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ESPAC-3(v2)

ESPAC-3(v2) A multicentre, international, open label, randomised controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma. European Study Group for Pancreatic Cancer

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ESPAC-3(v2)

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  1. ESPAC-3(v2) A multicentre, international, open label, randomised controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma European Study Group for Pancreatic Cancer CR-UK Liverpool Cancer Trials Unit

  2. Background ESPAC-1 compared chemotherapy [5FU/FA with chemoradiation Using a 2x2 factorial design • Observation Chemotherapy (CT) • Chemoradiotherapy (CRT) CRT CT

  3. ESPAC-1 Lancet, 2001: No benefit for Chemoradiation – Potential benefit for Chemotherapy Lancet, 2001;358(9293):1576-85

  4. JNCI 2008; 100: 1670-1

  5. ESPAC-3(v1) Trial Design Patients with ductal adenocarcinoma undergoing ‘curative’ resection Target N=990 RANDOMISE 5FU/ FA 5-FU 425mg/m2 & FA 20mg/m2 for 5 days every 28 days for 6 cycles Target N=330 GEMCITABINE 1000mg/m2 once a week for 3 of 4 weeks for 6 cycles Target N=330 OBSERVATION Target N=330 330 per group to detect 10% difference in 2y survival rate ( = 5%, 1-b = 80%) Trial opened July 2000

  6. Eligibility Complete macroscopic resection for pancreatic ductal adenocarcinoma (WHO Classification) R0 or R1 resection No: ascites, liver or peritoneal metastasis, or any other distant abdominal or extra-abdominal organ spread No previous or concurrent malignancy diagnoses WHO performance status < 2 Life-expectancy of more than 3 months Fully informed written consent

  7. ESPAC-1 ESPAC-1 NEJM 2004: No benefit for Chemoradiation confirmed Survival rates 2-year 5-year No CRT: 41.4% 19.6% CRT: 28.5% 10.0% HR=1.28 (0.99, 1.66), p=0.053 NEJM 2004; 350:1200-10

  8. ESPAC-1 ESPAC-1 NEJM 2004: Benefit for Chemotherapy confirmed Survival rates 2-year 5-year No CT: 30.0% 8.4% CT: 39.7% 21.1% HR=0.71 (0.55, 0.92), p=0.009 NEJM 2004; 350:1200-10

  9. Impact • OBSERVATION arm closed on DMC advice June 2003 (n=61) • Target recruitment updated to detect 10% difference in survival at 2-years with 90% power, DMC July 2005 • Updated Target: 515 pancreatic ductal adenocarcinoma patients (275 events) per chemotherapy group

  10. ESPAC-3(v2) Trial Design Patients with ductal adenocarcinoma undergoing ‘curative’ resection Target N=1030* RANDOMISE 5FU/ FA Target N=515 Actual=551 GEMCITABINE Target N=515 Actual N=537 3-monthly follow-up to death 515 per group to detect 10% difference in 2y survival rate ( = 5%, 1-b = 90%) *Actual N=1088

  11. In the meantime! CONK01 Adjuvant Trial: Gemcitabine vsObservation ESPAC Adjuvant Trials: 5FU/FA vsObservation Overall survival Disease free survival HR= 0.68 (0.50, 0.92) p = 0.001 Log rank p < 0.001 N = 354 Survival rates 2-year 5-year Obs: 37% 14% 5FU/FA: 49% 24% Cumulative survival % Cumulative survival % Gemcitabine N = 458 Observation Months No. at risk Gemcitabine Observation Br J Cancer 2009; 100 :246-50 Oettle et al JAMA, 2007 17;297:267-77

  12. July 2000 - Jan 2007

  13. Patient Demographics 5FU/FA GEM TOTAL n=551 n=537 n=1088 *Age (years) 63 (34-85)63 (31-81) 63 (31-85) Sex Male 301 (55%)297 (55%) 598 (55%) Female 250 (45%)240 (45%) 490 (45%) Baseline PS † 0 200 (36%)167 (31%) 367 (34%) 1 286 (52%)303 (57%) 589 (54%) 2 64 (12%)64 (12%) 128 (12%) Smoking † Never 207 (43%)189 (40%) 396 (41%) Past 192 (39%)207 (44%) 399 (42%) Present 87 (18%)78 (16%) 165 (17%) *Surgery to Rand (days) 45 (4-114)45 (5-98) 45 (4-114) * Median (Range) † Significant prognostic variable

  14. Tumour Pathology 5FU/FA GEM TOTAL n=551 n=537 n=1088 Stratification factor: R Status † R0 356 (65%)348 (65%) 704 (65%) R1 195 (35%)189 (35%) 384 (35%) *Max Tumour Size (mm) † 30 (2-350)30 (2-105) 30 (2-350) Grade † Well 81 (15%)66 (13%) 147 (14%) Mod 327 (60%)336 (63%) 663 (62%) Poor 135 (25%)125 (24%) 260 (24%) Undiff2 (0%)2 (0%) 4 (0%) Nodes † Neg161 (29%) 144 (27%) 305 (28%) Pos 387 (71%)391 (73%) 778 (72%) * Median (Range) † Significant prognostic variable

  15. On-Study Data 5FU/FA GEM TOTAL n=551 n=537 n=1088 Diabetic No 388 (75%)375 (75%)763 (75%) Non-insulin dep54 (11%)51 (10%)105 (10%) Insulin dep72 (14%) 73 (15%)145 (14%) Surgery Whipples286 (56%) 295 (59%)581 (58%) Pylorus Pres 158 (31%) 147 (30%)305 (30%) Total Panc27 (5%)14 (3%) 41 (4%) Distal Panc40 (8%)39 (8%) 79 (8%) Local Invasion †No 297 (58%) 284 (57%)581 (58%) Yes 213 (42%) 215 (43%)428 (42%) Post-op Comps No 396 (78%) 364 (74%)760 (76%) Yes 112 (22%) 130 (26%)242 (24%)

  16. χ2LR = 31.8, p<0.001 χ2LR = 24.2, p<0.001 χ2LR = 52.7, p<0.001 χ2LR = 16.3, p<0.001

  17. Follow-Up

  18. 5-FU 425mg/m2 d1-d5 @28d for 6 cycles Total protocol 5FU=2,125mg/m2 per cycle, overall=12,750mg/m2 60 (11%) of 551 patients received NO 5FU/FA 301 (55%) of 551 patients received 6 cycles 5FU/FA Median total 5FU dose: 10,125mg/m2 (Range: 425-17,950) Median protocol 5FU dose: 79% (Range: 3-141%) GEMCITABINE 1000mg/m2 d1 @wk for 3/4 wks for 6 cycles Total protocol GEM=3,000mg/m2 per cycle, overall=1,8000mg/m2 53 (10%) of 537 patients received NO GEMCITABINE 323 (60%) of 537 patients received 6 cycles GEMCITABINE Median total GEM dose: 16,000mg/m2 (Range: 1,000-21,974) Median protocol GEM dose: 89% (Range: 6-122%) Treatment Received

  19. Reported Toxicity Number of patients with at least one NCI CTC v2. grade 3/4 event p=0.013 p=0.94 p=0.0034* p=0.37 p=0.34 p<0.001* p=1.0 p=0.16 p<0.001* p=0.027 * Exploratory analysis: sig level p<0.005 using Bonferroni adjustment

  20. Serious Adverse Events 612 patients reported 892 SAE 304 5FU/FA patients reported 458 SAE 308 GEM patients reported 434 SAE 117 (11%) patients reported 149 Treatment Related SAE 77 (14%)* 5FU/FA patients reported 97 SAE 40 (7.5%)* GEM patients reported 52 SAE *Exploratory analysis: Fishers Exact test p<0.001

  21. Overall Survival Median S(t)= 23.2 months (95%CI:21.7, 24.9)

  22. Survival by Treatment Median S(t)= 23.0 months (95%CI:21.1, 25.0) Median S(t)= 23.6 months (95%CI:21.4, 26.4) c2LR=0.74, p=0.39, HRGEM VS 5FU/FA=0.94 (95%CI: 0.81, 1.08)

  23. Treatment Effect by R-Status

  24. Adjusted Treatment Effect Treatment effect adjusted by Stratification Factors at randomisation: R-Status and Country Frailty Model: Country, p=0.61 (random effect) R-Status, p<0.001 (fixed effect) Treatment, p=0.36, HR=0.94 (9%%CI: 0.81, 1.08)

  25. PFS by Treatment Median PFS(t)= 14.1months (95%CI:12.5, 15.3) Median PFS(t)= 14.3months (95%CI:13.5, 15.7) c2LR=0.59, p=0.44, HRGEM VS 5FU/FA=0.95 (95%CI: 0.83, 1.09)

  26. Conclusions No difference in survival between adjuvant gemcitabine and 5-FU/FA in patients with resected pancreatic cancer The safety profile of gemcitabine was better than that of 5-FU/FA Data reinforce the perfect design of the ESPAC-4 trial comparing gemcitabine with the combination of gemcitabine with capecitabine

  27. Acknowledgements Cancer Research-UK Fonds de Recherche de la Société Nationale Française de Gastroentérologie Ministero Università e Ricerca Scientifica e Tecnologica, Rome; Associazione Italiana Ricerca Cancro Health and Medical Research Council of Australia National Cancer Institute of Canada

  28. Leading ESPAC Contributors JP Neoptolemos, P Ghaneh, DD Stocken, D Smith, D Cunningham, D Goldstein, R Padbury, M Moore, S Gallinger, C Mariette, M Wente, M Lerch, H Friess, J Izbicki, C Dervenis, A Olah, G Butturini, R Doi, P Lind, J Valle, C Rawcliffe, C McKay, R Carter, D Palmer, J Buckels, C Bassi and M Büchler

  29. UK Contributors F Adab, DJ Adamson, A Anthoney, C Archer, C Askill, CA Baughan, S Bramhall, J Bridgewater, J Buckels, R Carter, F Campbell, R Charnley, I Chau, MJ Churn, PI Clark, P Corrie, F Coxon, T Crosby, D Cunningham, F Daniel, BR Davidson, J Dent, M Eatock, TRJ Evans, S Falk, D Ferry, D Furniss, D Fyfe, P Ghaneh, S Gollins, P Harper, MN Hartley, AB Hassan, R Hawkins, D Haylock, M Highley, M Hill, CW Imrie, T Iveson, A Jamil, C Johnson, P Johnson, A Kingsnorth, R Kulkarni, JA Ledermann, PC Leonard, F Lofts, S Madhusudan, U Mallick, A Maraveyas, E Marshall, TS Maughan, K Mcadam, CJ McKay, A Mcdonald, T Meyer, M Middleton, G Middleton, S Mukherjee, P Mulvenna, M Napier, BT Orr, R Osborne, MJ Ostrowski, D Palmer, S Pascoe, T Plunkett, D Propper, P Ross, M Seymour, A Shaukat, D Smith, S Sothi, D Spooner, W Steward, DD Stocken, R Sutton, S Tahir, J Thompson, AR Todd, E Toy, G Ullenhag, J Valle, C Verbeke, N Wadd, J Wadsley, L Wall, N Warner, H Wasan, J Waters and C Wilson ISDMC – R A’Hern, P Clark and RCG Russell

  30. European Contributors Czech Republic: M Ryska and Dr R Strnad Finland: I Nordback, T Salminen and J Sand France: A Champault, PR Chiche, B Derousseaux, C Dilin, B Dousset, A Elhadad, A Fingerhut, Y Flamant, F Lacaine, C Mariette, O Oberlin, V Pannegeon, JM Regimbeau, Di Rio, B Sastre and MS Sbai-Idriasy Germany: WE Aulitzky, MW Buchler, A Chromik, I Esposito, A Finke, H Friess, A Frilling, P Herzog, D K Hossfeld, JR Izbicki, R Klapdor, G Leder, M Lerch, K Link, F Lordick, J Mayerle, B Rau, P Schafhausen, K Schoppmeyer, J Stohlmacher, M Wente and PD Werner Greece: C Dervernis and E Chatzitheoklitos Hungary: D Kelemen, A Olah and A Pap Italy: C Bassi, G Butturini, P Pederzoli and S Pedrazzoli Poland: W Polkowski Serbia: M Milicevic and D Radenkovic Sweden: A Berglund, N Bjorkman, C Bratthall, B Glimelius, MG Johansson, BM Karlsson, P Lind, P Naredi, P Nygren, J Permert LB Rasmussen and A Thune Switzerland: J Kleeff and M Wagner

  31. Canada, Australia, New Zealand and Japan Contributors Canada: T Alcindor, HJ Au, G Batist, E Bergeron, S Berry, G Bjarnason, J Blondal, C Butts, E Chen, S Cheng, B Colwell, C Cripps, P Czaykowski, B Dingle, M Doreen, R Feld, A Fields, C Fitzgerald, S Gallinger, A Haq, D Hedley, D Jonker, P Kavan, I Kerr, K King, J Knox, Y Ko, S Koski, M Krahn, M Krzyzanowska, W Lofters, A Maksymiuk, J Maroun, M Moore, C O'Callaghan, A Oza, S Rao, D Rayson, A Saltman, B Samson, M Sanatani, A Scarfe, L Siu, N Spry, A Tomiak, K Virik , B Weinerman, M Wexler, R Wong and L Wood Australia: E Abdi, S Ackland, M Brown, WI Burns, I Byard, P Cooray, R Eek, V Ganju, D Goldstein, D Grimes, A Haydon, C Karapetis, P Kho, F Kirstan, B Koczwara, D Kotasek, D Leong, L Lipton, G Marx, SA Mclachlan, E Moylan, IN Olver, R Padbury, F Parnis N Paulakis, D Pook, T Price, J Shannon , J Shapiro, B Stein, N Tebbutt, C Underhill, G Van Hazel, D Wyld, D Yip and R Young New Zealand: P Bagshaw, D Gibbs, S Connor, M Jeffrey and B Robinson Japan: T Asano, R Doi, A Funakoshi, A Funakoshi, T Hatori, S Nakamori, M Sunamura, K Takasaki and K Yamaguchi

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