Surgery of colorectal metastasis in the Optimox 1 study. A GERCOR Study. N. Perez-Staub, G. Lledo, F. Paye, B. Gayet, M. Flesch, A. Cervantes, A. Figer, O. Bourges, T. André, A. de Gramont GERCOR Paris, France.

Abstract Background: Surgery of metastasis can cure approximately 20% of metastatic colorectal cancer (MCRC) patients. The Optimox 1 study achieved a response rate over 50% with FOLFOX therapy in patients (pts) with initially unresectable metastasis which allowed to perform surgery in a significant number of pts (JCO 2006). We report here the results in pts who underwent surgery of metastasis (met). Methods: From jan 2000 to june 2002, 620 previously untreated patients with unresectable metastasis were randomized between FOLFOX4 every two weeks until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). 98 pts (15.8%) were resected with a curative intent, 54 in arm A and 44 in arm B. Results: Patients characteristics were (arm A/B %): metachronous metastasis 19/23, liver met 85/93, lung met 20/20, other met 7/2, PAL < 3 ULN: 98/98, normal LDH: 51/50. 9% of pts achieved a complete response, 72.5% a partial response, 17% a stable disease. 86 pts had a single resection, 12 had a two-stage surgery. Four patients died in arm B. Fourteen pts who relapsed had a second surgery. Resection was radical (R0) for 72 pts (43 in arm A and 29 in arm B), 13 were R1 (margin invasion) and 12 were R2. R0/R1 patients had a median overall survival (OS) of 51 mo in arm A and 38 mo in arm B. Median disease-free survival (DFS) since surgery was 12 mo in arm A and 9 mo in arm B, with no statistical difference. 32% of R0/R1 pts were alive with no progression at 3 years in arm A and 20% in arm B. Median time from randomization to surgery was 8 mo. No difference was found between patients resected before 8 mo (n = 50) and after (n = 37) in OS (39 vs 45 mo, p = .67) nor in DFS (11.6 vs 9.5 mo, p = .24). Neither in pts resected before and after 6 mo in OS (p=.77) and DFS (p = .44). Conclusion: FOLFOX treatment allowed 14 % of unresectable patients to have R0 or R1 surgery of their metastases. There was no additional benefit to perform surgery after 6 months of therapy compared to early surgery.

INTRODUCTION Oxaliplatin-based chemotherapy induction strategy enable 10 - 15 % of liver colorectal metastatic patients to be secondarly resected (Adam et al, Ann Surg 2004). Long term survival can be reached with a 30 - 40 % 5-year survival rate for these patients (Adam et al, Ann Surg 2004). 5-year survival rate for patients with extra hepatic disease who can be resected is also 35% 98 patients initialy unresectable were resected with curative intent in the Optimox 1 study (Tournigand et al, JCO 2006).

Patients and Methods Inclusion criteria Optimox 1 study design Histologically proven colorectal cancer Unresectable metastases No prior CT except adjuvant CT if ended  6 months before study entry WHO PS  2 Adequate hematological, renal and liver functions < 80 years Evaluation after 4, 6 and then every 6 cycles

Optimox 1 surgery Patients Characteristics Folfox4 N = 54 Folfox7 N = 44 All N= 98 (%) Age 62 [36 - 79] 61 [48 - 77] 62 [36 - 79] Male/Female 23/31 25/19 48/50 (49/51) WHO PS 0/ 1-2 36/18 35/9 71/27 (72/28) Colon/Rectum/both 38/15/1 27/17/0 65/32/1 (66/33/1) Adjuvant CT 8 7 15 (15) Ph Alk ≤ 3/ > 3 UNL 53/1 43/1 96/2 (98/2) LDH N/ >UNL/uk 28/16/10 22/14/8 50/30/18 (52/30/18) CEA - N 21 14 35 (36) - < 10 UNL 16 19 35 (36) - 10 – 100 UNL 13 6 19 (19) - > 100 UNL 3 5 8 (8) - uk 1 0 1 (1)

Optimox 1 Surgery: Metastases at diagnosis Folfox4 N=54 Folfox7 N=44 All N= 98 (%) Synchro/Metachronous 44/10 33/10/1uk 77/20 (78,5/20) Nb of metastatic sites 1/ ≥2 48/6 34/10 82/16 (84/16) Metastases location Liver 46 41 87 (89) Lung 11 9 20 (20) Other: peritoneum/ 4 1 5 (5) ovary/ lymph nodes Median size (mm) 40 [5- 176] 45 [12 - 110] 40 [5 - 176]

Optimox 1 Surgery Response rate, delay, cycles number Folfox4 N = 54 Folfox7 N = 44 All N = 98 (%) Complete Response 4 5 9 (9%) Partial Response 39 32 71 (72.5%) Stable Disease 10 7 17 (17.5%) Progressive Disease 1 0 (1%) Median delay chemo-surg. 8 9 8.0 months N cycles [range] 12 [4 - 23] 13 [5 - 25] 12 [4 - 25] Median follow-up 30.8 months

Optimox 1 surgery Surgery characteristics (2) Folfox4 N = 54 Folfox7 N = 44 All N = 98 (%) One stage surgery 48 37 85/ 1NA (87/1) Two stages surgery 6 6 12 (12) New surgery after progression - 2nd 9 5 14 (14) - 3rd 1 2 3 (3) Resection - R0 43 29 72 (73,5) - R1 6 7 13 (13) - R2 5 7 12 (12) - NA 1 hepatocarcinoma 1 Post operative mortality 0 1 4 (4) 3 patients died after third surgery

Optimox 1 Surgery: Disease-free survival since R0-R1 surgery

Optimox 1 Surgery: Overall Survival since R0-R1 surgery

Optimox 1 Surgery: OS according to time to surgery

Optimox 1 Surgery: DFS according to time to surgery

Optimox 1 Surgery Conclusion