Liver Metastases in Colorectal Cancer: Current and Emerging Approaches to Treatment

1. Liver Metastases in Colorectal Cancer: Current and Emerging Approaches to Treatment Ali Shamseddine ,MD Professor of Medicine AUBMC

2. Summary of Therapy for Initially Resectable Disease Use of chemotherapy appears to enhance outcomes achieved with surgery Adjuvant chemotherapy Perioperative chemotherapy Adjuvant hepatic artery infusion chemotherapy combined with systemic chemotherapy

3. Managing Liver Metastases in Colorectal Cancer: Key Issues Defining “resectability” Role of chemotherapy Resectable patients Initially nonresectable patients Optimal chemotherapy regimen Role of targeted therapy Treat to best response or resectability? Multidisciplinary approach

4. Liver Metastases in Colorectal Cancer: Outcomes Liver Metastases Location Nonresectable75% to 80% Resectable20% to 25% Number Size Downsizing Survival Benefit 30% to 40% at 5 years 15% at 10 years Resectable10% to 20%

5. Changing Definition of Resectability Old: What must come out? New: What will stay in? • How many metastases? • 4 < lesions, with unilobar location, resectable • How large? • < 5 cm resectable • Extrahepatic disease? • If none, resectable Can R0 resection (negative margins) be achieved? Can two contiguous liver segments be preserved? Can adequate future liver remnant (>20%) be preserved? Charnsangavej C, et al. Ann Surg Oncol. 2006; 13:1261-1268.

6. Role of Chemotherapy for Resectable Disease One adjuvant systemic chemotherapy versus surgery alone One peri-operative trial Hepatic artery infusion therapy

7. Adjuvant Therapy: AURC 9002 5-FU + LV days 1-5 every 4 weeks x 6 Surgery R • 171 patients • Resected liver metastases • 95% had 3 or fewer • Goal: Improved DFS Surgery Portier, G. et al. J Clin Oncol 2006; 24:4976-4982.

8. Disease-free Survival After Liver Resection 100 Chemotherapy No chemotherapy 90 80 GroupMedian DFS Surgery 17.6 months Chemotherapy 24.4 months (p=0.028) 70 60 50 Survival (%) 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Months Portier, G. et al. J Clin Oncol; 2006;24:4976-4982.

9. EORTC 40983 (EPOC Trial) 364 patients randomized Potentially resectable (≤ 4 liver metastases) Goal: Improve PFS Interim objective: Evaluate tumor response to perioperative CT Perioperative CT (n = 182) 159 (87.3%) underwent surgery 151 (83.0%) resected Surgery (n=182) 170 (93.4%) underwent surgery 152 (83.0%) resected FOLFOX4 x 6 cycles FOLFOX4 x 6 cycles Surgery R Surgery Nordlinger B, et al. ASCO 2007 Abstract LBA5

10. EORTC 40983: Progression-Free Survival in Resected Patients HR= 0.73; CI: 0.55-0.97, p=0.025 100 90 +9.2%At 3 years 80 Periop CT 70 60 50 42.4% 40 Surgery only 30 33.2% 20 10 0 0 1 2 3 4 5 6 (years) Nordlinger B, et al. ASCO 2007 Abstract LBA5

11. Hepatic Artery InfusionMemorial Sloan-Kettering Randomized Study 156 patients randomized Initial resection of liver metastases Systemic 5-FU/CF4 wks post-surgery+HAI FUDR + DEX2 wks later for 2 wks; 1 wk rest (6 cycles) R Systemic 5-FU/CFq 4 wks (6 cycles) Kemeny N, et al. N Engl J Med. 1999;341:2039-2048

12. HAI Versus Systemic Therapy Alone: Long-term Follow-up* 1.0 0.8 Combined therapy 0.6 Proportion surviving 0.4 Monotherapy 0.2 0 0 50 100 150 Months after resection Kemeny N, et al. N Engl J Med. 2005;352:734.

13. Meta-analysis of two phase III trials: FFCD 9002 and EORTC/NCIC CTG/GIVIO Mitry et al, ASCO 2006

14. Summary of Therapy for Initially Resectable Disease Use of chemotherapy appears to enhance outcomes achieved with surgery Adjuvant chemotherapy Perioperative chemotherapy Adjuvant hepatic artery infusion chemotherapy combined with systemic chemotherapy

15. Randomized phase III trial comparing infused 5-fluorouracil/folinic acid (LV5FUs) versus LV5FUs+irinotecan (FOLFIRI) as adjuvant treatment after complete resection of liver metastases from colorectal cancer (LMCRC)CPT-GMA-301* M. Ychou, W. Hohenberger, S. Thezenas, M. Navarro, P. Gascon, C. Bokemeyer, E. Shacham-Shmueli, F. Rivera, C. Kwok-Keung Choi, A. Santoro * Sponsored by Pfizer

16. Disclosure Slide Yes, I have Honoraria to disclose. Amgen,Merck, Roche, Pfizer Yes, I have Research Funding to disclose. Merck, Roche, Sanofi-Aventis, Pfizer

17. Meta-analysis of two phase III trials: FFCD 9002 and EORTC/NCIC CTG/GIVIO Mitry et al, ASCO 2006

18. Study design R FA 2 hrs. IV 400mg/m2(200 if Lform) 5-FU bolus 400 mg/m2 5-FU CI 46 hrs. 2400 mg/m2 LV5FUs and FA 2 hrs. IV 400mg/m2(200 if Lform) 5-FU bolus 400 mg/m2 5-FU CI 46 hrs. 2400 mg/m2 and FOLFIRI Irinotecan30-90 min. IV180 mg/m2 • Every two weeks • Chemotherapy will be administered for a total of 12 cycles (6 months) except in case of unacceptable toxicity, progression or consent withdrawal.

19. Stratification factors A. Number of liver metastases 1 vs. 2-4 vs. 5+ B. Prior adjuvant chemotherapy Yes / No C. Delay between resection of primary tumour and diagnosis of liver metastasis  1 year / >1 year

20. Main eligibility criteria - 1 Histologically proven adenocarcinoma of the colon or rectum with complete resection of primary tumour. Complete surgical resection (R0) of the liver metastasis(es) within a minimum of three weeks, and a maximum of 8 weeks prior to the first study treatment infusion.   Prior adjuvant chemotherapy for the primary tumour allowed except Irinotecan based combination, with the last dose given at least six months before the first infusion of study treatment.

21. Main eligibility criteria - 2 18 < Age < 75. WHO PS < 2. Exclusively hepatic metastasis (es) No prior hepatic resection and no prior radiofrequency ablation or cryoablation No prior chemotherapy for metastatic disease.

22. Endpoints Primary Disease-Free Survival (DFS): time from randomization to local or regional recurrence, metastasis, or death due to cancer Secondary Safety Overall Survival

23. Sample size Initial hypothesis (data from Kemeny et al. 1999) Expected median DFS LV5FUs: 32.4 months FOLFIRI: 55.4 months  HR=0.58 128 DFS events and 420 patients ( = 0.05,  = 15% ) • Protocol amendment (may 2006) • Expected median DFS • LV5FUs: 19.0 months • FOLFIRI: 29.7 months  HR=0.64 • 147 DFS events and 320 patients

24. Results 321 patients from 16 countries (66 centers) 54 month accrual from 12/2001 to 07/2006 15 patients non treated 8 consent withdrawal 4 progressive disease before treatment 2 too long delay after surgery 1 neutropenia before treatment 1 patient randomised to LV5FUs received FOLFIRI 42 months median follow-up

25. Patient characteristics

26. Surgical Procedures

27. Treatment administration

28. Safety results

29. Survival Status

30. Disease-Free Survival 1-year DFS: 63% vs. 77% 2-year DFS: 46% vs. 51%

31. Multivariate analysis (Cox)

32. Delay to start CT from surgery Disease-Free Survival Treatment 42 days from surgery HR=1.07: 95%CI [0.71-1.63] 1.00 0.75 Probability 0.50 0.25 p=0.75 0.00 0 12 24 36 48 Months Number at risk LV5FUs 73 47 31 17 9 FOLFIRI 75 51 29 15 0 LV5FUs FOLFIRI

33. Conclusion 1 No difference was observed in DFS between the 2 arms, adjusted or not for important prognostic factors The safety profile of both treatment regimens was as expected Lower relative dose intensity of 5FU and FA was observed in the combination arm

34. Conclusion 2 We cannot exclude a positive effect of FOLFIRI if chemotherapy starts before 6 weeks after surgery No bitherapy has yet been proven superior to 5FU alone even in peri-operative way (FOLFOX was compared to surgery alone in EORTC trial 40983) We urgently need large trials in this setting integrating tailored chemotherapy and targeted therapies

35. ACKNOWLEDGEMENTS All the patients participating in this trial and their families All the investigators from the following countries (nb pts): France (79), Germany (61), Spain (43), Korea (31), Italy (26), Israël (18), Hong-Kong (9), Sweden (9), Belgium (8), Denmark (7), United-Kingdom (7), Ukraine (7), Switzerland (6), Portugal (4), South-Africa (4), Taiwan (2).