EORTC Tumor response to pre-operative chemotherapy (CT) with FOLFOX-4 for resectable colorectal cancer liver metastases (LM) Interim results of the EORTC Intergroup randomized phase III study T. Gruenberger*, H. Sorbye, M. Debois, U. Bethe, J. Primrose, Ph.Rougier, D. Jaeck, M. Finch-Jones, E. Van Cutsem, B.Nordlinger, For the EORTC GI, CRC, ALMCAO, AGITG and FFCD *University Hospital, Dept. General Surgery, HPB Service,Vienna, Austria

EORTC After resection of liver metastases 5 year- survival is 30% Recurrence of disease occurs in about 70% The benefit of combining surgery and chemotherapy is not yet formally proven Background

EORTC Objectives Objective of the study Improve progression-free survival with peri-operative CT with Oxaliplatin and LV5FU2 as compared to surgery alone Objective of this analysis To evaluate tumor response to pre-operative CT and to determine if CT induces a tumor size reduction The safety and feasibility of the regimen were already reported (ASCO ’05)

EORTC Potentially resectable liver metastases of CRC (metachronous or synchronous) No extra-hepatic disease No previous chemotherapy with oxaliplatin Informed consent Main Eligibility Criteria

EORTC Study Design

EORTC LV5FU2 + Oxaliplatin 1 Cycle: 15 Days Chemotherapy Regimen

EORTC Patient Population Age: median 62.5 y (range: 25-79) 1-3 liver metastases on CT-scan: 92.3% < 2yrs between diagnosis of primary cancer and diagnosis of liver mets: 74.7% T0-2: 17.6%, T3-4: 80.8%, Tx: 1.6% N0: 42%, N1: 37.4%, N2: 18.4%, Nx: 2.2%

EORTC Chemotherapy Pre-op CT (N=182) N (%) # cycles 09 (4.9) <=315 (8.2) 47 (3.8) 56 (3.3) 6141 (77.5) unknown4 ( 2.2) Median6.0 Pre-op CT (N=173) N (%) Cycles with reduced dose (71.1) 1 40 (23.1) 2 9 ( 5.2) 3 1 ( 0.6) Delayed cycles 0 97 (56.1) 1 52 (30.1) 2 17 ( 9.8)  3 7( 4.1)

EORTC Largest diameter of the largest lesion  of largest lesion (mm) Peri-op CT (N=182) Baseline(N=176) Median33 mm Q1-Q325 mm – 50 mm Range5 mm – 170 mm After preop CT(N=144) Median24 mm Q1-Q314 mm to 40 mm Range0 mm to 170 mm on imaging

EORTC Change in the largest diameter of the largest lesion Shrinkage of diameter of the largest lesionPeri-op CT Absolute change (mm) Median- 8 mm Q1-Q3-17 mm to -1 mm Range-70 mm to +62 mm Nb of patients with largest lesion >50 mm N (%) At baseline40 (22.0%) After CT24 (13.2%)

EORTC Change in the SUM of the largest diameter of the lesions Sum of largest  of lesions (mm) Peri-op CT (N=182) Baseline(N=176) Median45 mm Q1-Q330 to 74 Range5 to 255 After preop CT(N=145) Median30 mm Q1-Q315 to 55 Range0 to 230 Overall lesion size shrinkagePeri-op CT Absolute change (mm)* (N=143) Median-13 mm Q1-Q3-25 to -3 Range-85 to +160 Relative change* (%) (N=143) Median-29.7% Q1-Q3-52.9% to -6.7% Range-100% to % * Change in the SUM of largest  of lesions (mm)

EORTC Response to Chemotherapy (RECIST) Complete response: 6 (3.3%) Partial response: 64 (35.2%) Stable disease: 61 (33.5%) Progressive disease: 14 (7.7%) Not available: 37 (20.3%) 182

EORTC Surgery Peri-op CT (N=182) Surgery (N=182) Operated158 (86.8)167 (91.8) Resected151 (83.0)149 (81.9) Not operated due to PD due to refusal or toxicity due to other reason 21 (11.5) 7 9 (4.9) Unknown if operated3 (1.6)6 (3.3)

EORTC Pathology Peri-op CT Surgery SUM of largest  of lesions on pathology specimen (mm) Median Q1-Q3 Range 33.5 mm mm 30 – 69 0 – 307  of largest lesions on pathology specimen (mm) Median Q1-Q3 Range 25 mm mm 24 – 50 0 – 300

EORTC Conclusions 1. CT-scan measurements were consistent with the measurements performed at pathological examination 2. Pre-op CT with 6 cycles of FOLFOX4 decreased the diameter of lesions 3. Since size of metastases at the time of surgery is a known prognostic factor for survival, there is hope that pre-op FOLFOX4 may improve survival 4. The trial results regarding progression-free and overall survival will become available at the end of 2006