The document discusses the management of liver metastases from colorectal cancer. It reports on a study that found perioperative chemotherapy with FOLFOX4 improved progression-free survival in patients with resectable liver metastases, especially in those whose metastases were resected. The study established perioperative chemotherapy as the new standard of care for these patients. It also discusses challenges in treating colorectal cancer patients with only liver metastases and strategies for increasing resection rates and long-term survival, including optimizing systemic therapies and utilizing a multidisciplinary team approach.

1. ADVANCED COLON CANCER: MULTIDISCIPLINARY MANAGEMENT OF LIVER METASTASES Andrés Cervantes BALKAN MASTERCLASS IN CLINICAL ONCOLOGY Dubrovnik, 13 May 2011

3. Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver metastases from colorectal cancer Final efficacy results of the EORTC Intergroup phase III study 40983. B. Nordlinger , H. Sorbye, B. Glimelius, G.J. Poston, P.M. Schlag, P. Rougier, W.O. Bechstein, J. Primrose, E.T. Walpole, T. Gruenberger Statistical analysis L. Collette For the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCD ALM CAO AGITG g

4. Study design Randomize Surgery FOLFOX4 FOLFOX4 Surgery 6 cycles (3 months) N=364 patients 6 cycles (3 months)

5. Patient Flow Patient flow Informed consent Randomized: 364 Pre&Postop CT 182 Surgery 182 Ineligible 11 11 Started pre-op CT 171 Resected 152 Resected 151 Started post-op CT 115 Resectable on imaging Resectable at surgery

6. Progression-free survival in eligible patients HR= 0.77 ; CI: 0.60-1.00, p=0.041 Periop CT 28.1% 36.2% +8.1% At 3 years (years) 0 1 2 3 4 5 6 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : 125 171 83 57 37 22 8 115 171 115 74 43 21 5 Surgery only

7. Progression-free survival in resected patients HR= 0.73 ; CI: 0.55-0.97, p=0.025 Surgery only Periop CT 33.2% 42.4% +9.2% At 3 years (years) 0 1 2 3 4 5 6 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : 104 152 85 59 39 24 10 93 151 118 76 45 23 6

10. Unresectable liver metastases: 20–25% long-term survival after induction chemotherapy and resection Colon Cancer Collaborative Group. BMJ 2000;321:521–522 Tournigand C, et al. J Clin Oncol 2004;22:229–237; Adam R, et al. Ann Surg 2004;240:644–658 --- BSC — 5-FU — FOLFIRI/FOLFOX6 --- FOLFOX6/FOLFIRI — Resectable liver metastases — Resectable after chemotherapy 48% 30% 23% 33% 20 40 60 80 100 0 1 3 4 2 5 6 8 9 7 10 Time (years) Survival (%) 0

11. Overall Survival for patients with mCRC treated at MDACC and Mayo Clinic by year of diagnosis 2470 patients included in the registry in two highly specialized Centers In the last decade, overall survival in mCRC patients improved substantially Kopetz S et al, J Clin Onc 2009;27:3677-3683

13. Resection is significantly associated with response Response 0,9 0,8 0,7 0,6 0,5 0,4 0,3 Resection rate 0,6 0,5 0,4 0,3 0,2 0,1 0 Liver metastasis only All patients Folprecht G, et al. Ann Oncol 2005;16:1311–1319

14. Downsizing after chemotherapy: A role for surgery?

15. Doublet or triplet chemotherapy? >22 32 69 47 FOLFOXIRI Abad - 82 (27 b ) 71 34 FOLFIRINOX Ychou, Quenet 25.4 23 78 30 OCFL alternating Seium 36.8 a 26 72 74 FOLFOXIRI Masi 26 40 60 42 FOLFOX4 Alberts 31.5 33 48 40 FOLFIRI Barone, Pozzo Survival (months) Resection rate (all pts) (%) Response rate (%) n Regimen Study Barone C, et al. Br J Cancer. 2007;97:1035–1039; Alberts SR, et al. J Clin Oncol 2005;23:9243–9249; Masi G, et al. Ann Surg Oncol 2006;13:58–65; Falcone A, et al. J Clin Oncol 2007;25:1670–1676; Seium Y, et al. Ann Oncol 2005;16:762–766; Ychou M, et al. Can Chemother Pharmacol 2008;62:195–20; Abad A, et al. Acta Oncol 2008;47:286–292 a Subpopulation of patients who were resected. b Confirmed R0 resections Doublets Triplets 22.6 16.7 15 b 6 b 60 34 122 122 FOLFOXIRI FOLFIRI Falcone Randomized

16. Triple combination: FOLFOXIRI Falcone A et al. J Clin Oncol 2007

17. Bevacizumab in advanced CRC: ORR from randomized trials IFL XELOX/FOLFOX FOLFOX p=0.004 p=0.99 p<0.0001 Hurwitz et al. NEJM 2004 Saltz et al. JCO 2008 Giantonio et al. JCO 2007 50 40 30 20 10 0 Bevacizumab Placebo Bevacizumab Placebo Bevacizumab ORR (%) First-line Second-line

18. CRYSTAL - Response rates increase in patients with liver-limited disease FOLFIRI Cetuximab + FOLFIRI KRAS wild-type Response rate (%) Liver-limited disease 17% 37% Cetuximab + FOLFIRI Van Cutsem E, et al. ASCO GI 2010(Abstract No. 281) ; *Van Cutsem E, et al. Ann Oncol 2008;19(Suppl. 8):viii4 [update to 710] p<0.0001 *

19. CRYSTAL - Cetuximab increases R0 resection rate in patients with liver-limited disease Liver-limited disease cohort from ITT population Van Cutsem E, et al. Ann Oncol 2008;19(Suppl. 8):viii4 [update to 710]; Van Cutsem E, et al. Eur J Cancer Suppl. 2007;5:235(Abstract No. 3001) (updated information presented) 4.5 9.8 0 1 2 3 4 5 6 7 8 9 10 FOLFIRI (n=134) Cetuximab + FOLFIRI (n=122) R0 resection rate (%)

20. OPUS - Cetuximab increases R0 resection rate R0 resection rate Bokemeyer C, et al. J Clin Oncol 2009;27:663–671 ITT population KRAS wt 4.1 9.8 Cetuximab + FOLFOX4 2.4 4.7 0 1 2 3 4 5 6 7 8 9 10 Patients (%) FOLFOX4 Cetuximab + FOLFOX4

21. CELIM: Study design Randomization Primary endpoint: Response rate Patients with unresectable mCRC (technically unresectable / ≥ 5 liver metastases) or CRC without extrahepatic metastases Biopsy EGFR screening FOLFOX6 + Cetuximab FOLFIRI + Cetuximab Therapy: 8 cycles (~4 months) Folprecht G, et al. Lancet Oncol 2010;11:38–47 Retrospectively: Blinded surgical review Evaluation of resectability Technically resectable Technically unresectable 4 further treatment cycles Resection Therapy continuation for 6 cycles (~3 months)

22. CELIM: High response and liver resection rates in patients with KRAS wt tumors RFA=radio frequency ablation Folprecht G, et al. Lancet Oncol 2010;11:38–47 Response rate Patients (%) 79 R0 resection rate 0 10 20 30 40 50 60 70 80 33 Patients (%) R0/R1/RFA resection rate 46 0 10 20 30 40 50 60 70 80 Patients (%) 46

23. mCRC with only liver disease Resectable 10–20% Non–resectable 80-90% Challenges in patients with mCRC and only liver disease Modified from Renè Adam Increasing resectability Optimizing systemic treatment

24. mCRC with only liver disease Increasing NED status 40-50% Modified from Renè Adam Challenges in patients with mCRC and only liver disease Expanding indications Resectable 20-30% Specific techniques Non–resectable 60-70% Optimizing systemic treatment Increasing RR / Shrinkage Salvage surgery

25. The multidisciplinary team Surgeon Oncologist Histopathologist Collaboration is essential from diagnosis onwards “ Strategic choices determine the therapeutic options” Expert discussion at ESMO/WCGIC June 2009, Barcelona Radiologist Nurse