1. Bernard NORDLINGER M.D. Hôpital Ambroise Paré – Boulogne Assistance Publique Hôpitaux de Paris The multimodal treatment of liver metastases: FREQUENTLY ASKED QUESTIONS

2. Questions What is resectable? Chemotherapy before or after resection? Indications for immediate surgery? How to manage metastases which disappear from imaging? Does neoadjuvant chemotherapy increase the risks of surgery? Targeted agents before surgery for liver metastases ? Should all patients with liver metastases be considered for resection?

3. What is a resectable metastasis? Question

4. A resectable metastasis: a principle Complete resection of tumor is feasible Free resection clearance: R0 Preservation of hepatic vein(s) and portal pedicle to remnant liver Remnant liver parenchyma  25 % Resectability does not depend on the number of metastases

5. Resectable metastases Categories: - Easily resectable - More difficult to resect; need for specific skills - Resectable + RFA - Potentially resectable after response to chemotherapy - Unresectable and unlikely to ever be resected Do not deny the potential benefit of major liver resection; if local surgeon does not have the expertise,refer to an expert institution

6. Bilobar disease right lobectomy + RFA Complete local treatment with resection and radio frequency ablation

7. Message: Discuss all cases in multidisciplinary meetings

8. Question: Chemotherapy combined with surgery for resectable metastases: before or after?

9. Aim and design Demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone R a n d o m iz e SurgeryFOLFOX4 Surgery 6 cycles (3months) N=364 patients 6 cycles (3 months) FOLFOX4 Main Eligibility criteria Potentially resectable liver metastases of colorectal cancer Up to 4 deposits (on CT-scan, at randomization)

10. Progression-free survival in eligible patients Nordlinger et al. Lancet 2008 HR= 0.77; CI: 0.60-1.00, p=0.041 LV5FU + Oxaliplatin Periop CT 28.1% 36.2% +8.1% At 3 years Surgery only

11. Overall survival in eligible patients Nordlinger et al. ASCO 2012 HR= 0.87; CI: 0.66 -1.14, p=0.303 LV5FU + Oxaliplatin Periop CT median OS: +8.7 months 5 years OS:+4.1 % Surgery only 63.7M55M 52.4.% 48.3% 5

12. Message: Peri-operative chemotherapy with FOLFOX considered the treatment of reference in patients with resectable metastases

13. Question: Are there indications for immediate surgery of resectable metastases?

14. Is this « good risk »case an indication for surgery only?  Metastasis is easily resectable with adequat margin  Risk of cancer relapse is 50%: surgery alone is not sufficient

15. Post-operative chemotherapy pooled-analysis of two 5-FU studies Months 020406080 Survival Adjuvant chemotherapy Surgery alone 0.0 0.2 0.4 0.6 0.8 1.0 Mitry E, et al. J Clin Oncol 2008;26:4906-11. p=0.058

16. Post-operative chemotherapy only? - No sufficient evidence to be standard treatment at the moment - 1/3 patients do not receive planned post-op treatment, although almost all can receive pre-op treatment ( EORTC study ) - No trials available comparing pre vs post - Post-operative chemotherapy is an option in patients who did not receive peri-operative chemotherapy: - Small and poorly located metastasis which may disappear after chemotherapy - Small synchronous metastasis with indication to resect the primary

17. Question: How to manage metastases which disappear from imaging during chemotherapy?

18. « Complete response » on imaging Complete response does not mean cure in up to 80% of cases It is preferable to resect liver metastases before complete response when surgeons can see them, and not overtreat patients with chemotherapy 1 Benoist et al. JCO 2006 2 Tan et al. J GastroIntest Surg 2007 3 Adam et al. JCO 2008 4 Elias et al. Ann Surg Oncol 2007

19. « Complete response » on imaging: looking for lost metastases Try other imaging methods: - MRI - FDG Pet scan probably unhelpful ( Tan, J Gastrointest Surg 2007 Covas ASCO 2008) - Contrast Enhanced US If they are no longer visible - resect the site - hepatic artery infusion - follow up for recurrence

20. Localisation of small lesions which may be lost Evaluate patients every 3-4 cycles and resect before metastases disappear Localisation is not a problem if an indication for anatomical resection Percutaneous radiofrequency ablation and resection of scar Coils before chemotherapy to mark small lesions Zalinski et al, Ann Surg Oncol 2009

21. Question: Does neoadjuvant chemotherapy increase the morbidity or mortality of surgery?

22. Clinical significance: impact on surgery Karoui Nordlinger et al, Ann.Surg. 2006 Aloia Adam et al, 2006 : Morbidity increased after 12 cycles Nakano Jaeck et al, 2008 : Morbidity increased after 6 cycles Mortality rate not increased Morbidity rate related to the number of cycles of CT

23. EORTC 40983 : complications of surgery Peri-op CTSurgery Reversible complications (pts) * 40 /159 (25%) 27 / 170 (16%) Cardio-pulmonary failure 3 2 Bleeding 3 3 Biliary Fistula 13 7 (Incl Output > 100ml/d, >10d) (9) (2) Hepatic Failure 11 8 (Incl. Bilirubin>10mg/dl, >3d) (10) (5) Wound infection 5 4 Intra-abdominal infection 11 4 Need for reoperation 5 3 Other (lung, urinary, ascites, etc…) 20 10 Post-operative deaths1 patient2 patients *P=0.04Nordlinger et al., Lancet 2008

24. Risks of surgery depend on the number of cycles Message:

25. Optimal duration of pre-operative chemotherapy? Question:

26. Different - when metastases are resectable - when metastases are not resectable Optimal duration of pre-operative chemotherapy

27. - 6 cycles according to EORTC 40983 - Could fewer cycles be sufficient? Duration of pre-operative chemotherapy in resectable metastases

28. Duration of pre-operative chemotherapy in initially unresectable metastases? Aim: convert patients to resection with a hope for cure Chemotherapy should be discontinued when metastases have become resectable and not given until best response is observed Overtreatment can damage the liver and preclude surgery

29. Question: If resectable metastases progress during pre-operative chemotherapy?

30. Progression during pre-operative CT A biological marker for poor prognosis No surgery if metastases progress Change chemotherapy,

31. Question: Targeted agents before liver surgery for metastases ?

32. Cetuximab: 1 st -line mCRC treatment in KRAS wild-type OxFp, Oxaliplatin + fluoropyrimidine; p-value for primary endpoint only The methodologies applied in the studies shown are not identical and studies should therefore not be compared 1 Van Cutsem E, et al. J Clin Oncol 2010; 28(15s):3570; 2 Bokemeyer C, et al. ASCO-GI 2010, #428; 3 Maughan TS, et al. J Clin Oncol 2010; 28(15s):3502. CRYSTAL 1 Phase 3 n PFS (months) ORR OS (months) FOLFIRI3508.439.7%20.0 FOLFIRI + cmab316 9.9 HR: 0.70; p=0.0012 57.3%23.5 OPUS 2 Phase 2 nPFSORROS FOLFOX977.234%18.5 FOLFOX + cmab828.3 57% OR: 2.5512; p=0.0027 22.8 COIN 3 Phase 3 nPFSORROS OxFp CT3678.657%17.9 OxFp CT + cmab3628.664% 17.0 HR: 1.038; p=0.68

33. Panitumumab: 1 st -line mCRC treatment in KRAS wild-type PRIME 1 Phase 3 n PFS (months) ORR OS (months) FOLFOX43318.048%19.7 FOLFOX4 + pmab325 9.6 HR: 0.80; p=0.02 55%23.9 1 Siena S, et al. ASCO-GI 2010, #283;.

34. Bevacizumab: 1 st -line mCRC treatment NO16966 1 Phase 3 n PFS (months) ORR OS (months) FOLFOX4/XELOX + placebo 7018.038%19.9 FOLFOX4/XELOX + bevacizumab 699 9.4 HR: 0.83; p=0.0023 38%21.3 1 Saltz LB, et al. J Clin Oncol 2008; 26:2013-9; 2 Hurwitz H, et al. N Engl J Med 2004; 350:2335-42. p-value for primary endpoint only The methodologies applied in the studies shown are not identical and studies should therefore not be compared AVF2107 2 Phase 3 nPFSORROS IFL + placebo4116.235%15.6 IFL + bevacizumab40210.645% 20.3 HR: 0.66 p<0.001

35. RECIST criteria may not fully evaluate the efficacy of bevacizumab in CLM Major response Interobserver variation: κ=0.78 Chun & Vauthey. JAMA 2009

36. Response and resection; phase 2 trials: Cetuximab and Bevacizumab CELIM *: Phase 2 Non-resectable or ≥ 5 liver metastases KRAS wt ORRResection R0 FOLFOX or FOLFIRI + cetuximab 79%33% * Bechstein WO, et al. J Clin Oncol 2009;27(Suppl. 15): Abstract No. 4091** Garufi C, et al. ASCO GI 2008. Abstract No. 367; ***Wong R. ESMO34 th -ECCO15 th POCHER**: Phase 2 ORR Resection R0 FOLFIRINOX + cetuximab 79%58% BOXER ***: Phase 2 ORR Resection R0 CAPOX + bevacizumab n=46 78%31%

37. Targeted therapies and risk of surgical complications - EGFR blockers: no interference with surgery - VEGF inhibitors: surgery delayed 6 – 8 weeks

38. Targeted agents in resectable metastases Standard treatment is FOLFOX4 Should we extrapolate that « the most effective regimen » is the best? Which reference? Metastatic or adjuvant treatment?

39. Ongoing and future trials in resectable metastasis CRUK 06/031: FOLFOX ± cetuximab in KRAS WT EORTC: 2 trials

40. FOLFOX + Panitumu mab R Resectable Liver Metastases from CRC n < 8 FOLFOX FOLFOX + Panitumu mab FOLFOX Follow up SURGERY FOLFOX+ Bevacizum ab SURGERY FOLFOX + Bevacizu mab Follow up KRAS WT EORTC 40091: BOS2 (Biologics, Oxaliplatin, Surgery) KRAS Wild type Endpoints: PFS; Pathological Response

41. EORTC 1207: BOS3 (Biologics, Oxaliplatin, Surgery) KRAS Mutated Randomization Resectable liver metastases (n° ≤ 8) from CRC KRAS mutant mFOLFOX6 Follow up SURGERY mFOLFOX6 mFOLFOX6+ Aflibercept SURGERY mFOLFOX6 + Aflibercept Follow up

42. Targeted agents in unresectable metastases Aim is resection Regimen with high response rate - intensified chemotherapy - addition of biologics to chemotherapy

43. Question: Should all patients presenting with liver metastases be considered for resection?

44. Patients usually divided in 3 groups: - Resectable - Never resectable - Potentially resectable in case of good response to chemotherapy

45. Some patients have such a major response to chemotherapy that it allows to consider surgery although not expected initially

46. Falcone, et al. Ann Surg 2009 GONO study: FOLFOXIRI – PFS in R0 patients Median PFS: 17.8 months 5-years PFS: 16% Time (months) 01224364860 1.0 0.8 0.6 0.4 0.2 0 R0 patients OS estimate n=37 Events (n)=31 Median Follow up: 60.5 months

47. Resection after chemotherapy Resection after chemotherapy: Never say never; keep eyes open Be aware that resection does not solve all the problems Discuss all patients in multidisciplinary meetings

48. Any other question?