5% censored) ObservationMedian: 20.2 months (95% CI. 17.7-22.8) (10.9% censored) Log Rank P=0.005(17.2% censored)

  18. CONKO-001 Longterm Survival

  19. CONKO-001 OS Resection Margin R0 n=293 Gemcitabine Median: 22.8 months (95% CI. 18.0-27.6) (24.8% censored) ObservationMedian: 20.3 months (95% CI. 17.9-22.7) (11.5% censored) Log Rank P=0.018(18.1% censored) R1n=61 Gemcitabine Median: 22.1 months (95% CI. 9.4-34.9) (17.6% censored) ObservationMedian: 14.1 months (95% CI. 12.2-16.0) (7.4% censored) Log Rank P=0.088 n.s.(13.1% censored)

  20. CONKO-001 OS Primary Tumor T3+T4n=305 Gemcitabine Median: 21.0 months (95% CI. 16.2-25.8)(20.1% censored) Observation Median: 19.0 months (95% CI. 16.3-21.7) (9.3% censored) Log Rank P= 0.018(14.8% censored) T1+T2n=49 Gemcitabine Median: 40.6 months (95% CI. 26.6-54.5)(44.0% censored) Observation Median: 27.0 months (95% CI. 21.4-32.7) (20.8% censored) Log Rank P= 0.12 n.s.(32.7% censored)

  21. CONKO-001 OS Hazard Ratios OS (fixed) 95% CI Hazard ratio 95% CI Sub-category R StatusR0 R1 0.74 [0.57, 0.95] 0.62 [0.36, 1.08] Test for heterogeneity: Chi² = 0.30, df = 1 (P = 0.59), I² = 0% N stage N- N+ 0.57 [0.36, 0.91] 0.80 [0.61, 1.04] Test for heterogeneity: Chi² = 1.50, df = 1 (P = 0.22), I² = 33.5% T stageT1-2 T3-4 0.58 [0.29, 1.16] 0.74 [0.58, 0.95] Test for heterogeneity: Chi² = 0.44, df = 1 (P = 0.50), I² = 0% Total (95% CI) 0.72 [0.57, 0.91] Test for overall effect: Z = 2.74 (P = 0.005) 0.2 0.5 1 2 5 Favours gemcitabine Favours control

  22. CONKO-001 Conclusions • Treatment with gemcitabine as compared to observation in patients with resected pancreatic cancer results in improved disease free survival and overall survival • Adjuvant treatment with gemcitabine doubles the longterm survival rate after 5 years compared to observation • Gemcitabine should be the standard of care for adjuvant treatment of pancreatic cancer

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