IFCT-0002 : Early results (ASCO 2007)
Transcription
IFCT-0002 : Early results (ASCO 2007)
IFCT-0002 : Early results (ASCO 2007) Phase III Study Comparing a Preoperative (PRE) and a Perioperative (PERI) Chemotherapy with Two Different CT Regimens in Resectable Non-small Cell Lung Cancer (NSCLC): Early Results (IFCT 0002) B. Milleron, E. Quoix, V. Westeel, M. Puyraveau, D. Braun, J.L. Breton, L. Bigay-Game, J.L.Pujol, F. Morin, A. Depierre, On Behalf of the “Intergroupe Francophone de Cancérologie Thoracique” IFCT-0002 : Early results (ASCO 2007) Rationale (1) Cisplatin-based adjuvant chemotherapy Pignon JP et al, J Clin Oncol 2006; 24 , 18S Part I of II : 366s IFCT-0002 : Early results (ASCO 2007) Rationale (2) Meta-analysis Group, MRC Clinical Trials Unit S Burdett et al, Journal of Thoracic Oncology • Volume 1, Number 7, September 2006 IFCT-0002 : Early results (ASCO 2007) End Points Main objective : to define the best timing of CT (all before surgery (PRE) versus perioperative (PERI), Secondary objectives : To compare response rates with CDDP -GEM and CBDCA-PAC, To compare CDDP-GEM- and CBDCA-PAC toxicity , To compare TTP and sites of relapse in each arm, To compare quality of life, To assess predictive and pronostic factors with biological markers. IFCT-0002 : Early results (ASCO 2007) CDDP-GEM (A, B) Study design CADDP-PAC (C, D) Week 1 3 Arm PRE (A+C) Cycle 1 Cycle 2 Arm PERI (B-D) 6 7 E V A L U A T I O N GEM : 1250 mg/m2, J1-J8 CDDP : 75 mg/m2, J1 PAC : 200 mg/m2, J1 CADDP : AUC 6, J1 9 11 Cycle 3 + Cycle 4 (in responders) Surgery Surgery Cycle 3 + Cycle 4 (in responders) IFCT-0002 : Early results (ASCO 2007) Statistical considerations Open, multicentric, randomized study, Stratification by center, histology, clinical stage, Comparison of overall survival in arms PRE (A+C) vs PERI (B+D), Benefit expected for 3-year survival rate in the PRE arms : 20%, (60 to 72%), 522 patients (alpha 5 % and beta 20 %), Interim analyses planned after inclusion of 175 and 350 patients. IFCT-0002 : Early results (ASCO 2007) Inclusion criteria Histological or cytological proof of NSCLC, cTNM stage : I or II, With at least 1 mesurable or evaluable lesion, OMS ≤ 2, Age ≤ 75 years, Fit to receive chemotherapy, Written informed consent. Exclusion criteria Mediastinal lymph nodes ≥ 1 cm, Previous history of cancer, Creatinine ≥ 120 µol/l, PNN < 1500 /mm3, Platelets < 100 000 / mm3, Bilirubine > 25 µol/l, Peripheral neuropathy. IFCT-0002 : Early results (ASCO 2007) Early Results (at 21 weeks) Efficacy : Clinical response, Pathological response (PCR, tumoral necrosis, lymphatic and vessels invasion) : In PRE and PERI arms, In GEM-DDP and PAC-CADDP arms. Tolerance of treatment : Toxicity of chemotherapy, Feasibility of surgery and adjuvant chemotherapy, Post-operative mortality. IFCT-0002 : Early results (ASCO 2007) Patients Characteristics Total (%) Arm A Arm B Arm C Arm D Sex M/F 427/101 (80.9) 114/20 108/24 101/32 104/25 Stage IA 92 (17.4) 20 27 22 23 IB 248 (47) 55 64 73 56 IIA 21 (4) 7 7 3 4 IIB 150 (28.4) 48 31 31 40 Other (ineligible) 17 (3.2) 4 3 4 6 0 419 (79.4) 102 107 102 108 1 106 (20.1) 31 24 31 20 2 3 (0.6) 1 1 0 1 Squamous 231 (43.7) 58 59 57 57 Adenocarcinoma 201 (38.1) 57 51 46 47 Other 96 (18.2 19 22 30 25 PS Histology IFCT-0002 : Early results (ASCO 2007) Pre vs Peri results : 1- Chemotherapy compliance N° cycle % of patients receiving cycles p PRE PERI (CDDP-GEM and CADDP-PAC) (CDDP-GEM and CADDP-PAC) 1 and 2 96.6 93.8 ns 3 and 4 (responders only) 90.4 75.2 0.0011 PRE: cycles 3-4 administered before surgery PERI: cycles 3-4 administered after surgery IFCT-0002 : Early results (ASCO 2007) Pre vs Peri results (2) Surgery Total (%) PRE PERI (CDDP-GEM and CADDP-PAC) (CDDP-GEM and CADDP-PAC) N 528 267 261 Lobectomy 354 (67.0) 182 (68.1) 172 (65.9) Pneumonectomy 115 (21.7) 54 (20.2) 61 (23.3) Other 36 (6.8) 19 (7.1) 17 (6.5) No surgery 21 (4) 10 (3.7) 11 (4.2) IFCT-0002 : Early results (ASCO 2007) Pre vs Peri results (3): Toxicity PRE PERI (CDDP-GEM and CADDP-PAC) (CDDP-GEM and CADDPPAC) p Grade III-IV Toxicity % cycles % patients % cycles % patients Neutropenia 31.5 41.2 30.4 36 ns Febrile neutropenia 1.3 3.7 1.3 3.7 ns Thrombopenia 4.3 10.5 6.9 11.5 ns Nausea/Vomiting 1.6 3.7 2.2 5 ns 11.7 ns Neuropathy at 6 months (all grades) 12.2 Mortality Pre-operative /chemo mortality (%) 2/1 (0.74 /0.37) 2/0 (0.76 /0) ns Post-operative mortality (%) 8 (3 ) 8 (3.1 ) ns IFCT-0002 : Early results (ASCO 2007) Pré vs Peri results (4): Pathologic results Total PRE PERI (CDDP-GEM and CADDP-PAC) (CDDP-GEM and CADDP-PAC) p pT0N0 38 22 (8.6) 16 (6.4) ns Peri T vascular invasion 36 20 (7.8) 16 (6.4) ns Peri T lymphatic invasion 84 41 (16) 43 (17.2) ns Visceral pleura involvement 106 54 (21) 52 (20.8) ns Necrosis 264 126 (49.6) 138 (55.6) ns IFCT-0002 : Early results (ASCO 2007) DDP-GEM vs CADDP-PAC Clinical (after 2 cycles) an Pathological Response Total (%) CDDP-GEM (%) CADDP-PAC (%) n 528 266 262 CR 14 (2.6) 10 (3.8) 4 (1.5) PR 254 (48.1) 129 (48.5) 125 (47.7) OR 268 (50.7) 139 (52.3) 129 (49.2) NC 223 (42.6) 111 112 PD 17 (3.2) 5 12 NE 20 (3.8) 11 9 pT0N0 38 17 21 IFCT-0002 : Early results (ASCO 2007) DDP-GEM vs CADDP-PAC (2) : Chemotherapy compliance % of patients receiving cycles N° cycle p CDDP-GEM CADDP-PAC 1 and 2 93.2 97.3 ns 3 and 4 (responders only) 79.9 86 ns IFCT-0002 : Early results (ASCO 2007) DDP-GEM vs CADDP-PAC (3) : Toxicity (WHO grade 3-4) CDDP-GEM CADDP-PAC p % cycles % patients % cycles % patients Neutropenia 28.9 36.1 33 41.2 ns Febrile neutropenia 1.7 4.1 1 2.7 ns Thrombopenia 9.7 18.4 1.4 3.4 0.0001 Nausea/Vomiting 3.4 7.5 0.4 1.1 0.0003 19 <0.0001 Neuropathy at 6 months (all grades) 5.1 IFCT-0002 : Early results (ASCO 2007) DDP-GEM vs CADDP-PAC (4) Relation between response, chemotherapy, stage and histology Factors Group Stage Histology Odds Ratio GEM-DDP 1 PAC-CAR 0.846 I 1 Other 1.081 Squamous 1 Other 0.263 95% CI p 0.589-1.216 0.3669 0.740-1.581 0.6865 0.182-0.381 <0.0001 IFCT-0002 : Early results (ASCO 2007) Bio-IFCT 0002 Goals: to assess predictive and prognostic value of biological markers in IFCT 0002 cohort : Molecular markers, IHC putative markers of Chemo Resistance, 250 snap-frozen surgical post-chemo specimens (DNA and RNA extraction), 499 paraffin-embedded surgical post-chemo specimens. G. Zalcman (PI) and M Beau-Faller, E. Brambilla, MC Favrot, P. Hainaut, JC Soria PNES Poumon / National Program of Scientific Excellency- Lung IFCT-0002 : Early results (ASCO 2007) Conclusion Administration of four cycles of CT before surgery is feasible, Post operative mortality is low in both preoperative and perioperative arms, After 2 cycles of CT, compliance to 2 additional cycles in responders is better before than after surgery, No significant difference in terms of pathological response was observed after 2 or 4 cycles, Higher response rates were observed in squamous cell cancers than in other histological subtypes, Gemcitabine-Cisplatin and Paclitaxel-Carboplatine are effective and safe, with no difference in response rates but a different toxicity profile. IFCT-0002 : Early results (ASCO 2007) DEPIERRE A WESTEEL V Besançon MILLERON B LAVOLÉ A Paris - Tenon QUOIX E MENECIER B Strasbourg BRAUN D BRETON JL Briey Belfort CARLES P Toulouse PUJOL JL Montpellier OZENNE G Bois-Guillaume RIVIERE A Caen DOUILLARD JY LEBEAU B DEBIEUVRE D POUDENX M DAVID Ph DUCOLONE A LEBAS FX Nantes LEMARIÉ E Tours TANGUY B MONNET I Créteil VAYLET F SOUQUET PJ FOURNEL P St Denis La Réunion Clamart - Percy Lyon MENARD O Vandoeuvre Saint-Etienne OSTER JPh Colmar CREQUIT J Beauvais MAURY B Cholet DUHAMEL JP Harfleur FRIARD S Suresnes - Foch MORO-SIBILOT D Grenoble PEROL M Lyon JANICOT H HERMANN J Clermont-Ferrand Metz-Belle-Isle LEVEL MC OLIVIERO G Verdun Longjumeau PAILLOT N Metz THIBERVILLE L DANSIN E Lille GOUVA S Vesoul BENICHOU M Pau MONTCHATRE M Nice-CAC BLANCHON F Meaux AZARIAN R Versailles Marseille -CAC Paris - SaintAntoine Rouen Brest Ermont Elbeuf MORERE JF Bobigny VIALLAT JR Strasbourg MORNET M Bourges BOMBARON P ROSSIGNOLI N Mâcon LE GROUMELLEC A Vannes Le Mans COETMEUR D St Brieuc ZALCMAN G Caen - TREDANIEL J Paris - Saint-Louis HERMAN D Nevers RODIER JM LAUWERIER C Paris - Bichat St Omer TERRIOUX Ph Mulhouse Coulommiers