1. Targeted therapies in metastatic colorectal cancer: The impact for the surgeon Graeme Poston Consultant Hepatobiliary Surgeon Aintree University Hospital, Liverpool UK 10 th ESO-ESMO Masterclass in Clinical Oncology Ermatingen, 5 th April 2011

4. Five-year survival of all (n=114,155) English colorectal cancer patients first diagnosed 1998–2004 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Survival probability Years All Stage 4 All patients All stage 3 All stage 4 resected n=3116 Patients with resected liver metastases All patients without resected metastases Dukes C Dukes D Morris EJA, Forman D, Thomas JD, Quirke P, Taylor EF, Fairley L, Cottier B, Poston G. Brit J Surg 2010; 97: 1110-8

7. Survival of CRC patients after liver resection in England 1997-2005 Morris EJA et al. Brit J Surg 2010; 97: 1110-8 0.0 0.2 0.4 0.6 0.8 1.0 4000 3000 2000 1000 0 Survival Time days Cumulative Survival Survival stratified by year of surgery (1997–2005) 1997 1998 1999 2000 2001 2002 2003 2004 2005 1997-censored 1998-censored 2000-censored 2001-censored 2002-censored 2003-censored 2004-censored 2005-censored N = 5870

9. 13,325 liver resections for CRC metastases 45 countries - 130 institutions (1974 – 2011) Villejuif Liverpool Torino Barcelona Geneva Zurich      

10. Long-term survival post hepatectomy Operative mortality 1.2% Operative mortality 1.4% 100 90 50 80 70 60 40 30 20 10 0             90% 74% 40% 29% 24% 1 2 6 3 4 5 7 8 9 10 0 Patient Survival post hepatectomy1 All LiverMetSurvey population: 13,325 patients (+ 196 missing data) All LiverMetSurvey (31/07/2010) GJP data Patient Survival post hepatectomy 526: patients (+0 missing data) 40%             92% 77% 30% 25% 100 90 50 80 70 60 40 30 20 10 0 1 2 6 3 4 5 7 8 9 10 0

11. Survival after liver resection: Response to pre-operative chemotherapy in resectable disease

12. Correlation of outcome after hepatectomy to histologic response to neoadjuvant chemotherapy 2008; 26: 5344-51 Blazer et al. Complete response Major response Minor response

13. Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver metastases from colorectal cancer The EPOC Intergroup Phase III Study (EORTC 40983) Bernard Nordlinger, Halfdan Sorbye, Bengt Glimelius, Graeme J. Poston, Peter M. Schlag, Philippe Rougier, Wolf O. Bechstein, John N. Primrose, Euan T. Walpole, Meg Finch-Jones, Daniel Jaeck, Darius Mirza, Rowan W. Parks, Laurence Collette, Michel Praet, Ullrich Bethe, Eric Van Cutsem, Wolfgang Scheithauer, Thomas Gruenberger . Lancet 2008; 371: 1007-16 ALM CAO AGITG g

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

15. 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

16. Survival after liver resection: Response to pre-operative chemotherapy in resectable metachronous solitary metastases Adam R, Bhangui P, Poston G et al. Ann Surg 2010; 252: 774-87

17. New EPOC study design UK NCRI/CRUK Randomize Surgery FOLFOX6 FOLFOX6 Surgery 6 cycles (3 months) Kras WT liver limited resectable disease N=360 patients. Opened 2008, 140 pts randomised Primary end point: 3 year PFS 6 cycles (3 months) FOLFOX6 + cetuximab FOLFOX6+ cetuximab

18. BOS-1 study design EORTC Randomize Surgery FOLFOX6 + bevacizumab FOLFOX6 + bevacizumab Surgery 6 cycles (3 months) Liver limited resectable disease: 2 arm Phase II N=100 patients. 2007-2009, 100 pts randomised Primary end point: Feasibility 6 cycles (3 months) FOLFOX6 + cetuximab FOLFOX6+ cetuximab

19. BOS-2 study design EORTC Randomize Surgery FOLFOX6 + bevacizumab FOLFOX6 + bevacizumab Surgery 6 cycles (3 months) Kras WT liver limited resectable disease N=200 patients. Opened 2010, randomised Phase II Primary end point: PFS 6 cycles (3 months) FOLFOX6 + panitumumab FOLFOX6+ panitumumab

20. Bringing more patients to resection: induction chemotherapy What is the difference between this patient and ... this patient? NOTHING! They are the same patient pre- and post-chemotherapy

21. Colon cancer: Resectability profile Liver metastases 80% non-resectable 20% resectable 10–30% initially non-resectable might become resectable 70–90% remain non-resectable Resection Chemotherapy Nordlinger B, et al. Eur J Cancer 2007;43:2037–2045 Potential for cure! 2 nd Line?

23. Secondary liver resection rates of metastases and tumour response Studies including non-selected patients with mCRC (solid line) (r=0.74; p<0.001) Studies including selected liver metastases only patients (no extrahepatic disease) (r=0.96; p=0.002) Phase III studies including non-selected patients with mCRC (dashed line) (r=0.67; p=0.024) Folprecht G, et al. Ann Oncol 2005;16:1311–1319 If we can achieve response rates >70% in unresectable liver only patients then >40% might come to liver resection? Resection rate Response rate 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9

24. Response and R0 resection rates according to Erbitux treatment Van Cutsem et al. ASCO GI 2011, Abstract No. 472 ? ? Van Cutsem E et al. NEJM 2009 Bokemeyer K et al JCO 2009

25. CELIM: Study design Randomization Primary endpoint: Response Liver surgeon defines patients with technically unresectable ( > 5) liver metastases Biopsy EGFR screening FOLFOX6 + ERBITUX FOLFIRI + ERBITUX Therapy: 8 cycles (~4 months) Liver surgeon re-evaluates resectability Technically resectable Technically unresectable 4 further treatment cycles Resection Therapy continuation for 6 cycles (~3 months) Folprecht G et al. Lancet Oncol 2010

26. CELIM: Response and resection rates in patients with KRAS wild-type tumours 79 43 Response rate ( n=67) Resections + R0 resections ERBITUX + FOLFOX/FOLFIRI Patients (%) Folprecht G et al. Lancet Oncol 2010 Resection rate = 43% R0 rate = 34% 34 100 90 80 70 60 50 40 30 20 10 0

27. POCHER Study Garufi C et al. Brit J Cancer 2010; 103: 1542-7 43 pts 26/43 R0 17/43 Assessed by liver surgeon Re-assessed by liver surgeon

28. POCHER Study Garufi C et al. Brit J Cancer 2010; 103: 1542-7 PFS: overall OS: overall

29. Comparison of response rate to secondary liver resection rate in kras WT liver limited disease Same RR with addition of Erbitux: Why the difference in secondary liver resection rates?

30. Comparison of process and liver resection rates in Erbitux trials in liver limited kras WT studies Study Who recruited? % RR Erbitux arm Who determined liver resectability? Liver resection rate Erbitux arm

32. Kras WT: Received 6 cycles FOLFOX +Erbitux

33. After 6 cycles FOLFOX + Erbitux

36. BOXER Study: patient flow Wong R et al. Ann Oncol 2011 (e-pub ahead of print)

38. Survival after liver resection : Initially resectable vs. initially unresectable Update: Adam R et al. Ann Surg 2004; 240:644–658 Resectable : 505 Initially non resectable : 205 Years 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 Survival (%) 92% 49% 31% 67% P< 0.0001 90% 30% 46% 18%

39. Problems with preoperative chemotherapy in liver surgery

40. Lancet 2008; 371: 1007-1016

41. Complications of surgery *P=0.04 Nordlinger et al. Lancet 2008; 371: 1007-16 Peri-op CT Surgery Post-operative complications* 40 /159 (25.2%) 27 / 170 (15.9%) Cardio-pulmonary failure 3 2 Bleeding 3 3 Biliary Fistula 12 5 (Incl Output > 100ml/d, >10d) (9) (2) Hepatic Failure 11 8 (Incl. Bilirubin>10mg/dl, >3d) (10) (5) Wound infection 4 4 Intra-abdominal infection 8 2 Need for reoperation 5 3 Other 25 16 Incl. post-operative death 1 patient 2 patients

42. Steatosis and steatohepatitis: seen with irinotecan Vauthey J-N , et al . J Clin Oncol 2006; 24: 2065 –2072. Steatohepatitis causes increased post-operative liver failure and death within 90 days Yellow liver

43. Sinusoidal Obstruction Syndrome Seen with oxaliplatin but not irinotecan Rubbia-Brandt L et al. Histopathology 2010; 56: 430-9 Causes increased peri-operative bleeding but not post operative death Blue liver

44. Complications of surgery following pre-operative chemotherapy Karoui M et al. Ann Surg 2006; 243: 1-7

45. &quot;Complete response&quot; : does it mean cure ? Before treatment After 6 cycles of chemotherapy ? Wait for it to come back?

46. Pre-chemotherapy Post-chemotherapy What do you do now?

47. CT- based evaluation Benoist et al. JCO 2006;24:3939-45 66 metastases disappeared on imaging after CT Surgical exploration Macroscopic residual disease: 20 LM No macroscopic residual disease: 46 LM 30% 15 initial sites resected 31 initial sites left in liver 55/66 (83%) LM non-cured 80% 74% Viable tumor cells in 12 sites In situ recurrence: 23

48. Macroscopic CR after chemotherapy: ~20% of cells in periphery are viable Courtesy of Professors G Mentha and L Rubbia Brandt, University of Geneva Dangerous Halo

49. Interval between chemotherapy and surgery

50. EORTC 40983: Peri-operative chemotherapy Randomi Ze d Surgery FOLFOX4 FOLFOX4 Surgery 6 cycles (3 months) 6 cycles (3 months) 4w (2-5) 2-5 w Postoperative complications: Surgery alone 15% Surgery + Chemo 25%

51. Interval Between Chemotherapy and Liver Surgery (cytotoxics) Welsh FKS et al. Br J Cancer 2007 p=0.009

52. Addition of targeted therapies to chemotherapy in the 1st-line treatment of mCRC: The evidence Van Cutsem E, et al. N Engl J Med 2009;360:1408–1417; Bokemeyer C, et al. J Clin Oncol 2008;27:663–671; Folprecht G, et al. ASCO GI 2009 Abstract No. 296; Hurwitz H, et al. N Engl J Med 2004;350:2335–2342; Klinger M, et al. Eur J Surg Oncol 2009;35:515–520; Hapani S, et al. Lancet Oncol 2009;10:559–568       (  ) ERBITUX Bevacizumab Significantly increases tumor response rate to CT regimens Specific tumor shrinkage effect Significantly increases R0 resection rate Perioperative setting: treatment can be used 2 weeks before/after surgery Safety profile: No potential risk of postsurgical complications

56. Strategies for the management of multiple metastases

59. Extended right trisectionectomy II III

62. Right Hemi-hepatectomy

65. Right hepatectomy with multiple metastasectomies

69. Expert review from ICACT 2009: Optimizing 1st-line treatment for mCRC Careful analysis of each patient and their tumor characteristics Is there the potential for cure? Aim: Maximum tumor shrinkage without delaying surgery Cetuximab + irinotecan- or oxaliplatin-based CT Choice of initial therapy is key due to the impact on subsequent options Is primary or secondary surgery possible? Cetuximab or bevacizumab + CT Bevacizumab + CT Bevacizumab + CT Consider: 5-FU vs oral fluoropyrimidine; continuous vs intermittent CT; neuroprotective measures when using oxaliplatin Adam R, Haller D, Poston G, Raoul JL, Spano JP, Tabernero J, Van Cutsem E. Ann Oncol 2010; 21:1579-84 YES KRAS testing KRAS wild-type KRAS mutant NO KRAS testing KRAS wild-type KRAS mutant

70. Liver only +/- resectable extrahepatic disease Fitness assessment as per local protocol Borderline resectable Primovist MRI, PET CT and K-ras status Kras test: chemotherapy +/- biologic Formal assessment at hepatobiliary SMDT Chemotherapy +/- biologic Post chemo re staging (CT / MRI) Liver surgery opinion Never likely to be resectable Resectable disease Primovist MRI and PET CT Formal assessment at hepatobiliary SMDT Formal assessment at hepatobiliary SMDT ‘ Accidental’ hepatectomy? Alberto Sobrero SURGERY

71. The impact of multidisciplinary management 0 1 2 3 4 5 100 50 0 % surviving Years after diagnosis of colorectal metastases 2011 chemotherapy + biologic Median survival >30 months 5 year survival 15 % 3% 2001 2011 overall (Surgery + Chemo) Median survival >40 months 5 year survival 30 % 30% Poston et al. J Clin Oncol 2008; 26: 4828-33, Kopetz et al. J Clin Oncol 2009;27:3677–83 15% 2021 1000% in 10 yrs >50%?