1. Alfredo Falcone Dipartimento di Oncologia - Azienda USL-6 di Livorno Cattedra di Oncologia Medica - Università degli Studi di Pisa Istituto Toscano Tumori Mediterranean School of Oncology Highlights in the management of colorectal cancer Roma – 1-2 Febbraio 2007 Optimal management of liver metastases: The opinion of the medical oncologist

2. Liver Metastases in Colorectal Cancer  60% of CRC pts develop liver mets  25% synchronous  35% methacronous  50% of initial recurrences are confined to the liver  In 20-30% of advanced CRC pts liver is the only site of mets

3. IMPROVEMENTS IN THE TREATMENT OF CRC LIVER METS MoreSurgery SomeBiologics BetterChemotherapy Better Integration

4. Improvements in MCRC treatment in the last 10 years 1990-19962000-2006 Response Rate20%40-60% Median PFS4 mos7-10 mos Median OS12 mos18-22 mos II-III line treatment?YES Post-CT resection of mets (liver) ?YES

5. Active treatments available in MCRC 1.Surgery 2.Fluoropyrimidines 1.Surgery (+RF ablation) 2.Fluoropyrimidines 3.Irinotecan 4.Oxaliplatin 5.Bevacizumab 6.Anti-EGFR monoclonal-Ab 1990-19962000-2006

6. UNRESECTABLE “Not easily” resectable “Easily” resectable “Potentially” resectable RESECTABLE PATIENTS WITH CRC LIVER METS “Never” resectable

7. ????????????????????????????????? ????????????????????????????????? ????????????????????????????????? ????????????????????????????????? ????????????????????????????????? ????????????????????????????????? What does “RESECTABLE” means?

8. > 12 months after resection of primary Unilobar disease < 4 metastases > 1 cm resection margin “TRADITIONAL” CRITERIA FOR RESECTION According to these criteria approximately only 10% of patients are eligible for surgery

9. The OncoSurge Decision Model in CRC liver mts Poston et al. J Clin Oncol 2005 SURGERY IS CONTRINDICATED WHEN: Not-treatable extrahepatic disease Unfit for surgery (es. ASA>3) Extensive liver involvement (>70% liver or >6 liver segments or all 3 hepatic veins involved) Major liver insufficiency in case of adequate radiological margins absence of portal lymph nodes involvement number of mts is ≤4 or >4 but unilobar involvement IMMEDIATE RESECTION IS APPROPRIATE WHEN:

10. CHEMOTHERAPY (Fluoropyrimidines, Irinotecan, Oxaliplatin)

11. Chemotherapy in initially resectable liver mets Pre-operative CT so far is not indicated in “easily” or “immediately” resectable patients (oncosurge) Pre-operative CT is rationale and there is a general consensus in its use in “not easily” or “marginally” resectable pts Post-operative CT is rationale and generally recommended, but limited data support its use

12. N Kemeny et al, N Engl J Med 1999 P<0.001 P=0.21 Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer 156 pts P=0.06 P=0.21

13. Adjuvant 5-FU/LV after resection of liver mets: FFCD ACHBTH AURC 9002 Trial G. Portier et al. J Clin Oncol 2006 Curve PFS ed S con HR, % e p 171 pts HR=0.66; p= 0.028 HR=0.73; p= 0.13

14. 364 Pts with RESECTABLE liver only MTS FOLFOX-4 (6 cycles) Surgery Surgery FOLFOX-4 EORTC-40983 Completed CT RRResected Perioperative morbidity Perioperative mortality SurgeryNA 84.4%13.3%0.9% Chemo- Surgery 71%39%84.7%24.5%1.6% Nordlinger et al. Proc. ASCO 2005 Gruenberger et al. Proc. ASCO 2006

15. Chemotherapy in initally unresectable MCRC and liver mets Initial use of a doublet is better than single agent Important to expose patients to 5FU, CPT, LOHP Infusional 5-FU is preferable to bolus Capecitabine can probably be an alternative to 5-FU Reevaluate for surgery responding patients More responses = more resections Initial use of a triplet is better than a doublet in selected patients Chemotherapy-free intervals do not reduce efficacy in selected patients

16. Trials supporting the use of doublets CPT-11/5FU-LV –Saltz, NEJM 2000 (IFL) –Douillard, Lancet 2000 (FOLFIRI) –Koehne, JCO 2005 (AIO-IRI) LOHP/5FU-LV –De Gramont, JCO 2000 (FOLFOX4) –Giacchetti, JCO 2000 (Chronoinfusion) –Grothey, ASCO 2002 (FUFOX)

17. Trials supporting equivalent efficacy of doublets containing CPT11 or LOHP with infusional 5FU/LV Tourningard JCO 2004 –FOLFIRI vs FOLFOX6 Colucci JCO 2005 –FOLFIRI vs FOLFOX4 N.B.: When these studies were performed no adjuvant LOHP was in use

18. Grothey, A. et al. J Clin Oncol; 22:1209-1214, 2004 RELATIONSHIP BETWEEN PERCENTAGE OF PTS RECEIVING 5FU, IRINOTECAN, AND OXALIPLATIN IN THE COURSE OF THEIR DISEASE AND THE MEDIAN OVERALL SURVIVAL RELATIONSHIP BETWEEN PERCENTAGE OF PTS RECEIVING 5FU, IRINOTECAN, AND OXALIPLATIN IN THE COURSE OF THEIR DISEASE AND THE MEDIAN OVERALL SURVIVAL

19. CORRELATION BETWEEN TUMOR RESPONSE AND RESECTION RATES Studies incl. selected pts. (liver metastases only, no extrahepat. disease) r=.96, p=.002 Studies incl. all patients with metastatic CRC (solid line) r=.74, p<.001 Phase III studies in metastatic CRC (dashed line) r=.67, p=.024, p=.024 G Folprecht, A Grothey, S Alberts, HR Raab, and CH Köhne, Ann Oncol 2005

20. FOLFOXIRI J Clin Oncol 2002 (N=42) sFOLFOXIRI Ann Oncol 2004 (N=32) Response Rate 71% (12%CR) 72% (13%CR) Median PFS10.4 mos10.8 mos Median OS26.5 mos28.4 mos FOLFOXIRI: Phase II trials

21. First line FOLFOXIRI (74 pts) Evaluated for surgery (30 pts) Curative Surgery (19 pts) POST-CT SURGICAL RESECTIONS 40% 26% Masi G, Ann Surg Oncol 2005

22. STUDY DESIGN FOLFIRI* CPT-11180 mg/m 2 1-h d.1 L-LV100 mg/m 2 2-h d.1,2 5FU400 mg/m 2 bolus d.1,2 5FU 600 mg/m 2 22-h d.1,2 q. 2 wks x 12 cycles FOLFOXIRI** CPT-11165 mg/m 2 1-h d.1 LOHP 85 mg/m 2 2-h d.1 L-LV200 mg/m 2 2-h d.1 5FU 3200 mg/m 2 48-h CI d.1 q. 2 wks x 12 cycles Stratification Center PS 0/1-2 Adjuvant CT RANDOMRANDOM  In pts progressed after FOLFIRI a second-line CT with an LOHP containing regimen (FOLFOX) was recommended * Douillard Lancet 2000 ** Masi Ann Oncol 2004 Falcone A. – J Clin Oncol 2007 (in press)

23. FOLFOXIRI SCHEDULE 5FU flat continuous infusion 3200mg/m 2 L-LV 200 mg/m 2 Oxaliplatin 85 mg/m 2 2 hours Repeated every 14 days CPT-11 165 mg/m 2 48 hours Day 1 Day 2 Day 3 1 hour Falcone A. – J Clin Oncol 2007 (in press)

24. FOLFIRI 122 pts FOLFOXIRI 122 pts Complete6%8% Partial35%58% Complete + Partial41%*66%* 95% Confidence Interval0.32-0.500.56-0.74 Stable33%21% Progression24%11% Not evaluable2% *P = 0.0002 RESPONSES (ITT analysis) INVESTIGATORS’ ASSESSMENT INVESTIGATORS’ ASSESSMENT Falcone A. – J Clin Oncol 2007 (in press)

25. FOLFIRI (122 pts) FOLFOXIRI (122 pts) Complete6%7% Partial28%53% Complete + Partial34%*60%* 95% Confidence Interval0.25-0.430.51-0.68 Stable34%21% Progression24%11% Not evaluable8% *P< 0.0001 EXTERNALLY REVIEWED EXTERNALLY REVIEWED RESPONSES (ITT analysis) Falcone A. – J Clin Oncol 2007 (in press)

26. FOLFIRI (122 pts) FOLFOXIRI (122 pts) R0 6%* (7 pts) 15%* (18 pts) R11%2% Explorative8%1% * p=0.033 POST-CT SURGICAL RESECTIONS (all patients) POST-CT SURGICAL RESECTIONS (all patients) Falcone A. – J Clin Oncol 2007 (in press)

27. FOLFIRI (42 pts) FOLFOXIRI (39 pts) R0 12%* (5 pts) 36%* (14 pts) * P=0.017 POST-CT SURGICAL RESECTIONS (patients with liver mts only) POST-CT SURGICAL RESECTIONS (patients with liver mts only) Falcone A. – J Clin Oncol 2007 (in press)

28. FOLFIRI 122 pts FOLFOXIRI 122 pts Progressed114111 Median PFS6.9 m9.9 m HR: 0.65 (95%CI: 0.47-0.83) log-rank P value = 0.0009 PROGRESSION FREE SURVIVAL Falcone A. – ASCO-GI 2007

29. OVERALL SURVIVAL FOLFIRI 122 pts FOLFOXIRI 122 pts Died9684 Median OS16.7 m23.6 m HR: 0.74 (95%CI: 0.55-0.99) log-rank P value = 0.042 19% 13% Median follow up: 36.2 months Falcone A. – ASCO-GI 2007

30. SURVIVAL OF PTS RESECTED AFTER FOLFOXIRI Personal unpublished data Actuarial 5-year survival: 49%

31. BEVACIZUMAB AND CETUXIMAB

32. TRIALS SUPPORTING THE USE OF BEVACIZUMAB PLUS CT TrialDesignResults First line AVF2107 IFL+ BV IFL Increased RR, PFS, OS TREE2 OXA based+BV OXA based Increased RR Combined analisys 5FU+BV 5FU or IFL Increased RR, PFS, OS Second lineE3200 FOLFOX4+BV FOLFOX4 BV Increased RR, PFS, OS

36. TRIALS SUPPORTING THE USE OF CETUXIMAB +/- CT TrialDesignResults Third line BOND1 Irinotecan+C225 C225 Increased RR, PFS NCIC-C017 C225 BSC Increased OS Press Release Second lineEPIC Irinotecan+C225 Irinotecan Increased RR, PFS Press Release First line CALGB FOLF-OX or -IRI + C225 Promising RR Early Stopped CRYSTAL COIN FOLFIRI + C225 FOLFOX + C225 Increased RR, PFS Press Release PENDING

37. cetuximab + IFL cetuximab + FOLFIRI cetuximab + AIO/irinotecan cetuximab + FOLFOX-4 No. of patients29422142 Response rate (CR+PR) 48%45% a 67%81% Stable disease (SD)10%38%29%17% Disease control [CR+PR+MR b +SD] 90%83%96%98% Resection of metastases N/A24% 23% a a 5 patients could not be assessed for confirmation of response because they underwent secondary resection of metastases; b Minor response Rosenberg, et al. Proc ASCO 2002;20 (Abstract No. 536); Peeters M, et al. Eur J Cancer Suppl 2005;3:188 (Abstract No. 664); Folprecht G, et al. Ann Oncol (2005); Cervantes A, et al. Eur J Cancer Suppl 2005;3:181 (Abstract No. 642) Cetuximab studies in non-resectable liver metastases – non-selected patients

38. UNRESECTABLE “Not easily” resectable “Easily” resectable “Potentially” resectable RESECTABLE PATIENTS WITH CRC LIVER METS “Never” resectable

39. RESECTABLE PATIENTS In “easily” or “immediately” resectable patients (oncosurge) surgery up-front and consideration for adjuvant CT (5FU-LV, FOLFOX, FUDR) In “not easily” or “marginally” resectable patients and after a multidisciplinary evaluation, an active CT for 2-3 months (doublet or triplet) followed by surgery and further CT

40. UNRESECTABLE, BUT POTENTIALLY RESECTABLE PATIENTS Systemic CT with a a triplet (FOLFOXIRI) or a doublet (FOLFIRI or FOLFOX) + Bevacizumab reevaluating resectability every 2-3 months Consider studies with an “intensive” approach (Cetuximab+CT, FOLFOXIRI + biologic, etc…)

41. UNRESECTABLE, BUT NEVER RESECTABLE PATIENTS Fit patients, aggressive disease –Systemic CT with a first-line doublet (FOLFIRI or FOLFOX) combined with bevacizumab or a triplet (FOLFOXIRI) and followed after PD by other active agents (FOLFOX or FOLFIRI or Cetuximab+CPT) Unfit patients, less aggressive disease –Sequential treatment beginninig with a fluoropyrimidine + bevacizumab (if not controindicated) –“Personalized” first-line doublet + bevacizumab followed after PD by other active agents (mainly in pts unfit for advanced tumor) –Consider interruption of CT after 2-3 months if SD or response and restart after 2 months break or at progression –BSC

42. CONCLUSIONS Il the lat 10 years we have made substantial progress in the treatment of pts with CRC liver mets. However the chances of long-term survival or cure remain limited Our therapeutic options are increased, treatment has become complex and a multidisciplinary approach is fundamental Need for further improvements through the development of better systemic and local treatments, better selection of pts, better integration

44. Surgery in resectable MCRC Score 0 Score 1 Score 3 Score 5 Score 2 Score 4 Fong Y et al. Ann Surg 230: 309, 1999

45. The Paul Brousse Experience (1988-1999) Resectable Years % pts surviving Resectable after CT 48% 33% 30% 23% p=0.01 Adapted from Adam et al. Ann Surg 2004; 240(4):644-657

46. Neoadjuvant CT in pts with Liver MTS of CRC: 5-FU + OXA Complete Resection Study N of pts N of Resected pts % Bismuth, 19963304614 Giacchetti, 19991515838 Adam, 20017019513,5 * Alberts, 2003421433 Tournigand, 20041111413 adapted from Leonard et al. JCO 2005; 23:2038-2048 * Not stated if Complete Resection

47. Neoadjuvant CT in pts with Liver MTS of CRC: 5-FU + CPT-11 Complete Resection Study N of pts N of Resected pts % Pozzo, 2004401127,5 Tournigand, 200410987 Ducreux, 2002551731 Slater, 2003321134 Zelek, 2003*311135 * A combination of systemic CT with 5-Fu/Irinotecan and HAI of pirarubicin has been tested

48. Adjuvant chemotherapy with 5FU/LV after potentially curative resection of mets from CRC. A meta-analysis of two randomized trials E. Mitry et al. Proc. ASCO 2006 N. ptsmPFS (yrs) mOS (yrs) 5 yrs OS CT1382.205.0953% S1401.553.9141% HR 95% CI 1.33 0.99-1.79 1.30 0.93-1.79 P value0.0590.125 Two phase III studies (FFCD 9002, EORTC/NCI CTG/GIVIO)

49. Hurwitz et al. N Engl J Med 2004 Phase III trial of IFL ± Bevacizumab in metastatic CRC (AVF2107g): OS

50. Combined analysis of bevacizumab + 5-FU/LV vs 5-FU/LV o IFL: OS Kabbinavar F, et al. J Clin Oncol 2005;23:3706-3712 Survival (%) 100 80 60 40 20 0 010203040 Months HR=0.74 (p=0.0081) Median OS: 14.6 vs 17.9 months 5-FU/LV/Beva 5 mg/kg 5-FU/LV o IFL 14.6 17.9

51. Phase III second-line FOLFOX4 ± Bevacizumab (E3200): OS Probability 1.0 0.8 0.6 0.4 0.2 0 Overall survival (months) 0369121518212427303336 AliveDeadMedianTotal A: FOLFOX4 + bevacizumab2892464312.9 B: FOLFOX42902573310.8 C: Bevacizumab2432162710.2 HR=0.76 A vs B: p=0.0018 B vs C: p=0.95 HR = hazard ratio 10.212.9 10.8 Giantonio BJ, et al. ASCO 2005

52. (NCI’s TRC-0301): responses Chen HX et al. ASCO Annual Meeting 2004 Abstract 3515