1. Neoadjuvant and Adjuvant Chemotherapy for Liver Limited Metastases from Colorectal Cancer Heinz-Josef Lenz, MD FACP Professor of Medicine USC Norris Comprehensive Cancer Center

2. Questions When to treat with chemotherapy What is the right chemotherapy prior surgery When to do the surgery for primary and liver metastases What is the right chemotherapy after surgery

3. Outline of Presentation Overview Therapy for Initially Resectable Liver Metastases Therapy for Initially Unresectable Liver Metastases Summary

4. Hepatic Metastases from Colorectal Cancer Approximately 30 to 40% of patients will have liver-only metastases at time of recurrence Approximately 20 to 30% will have liver- only metastases at the time initial evaluation 25-30,000 patients with Liver-only metastases

5. LIVER METASTASES RESECTABLE20-25% NON RESECTABLE 75-80% SURVIVAL BENEFIT 30-40% AT 5 YEARS 15% AT 10 YEARS RESECTABLE10-20% Downsizing size location number

6. Therapy for Initially Resectable Liver Metastases

7. Results of liver surgery for metastatic CRC (N > 100) N. of patients Operative mort 5-yr survival Adson, 1984 (1) 1412.8%23% Hughes, 1988 (2) 859-33% Doci, 1991 (3) 1005%30% Scheele, 1991 (4) 2196%39% Rosen, 1992 (5) 2804%25% Nordlinger, 1992 (6) 18182.4%26% Gayowski, 1994 (7) 2040%32% Rees, 1997 (8) 1141%37% 1 - MA. Adson et al., Arch. Surg., 1984; 119: 647-515 - CB. Rosen et al., Ann. Surg., 1992; 216: 493-505 2 - KS. Hugues, Surgery, 1988; 103: 278-886 - B. Nordlinger et coll., Ed. Paris Springer-Verlag, 1992; 141-59 3 - R. Doci et al., Br. J. Surg., 1991; 78: 797-8017 - TJ. Gayowski et al., Surgery, 1994; 116: 703-11 4 - J. Scheele et al., Surgery, 1991; 110: 13-298 - M. Rees et al., Br. J. Surg., 1997; 84: 1136-40

8. NCCN GUIDELINES 2007 “ Patients who have completely resected liver metastases should be offered 4 to 6 months of adjuvant chemotherapy… observation or a shortened course of chemotherapy is considered for patients who have completed neoadjuvant chemotherapy.”

9. Adjuvant Chemotherapy May reduce the risk of recurrence Focus of completed and current trials –Systemic chemotherapy –Hepatic artery infusion (HAI)

10. Adjuvant Chemotherapy Memorial Sloan-Kettering Randomized Study HAI + systemic CT Systemic CT #Pts 2-yr survival#Pts 2-yr survival p-value Survival 7486% 8272% 0.03 Hepatic DFS 7490% 8260% <0.001 Any DFS 7457% 8242% 0.07 1 Liver Met 2772% 3379% 0.55 2-4 Liver Mets 3397% 3460% 0.0003 >4 Liver Mets 1484% 1564% 0.24 Positive Margins 1090% 1144% 0.02 NEJM 341:2039, 1999

11. Kemeny, N. E. et al. N Engl J Med 2005;352:734-735 Overall Survival among Patients Treated with Hepatic Arterial Infusion plus Systemic Chemotherapy (Combined Therapy) or with Systemic Chemotherapy Alone (Monotherapy) Median: 68.4 months Median: 55.2 months

12. Adjuvant Chemotherapy Memorial Sloan-Kettering Randomized Study Site of recurrenceHAI groupSystemic group Lung15(50%)17(38.6%) Liver7(23.3%)30(68.2%) Ovaries4(13.3%)1(2.3%) Bone3(10%)3(6.8%) Pelvis4(13.3%)7(15.9%) Lymph nodes3(10%)10(22.7%) Other6(20%)6(13.6%) Lung15(50%)17(38.6%) Liver7(23.3%)30(68.2%) Ovaries4(13.3%)1(2.3%) Bone3(10%)3(6.8%) Pelvis4(13.3%)7(15.9%) Lymph nodes3(10%)10(22.7%) Other6(20%)6(13.6%)

13. N9945 - Preliminary Results 54 of 70 patients initiate HAI FUDR + SYS 52% had a solitary metastases and 24% presented with bilobar metastases No post-operative or treatment related deaths were reported Primary endpoint: 2-yr survival (2YS), with 80% of patients surviving 2 yrs as evidence of promising efficacy –78% (42/54) of evaluable patients are alive with a minimum 28 months of follow-up 6 deaths occurred in less than 2 yrs –48% (26/54) have recurred, with 42% having liver involvement –Median time-to-progression is 30 months with an estimated 2YS rate of 88% (95% CI 76-97%)

14. Adjuvant Chemotherapy - Current and Future Studies C-09: Metastasectomy followed by with Oxaliplatin and Capecitabine +/- FUDR Resection of liver metastases (1-6) Capecitabine + Oxaliplatin Capecitabine + Oxaliplatin alternating with HAI FUDR Randomize Open – Planned Accrual 400

15. 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

16. Trial Design and Objectives R FOLFOX4 x 6 cycles Surgery FOLFOX4 x 6 cycles Surgery 364 patients Potentially resectable (1-4) liver metastases Goal: Improve progression- free survival to demonstrate a 40% increase in median PFS (HR=0.71) with 80% power and 2-sided significance level 5%

17. Pre-Operative Assessment Outcome in chemotherapy arm –CR: 3.3% –PR: 35.2% –Stable: 33.5% –Progression 7.7% –Not evaluable: 20.3%

18. Surgery Peri-op CT (N=182) Surgery Surgery(N=182) Operated 158 (86.8) 167 (91.8) Resected Resected 151 (83.0) 149 (81.9) Not operated due to PD due to PD due to refusal or toxicity due to refusal or toxicity due to other reason due to other reason 21 (11.5) 777 9 (4.9) 504 Unknown if operated 3 (1.6) 6 (3.3)

19. Results N pts CT N pts Surgery % absolute difference in 3-year PFS Hazard Ratio (Confidence Interval) P-value All patients 182182 +7.2% (28.1% to 35.4%) 0.79 (0.62-1.02) P=0.058 All eligible Patients171171 +8.1% (28.1% to 36.2%) 0.77 (0.60-1.00) P=0.041 All resected Patients151152 +9.2% (33.2% to 42.4%) 0.73 (0.55-0.97) P=0.025

20. 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) 0123456 0 10 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk : 125171835737228 1151711157443215 Surgery only

21. FOLFOX6 modified + cetuximab 6 cycles RANDOMIZATION Resectable Liver Metastases from Colorectal Cancer no extrahepatic disease WHO PS 0,1 No previous chemo for mets FOLFOX6 modified + cetuximab + bevacizumab 6 cycles (no bevacizumab in cycle #6) FOLFOX6 modified + cetuximab 6 cycles FOLFOX6 modified + cetuximab + bevacizumab 6 cycles follow up SURGERY Trial 40051 (BOS)

22. Resectable Liver Metastases Summary Studies support role for adjuvant therapy Value of HAI-based therapy to be assessed

23. Therapy for Initially Unresectable Liver Disease

24. LIVER METASTASES RESECTABLE20-25% NON RESECTABLE 75-80% SURVIVAL BENEFIT 30-40% AT 5 YEARS RESECTABLE10-20% Downsizing size location number

25. DEFINITIONS: ASCO 2006 LIVER THINK TANK Neoadjuvant Therapy - Preoperative systemic therapy for resectable hepatic metastases followed by post resection therapy. Adjuvant Therapy - Systemic/regional therapy post hepatic resection. Conversion Therapy – Systemic/regional therapy utilized for patients with unresectable hepatic metastases in an attempt to make the metastases resectable.

26. Hepatic Artery Infusion (HAI) for Unresectable Liver Metastases

27. CALGB 9481: HAI FUDR versus Systemic 5FU and Leucovorin Eligibility –Liver-only, unresectable metastases from CRC –No prior therapy for metastatic CRC HAI FUDR 0.18 mg/kg + DEX 25 mg over 14 days Every 28 days (N = 68) 5-FU 425 mg/m2 + LV 20 mg/m2 Daily x 5 every 4 weeks (N = 67) R Kemeny NE et al. J Clin Oncol 24:1395-1403, 2006

28. CALGB 9481: Overall Survival HAI 5FU/LV Med OS (months) 24.420.0 (p=0.034) THP (months) 9.8 7.3 (p=0.034) TEP (months) 7.714.8 (p=0.029) RR 47% 24% HAI 5FU/LV

29. CALGB 9481: Hepatic vs Nonhepatic Disease Progression Kemeny et al. J Clin Oncol. 2006;24:1395. HepaticNonhepatic HAI Systemic, P=0.034 Years from trial entry Proportion hepatic progression–free 0123 0 0.2 0.4 0.6 0.8 1.0 0123 0 0.2 0.4 0.6 0.8 1.0 HAI Systemic, P=0.029 Proportion nonhepatic progression – free Years from trial entry

30. HAI as Neoadjuvant Therapy for Initially Unresectable Disease Potential Limitations –Invasive Percutaneously placed catheters have a high rate of complications Surgical placement may delay systemic therapy –Lack of treatment for potential extrahepatic disease –Limited studies

31. Role of Neoadjuvant Systemic Chemotherapy for Liver-only Metastases

32. Resection of non-resectable liver metastases after systemic chemotherapy Published series Authors Levi Fowler Bismuth Giachetti Adam Wein Rivoire Year 1992 1996 1999 2001 2002 No Pts 98 - 330 389 701 53 131 Type Chemo Fu-Fol-Oxali Fu-Fol Fu-Fol-Oxali Fu-Fol-Oxali* Fu-Fol-Oxali Fu-Fol Fu-Fol-Oxali No Resect 18 (19%) 11 53 (16%) 77 (20%) 95 (14%) 6 (11%) 57 (43%) 5-yr Surv - 40% 50% 39% - Fu-Fol-Oxali : Chronomodulated * Liver only metastases

33. Survival after Liver Resection of Colorectal Metastases Paul Brousse Hospital - 473 patients (Apr. 88 - Jul. 99) Years 20 40 60 80 100 012345678910 Survival (%) 91% 48% 30% 66% 33% 23% 52% P= 0.01 Adam R et al. Ann Surg 2004 No Surgery Resectable : 335 Initially non resectable : 138

34. Collaboration : Oncologists - Surgeons For Non Resectable Metastases 1- Current chemotherapy allows at least 20% of patients to be rescued by liver surgery 2- The survival benefit of these patients is substantial (30% and 20% rate at 5 and 10 years) 3- Resectability: a new end point for treatment strategy

35. Neoadjuvant Oxaliplatin Paul Brousse Hospital Study Adam R. et al., Ann. Surg. Oncol., 2001; 8: 347-353 Chemo: 701 (80%) 14% 900 800 700 600 500 400 300 200 100 0 0 Resection: 266 (31%) 86% 36% 64% 95 171 872 patients 1988 - 1996 872 patients 1988 - 1996 Initially non-resectable Non-resectable Resectable Initially non-resectable Non-resectable Resectable 14% of 701 CT-treated patients achieved a response permitting resection 171 ChemotherapyChemotherapy

36. Role of Neoadjuvant Treatment Patient status at a mean follow-up of 4.2 years 56 dead (59%) 39 alive (41%) 95 patients 25 alive disease free (26%) 14 alive with disease (15%)

37. Survival after primary or secondary resection of liver metastases

38. N014A: Resection of Unresectable CRC Limited to the Liver Using FOLFOX6 + Cetuximab CR/PR resectable  O.R.  CT x 2 PR, unresectable  Rx to Prog/Tolerability Prog  Off Study, Rx per M.D. Endpoints: Resectability, Response Rate, Survival Evaluation Oxaliplatin+5-FU/LV (FOLFOX6) + C225

39. Specific Chemotherapy Associated Hepatic Toxicity Irinotecan – Steatohepatitis Oxaliplatin – Sinusoidal/vascular injury  Acute & chronic clinical sequelae Biologics - ????  Bevacizumab – 6 to 8 wks before resection – Liver regeneration & hemorrhage Morbidity is increased with prolonged course of chemotherapy (Aloia et al, J Clin Oncol, 2006 )

40. Liver Toxicity of Neoadjuvant Therapy % of Patients Sinusoidal Dilation Steatosis >30% Steatohepatitis YesNo P *P *P *P *YesNo P *P *P *P *YesNo P *P *P *P * No chemotherapy 1.998.1–8.991.1–4.495.6– 5-FU/LV0100NS16.683.4NS4.895.2NS 5-FU/LV + irinotecan 4.395.7NS10.689.4NS20.279.80.0001 5-FU/LV + oxaliplatin 18.981.10.000013.896.2NS6.393.6NS Other0100NS8.391.7NS0100NS Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (P=0.001) *Comparison of each group vs no chemotherapy. Vauthey et al. J Clin Oncol. 2006;24:2065.

42. Vasodilation & Congestion Peliosis: Hemorrhagic Centrilobular NecrosisNodular Regenerative Hyperplasia Vascular Changes in Liver Post Systemic Chemotherapy Aloia et al, J Clin Oncol 24: 4983,2006 Hepatic atrophy & sinusoidal congestion ▼ ▼

43. Collaboration Oncologists - Surgeons for Timing of Surgery after Chemotherapy… As soon as the metastases become resectable… Not to miss the « good » therapeutic window: Tumoral progression: Surgery even potentially curative, has poor results Not to « overtreat » the patient Complete response: a major problem for the surgeon with however a minority of pathology-proven necrosis Hepatotoxicity: a clinical impact related to duration

44. Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001) Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96; p=0.002) Phase III studies including nonselected patients with mCRC (dashed line) (r=0.67; p=0.024) Folprecht G, et al. Ann Oncol 2005;16:1311–1319 Response rate 0.90.80.70.60.50.40.3 Resection rate 0.6 0.5 0.4 0.3 0.2 0.1 0 Impact of Increasing Response Rates

45. CRYSTAL Trial: Surgery with Curative Intent *CMH test n=599 / group n=134 / n=122 p=0.0034* odds ratio 3.0 [95% CI: 1.4 - 6.5] FOLFIRI alone ERBITUX + FOLFIRI No residual tumor in patients with liver metastases ITT population Liver-limited disease population Van Cutsem et al, ASCO 2007

46. OncoSurgical strategies in liver metastases from palliative to curative … Palliative Curative Survival Time

47. Summary - Unresectable Liver Metastases Patients with liver metastases benefit from chemotherapy followed by surgery Oxaliplatin-containing regimens render an additional 10% or more patients resectable Use of CPT-11 less well studied Role of HAI remains uncertain Response-enhancing agents needed Potential for chemotherapy-induced liver disease

48. Overall Summary Options available for patients in the adjuvant, perioperative, and neoadjuvant settings Patients amenable to surgery have a better outcome, even if recurrence Variety of new studies open or in development

49. Overall Summary Management requires multidisciplinary approach –Medical Oncology –Surgery –Radiology Development of practice guidelines