Perioperative chemotherapy for colorectal cancer livermetastases: what is the optimal strategy?

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1 Perioperative chemotherapy for colorectal cancer livermetastases: what is the optimal strategy? Prof Eric Van Cutsem, MD, PhD Digestive Oncology Leuven, Belgium

2 A classical case of mcrc in 2016 CONTINUUM OF CARE 3 months preterminal phase 3 months rechallenge 5 months first-line induction 3 months third line 3 months break 4 months second line OS 30 months 6 months maintenance 3 months reintroduction (or treatment beyond progression) 1991: OS 6 months

3 The continuum of care of mcrc Fluoropyrimidines: 5FU, capecitabine, TAS102 Oxaliplatin Irinotecan Surgery (RFA) Locoregional therapy: SIRS 1st line cytotoxic 2nd line cytotoxic 3rd line cytotoxic How to start? What is best strategy? What to do for liver metastases? Maintenance strategy At progression change chemo, biologic or both? Independent sequences? 1st line biologic Bevacizumab Cetuximab/panitumumab Aflibercept Ramucirumab Regorafenib 2 nd line biologic 3 nd line biologic

4 Liver metastases important factor in survival Vital organ no way to compensate for the absence of liver function death

5 Patients with unresectable liver metastases: OS is the primary treatment goal Classification Upfront resectable Borderline resectable Unresectable 10% 20% 70% Treatment strategy Resection 8% 1 CT ± biologic 12% 1 CT ± biologic 14% 2 Relapse Required outcome Curative surgery Overall survival / long-term disease control 4% 96% 1. Wong, et al. Ann Oncol 2011; 2. Zakaria, et al. Ann Surg Van Cutsem E et al. Ann Oncol 2014; 4. Adam R Van Cutsem E et al. Cancer Treat Rev 2015

6 Marginally resectable/ unresectable Definitely unresectable Easily resectable Number Surgery ± FOLFOX Size Optimal therapy + surgery Palliative therapy

7 Metastatic colorectal cancer CHEMOTHERAPY: combinaton of cytotoxic and biological targeted drugs Cytotoxic agents 5-FU/capecitabine (S1) irinotecan oxaliplatin raltitrexed (mitomycine) TAS-102 Biological agents bevacizumab cetuximab panitumumab aflibercept regorafenib ramucirumab early: Sym004, dabrafenib, trametenib,nintedanib, nivolumumab, pembrozulimab, atezolizumab, cobimetinib, MABp1.. Other contributing factors to improved outcome: surgery,.

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9 ESMO consensus on mcrc 2016 Chairs: Co-Chairs of working groups E Van Cutsem A Sobrero Advanced mcrc D Arnold R Adam Local and ablative treatment, oligometastasis A Cervantes H Van Krieken Molecular Pathology and Biomarkers Contributors D Aderka E Aranda A Bardelli A Benson G Bodoky F Ciardiello A D Hoore A Diaz Rubio JY Douillard M Ducreux A Falcone A Grothey T Gruenberger K Haustermans V Heinemann P Hoff K Köhne R Labianca P Laurent-Puig B Ma T Maughan K Muro N Normanno P Österlund W Oyen D Papamichael G Pentheroudakis P Pfeiffer T Price C Punt J Ricke A Roth R Salazar W Scheithauer HJ Schmoll J Tabernero J Taieb S Tejpar H Wassan T Yoshino A Zaanan

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12 Treatment of metastatic disease Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

13 Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

14 Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

15 Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

16 Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

17 Figure 1: toolbox of ablative treatments Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

18 Local and ablative treatment (including surgery) Recommendation 12: perioperative treatment. Both technical criteria for resection and prognostic considerations define the need for systemic perioperative therapy [IV, B]. In patients with clearly resectable disease and favourable prognostic criteria, perioperative treatment may not be necessary and upfront resection is justified [I, C; consensus >75%]. In patients with technically resectable disease where the prognosis is unclear or probably unfavourable, perioperative combination chemotherapy (FOLFOX or CAPOX) should be administered [I, B; consensus >75%]. Targeted agents should not be used in resectable patients where the indication for perioperative treatment is prognostic in nature [II, E]. Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

19 Local and ablative treatment (including surgery) recommendation 12: perioperative treatment. In situations where the criteria for prognosis and resectability are not sharply defined, perioperative therapy should be considered (as part of a continuum of treatment option) [IV, B] (Figure 2). Patients with synchronous onset of metastases should be allocated to this group and therapeutic pathway. In patients with favourable oncological and technical (surgical) criteria, who have not received perioperative chemotherapy, there is no strong evidence to support the use of adjuvant chemotherapy [II, C], whereas patients with unfavourable criteria may benefit from adjuvant treatment [III, B]. In patients who have not received any previous chemotherapy, adjuvant treatment with FOLFOX or CAPOX is recommended (unless patients were previously recently exposed to oxaliplatin-based adjuvant chemotherapy) [IV, B]. Decision-making should include patients characteristics and preferences [IV, B]. Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

20 PFS (%) EORTC Peri-operative chemotherapy FOLFOX PFS in eligible patients % 28.1% LV5-FU + oxaliplatin peri-operative CT Surgery only HR = 0.77 (95% CI, ) P = year PFS: + 8.1% No. at risk: Years CT, chemotherapy. Nordlinger B Van Cutsem E, et al. Lancet 2008;371:

21 New EPOC Study: Trial Design in resectable and borderline resectable patients Operable (including borderline operable) colorectal liver metastases KRAS wild-type 672 pts screened 272 pts randomised R Chemotherapy 3 months Liver resection Chemotherapy 3 months Chemotherapy + Cetuximab 3 months Liver resection Chemotherapy + Cetuximab 3 months Chemo FOLFOX (68% vs 67%) CAPOX (27% vs 24%) Primrose J, et al. Lancet Oncology 2014

22 PFS (%) New EPOC PFS of all randomised WT KRAS patients (primary analysis) Median (months) Arm A (CT) 20.5 Arm B (CT + cetuximab) HR = 1.48 (95% CI, ); P = No. at risk: Time (months) Primrose J, et al. Lancet Oncol 2014;15:

23 Table 4. Drivers for first-line treatment Tumour characteristics Clinical presentation: Tumour burden Patient characteristics Age Treatment characteristics Toxicity profile Tumour localisation Tumour biology Performance status Flexibility of treatment administration RAS mutation status Organ function Socio-economic factors BRAF mutation status Comorbidities, patient attitude, expectation and preference Quality of life Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

24 Treatment of metastatic disease Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

25 Treatment of metastatic disease Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

26 Treatment of metastatic disease Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

27 Treatment of metastatic disease Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

28 Treatment of metastatic disease Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

29 Local and ablative treatment (including surgery) Recommendation 13: conversion therapy. In potentially resectable patients (if conversion is the goal), a regimen leading to high RRs and/or a large tumour size reduction (shrinkage) is recommended [II, A]. There is uncertainty surrounding the best combination to use as only few trials have addressed this specifically: In patients with RAS wild-type disease, a cytotoxic doublet plus an anti-egfr antibody seems to have the best benefit risk/ratio, although the combination of FOLFOXIRI plus bevacizumab may also be considered and, to a lesser extent, a cytotoxic doublet plus bevacizumab [II, A]. In patients with RAS-mutant disease: a cytotoxic doublet plus bevacizumab or FOLFOXIRI plus bevacizumab [II, A]. Patients must be re-evaluated regularly in order to prevent the overtreatment of resectable patients as the maximal response is expected to be achieved after weeks of therapy in most patients. Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

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31 Unresectable liver metastases Number of metastatic deposits <10 Max. diameter of lesions to be treated by RFA =4cm RF performed during laparotomy, laparoscopy, or percutaneously Ruers T. Van Cutsem E et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3501.

32 LOCOREGIONAL THERAPY CLOCC Study in patients with unresectable CLM

33 LOCOREGIONAL THERAPY CLOCC Study in patients with unresectable CLM Median follow-up = 9,7 years Ruers T. Van Cutsem E et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3501.

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35 SIRFLOX Study Design Prospective open-label RCT Primary endpoint: Progression-Free Survival (PFS) in the ITT population by independent central imaging Eligible patients Non-resectable liver-only or liverdominant mcrc* No prior chemo for advanced disease WHO performance status 0 1 Stratified by Presence of extrahepatic metastases Degree of liver involvement Intended use of bevacizumab Institution Randomised 1:1 n = 530 n = 263 enrolled mfolfox6 (+ bevacizumab) (1) n = 267 enrolled mfolfox6 (+ bevacizumab) (1) Y-90 resin microspheres Secondary endpoints: PFS in the liver Tumour response rate in the liver Tumour response rate at any site (RECIST 1.0) Hepatic resection rate Toxicity & safety (NCI CTCAEv3.0) Health-related quality of life Overall survival, in a pre-planned combined analysis 1. Bevacizumab allowed at investigator s discretion, per institutional practice Van Hazel G et al, J Clin Oncol 2016

36 SIRFLOX trial Van Hazel G et al, J Clin Oncol 2016

37 SIRFLOX trial Van Hazel G et al, J Clin Oncol 2016

38 Evidence of SIR-Spheres Y-90 resin microspheres in 1st-line Investigator n Treatment ORR ORR L PFS PFS L Survival Gibbs 267 SIR-Spheres % 78.7% mo nr SIRFLOX mfolfox (+bev) 263 mfolfox6 68.1% 68.8% mo nr (+bev) statistically significant data P=0.113 P=0.042 P=0.429 P=0.002 HR 0.69 SIR-Spheres Y-90 resin microspheres; nr: not reported; L in the liver van Hazel GA et al. J Clin Oncol 2016; 34:

39 Local and ablative treatment Recommendation 16: Embolisation For patients with liver-limited disease failing the available chemotherapeutic options Radioembolisation with yttrium-90 microspheres should be considered [II, B] Chemoembolisation may be also considered as a treatment option [IV, B]. Radioembolisation (and chemoembolisation) of CLM in earlier treatment lines may be interesting as consolidation treatment but should be limited to clinical trials. Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

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41 Synchronous liver metastases: clinical scenarios SCENARIO 1: Asymptomatic CRC and resectable synchronous CRCLM: No strong evidence on best scenario Expert recommendation: chemotherapy first 4-6 cycles But: LiverMetsSurvey: 5 y survival: 42 vs 47 % for CT first vs Surgery of primary first For mid and low rectal primary tumours: * RT is often needed * One-stage surgery should not be performed, unless limited hepatic disease and easy to resect primary

42 Synchronous liver metastases: clinical scenarios SCENARIO 2: Asymptomatic CRC and non-resectable synchronous CRCLM: Most frequently observed scenario Chemotherapy first (expert opinion): optimal chemotherapy (doublets or triplets + biologicals) But: LiverMetsSurvey: no 5 y survival difference: 31 vs 33% for CT first vs Surgery of primary first One-stage surgery should not be performed If metastases become resectable: experts recommend reverse approach: liver first LiverMetsSurvey: 5 y survival 42 % for reverse strategy vs 33% for colon first and 28% for one stage surgery RT: either before starting CT or in window between CT and surgery

43 Synchronous liver metastases: clinical scenarios SCENARIO 3: Symptomatic CRC and resectable synchronous CRCLM: No strong evidence on best scenario More difficult for rectal cancer than colon cancer (where often resection of the primary tumour is adviced) Bleeding: start with CT or RT Obstruction: derivative colostomy for rectal cancer if not resectable Results with stents have been poor Expert recommendation: chemotherapy first 4-6 cycles For mid and low rectal primary tumours: * RT is often needed * One-stage surgery should not be performed, unless limited hepatic disease and easy to resect primary

44 Synchronous liver metastases: clinical scenarios SCENARIO 4: Symptomatic CRC and non-resectable synchronous CRCLM: Aim: make the liver metastases resectable Bleeding: start with CT or RT Obstruction: derivative colostomy for rectal cancer if not resectable Results with stents have been poor Chemotherapy first (expert opinion): optimal chemotherapy (doublets or triplets + biologicals) One-stage surgery should not be performed If metastases become resectable: experts recommend reverse approach: liver first (unless primary is still very symptomatic) RT: either before starting CT or in window between CT and surgery

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