This document discusses liver surgery after neoadjuvant chemotherapy for colorectal cancer metastases. It notes that survival rates have improved significantly with chemotherapy advances over the past decades. Several studies evaluating perioperative chemotherapy found improved progression-free survival compared to surgery alone. However, prolonged preoperative chemotherapy can cause liver injuries like steatosis and sinusoidal obstruction, increasing postoperative complications. The optimal timing between chemotherapy and surgery appears to be 4-6 weeks to balance tumor response and liver recovery. Strategies for extensive liver metastases include downsizing with chemotherapy followed by aggressive resection or ablation if the future liver remnant is insufficient.

1. Liver surgery after neoadjuvant chemotherapy Graeme Poston Consultant Hepatobiliary Surgeon Aintree University Hospital, Liverpool UK ESO-ESSO masterclass in Colorectal Cancer Surgery, Cascais 2011

4. Five-year survival of English colorectal cancer patients first diagnosed 1998–2004 (n=114,155) 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

5. 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

8. 13,325 liver resections for CRC metastases 45 countries - 130 institutions (1974 – 2011) Villejuif Liverpool Torino Barcelona Geneva Zurich      

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

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

11. 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

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

13. 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

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

15. 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

16. 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

17. 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

18. 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

19. 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?

20. 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%

21. 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

22. CELIM: Study design Randomization Primary endpoint: Response Patients with technically unresectable / ≥ 5 liver metastases without extrahepatic metastases Biopsy EGFR screening FOLFOX6 + ERBITUX FOLFIRI + ERBITUX Therapy: 8 cycles (~4 months) Evaluation of resectability Technically resectable Technically unresectable 4 further treatment cycles Resection Therapy continuation for 6 cycles (~3 months) Folprecht G et al. Lancet Oncol 2010

23. CELIM: Response and resection rates in patients with KRAS wild-type tumors 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

24. POCHER Study Garufi C et al. Brit J Cancer 2010; 103: 1542-7 43 pts 26/43 R0 17/43

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

26. Kras WT: Received 6 cycles FOLFOX +Erbitux

27. After 6 cycles FOLFOX + Erbitux

29. Problems with preoperative chemotherapy in liver surgery

30. Lancet 2008; 371: 1007-1016

32. 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

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

34. Liver after prolonged chemotherapy (not observed after < 6 cycles) We used to call this ‘ chemotherapy associated steato-hepatosis’ (CASH) Bilchik, Poston, Curley et al. J Clin Oncol 2005; 23: 9073-8

35. 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

36. 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

37. &quot;Complete response&quot; : does it mean cure ? Before treatment After 6 cycles of chemotherapy ?

38. 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

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

41. Interval between chemotherapy and surgery

42. 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 Although operative mortality was similar, operative morbidity was near-double in the chemotherapy arm

43. Interval Between Chemotherapy and Liver Surgery (cytotoxics) Welsh FKS et al. Br J Cancer 2007; 96: 1037-42 p=0.009

44. Predictive factors for chemotherapy-associated liver injuries (cytotoxics) Brouquet, Nordlinger et al, SSO 2008 Univariate analysis Multivariate analysis BMI > 27 0,0001 0,004 4,6 [1,6-12,9] Glycemia > 7mmol/l 0,015 0,006 6,15 [1,66 – 22,74] Interval < 4 weeks 0,04 0,01 1,16 [1,03-1,29] Aspirin intake 0,002 0,002 0,07 [0,01 - 0,37]

46. Strategies for the management of multiple metastases

49. Extended right trisectionectomy II III

52. Right Hemi-hepatectomy

55. Right hepatectomy with multiple metastasectomies

57. 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 (Epub ahead of print) YES KRAS testing KRAS wild-type KRAS mutant NO KRAS testing KRAS wild-type KRAS mutant

58. 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

59. The impact of multidisciplinary management 0 1 2 3 4 5 100 50 0 % surviving Years after diagnosis of colorectal metastases 2011 chemotherapy 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%?