Hepatic Resection for BCLC B/C HCC: A Comprehensive Review

1. Hepatic Resection for BCLC Stage B and C HCC 周嘉揚 台北榮總 一般外科 Gar-Yang Chau, MD Professor of Surgery Department of Surgery Taipei Veterans General Hospital

2. Outline Hepatic resection for BCLC stage B and C 1) 目前的 正反意見(pros and cons) 2) 現在主要的爭議點在那裡 3) 提出update evidences 4) 如何design 研究解決unsolved issue

3. Barcelona Clinic Liver Cancer (BCLC) Staging 0 A B C D

4. Treatment Option for HCC CURATIVE THERAPIES Liver resection Liver transplantation Tumor ablation PALLIATIVE THERAPIES Chemoembolization Chemotherapy Radiation therapy Target therapy Curative Palliative Liver Transplant Liver Resection Tumor Ablation Chemoembolization Target Therapy Chemotherapy Supportive Therapy

5. BCLC Staging and Treatment Strategy, 2014 Semin Liver Dis. 2014;34:444 Resection is recommended only for those with single tumor, well-preserved liver function, and no evidence of portal hypertension

6. Concept of “ideal” candidates for resection in BCLC guidelines • 5 years survival > 50% • Operative mortality < 3% • Transfusion rate < 10% • Comparative survival with non-surgical treatment was not described as a consideration Bruix J, et al. Hepatology 2002;35:519

7. BCLC Staging and Treatment Strategy, 2014 Semin Liver Dis. 2014;34:444 N0 N0

8. BCLC Staging and Treatment Strategy, 2014 Semin Liver Dis. 2014;34:444 Resectable Resectable

9. Hepatic Resection as the First-line Treatment for BCLC B/C Patients: Pros and Cons

10. Treatment Option for BCLC B/C HCC

11. Mortality Following Resection or TACE for HCC Patients (Taipei VGH)

12. BCLC B/C HCC: Treatment-related Mortality • 1. Torzilli G, et al. Ann Surg 2013;257:929 • 2. Zhong JH, et al. Ann Surg 2014;260:329 • Lei Y, et al. J Hepatol 2014;61:82 • Chang WT, et al. Surgery 2012;152:809

13. Treatment Option for BCLC B/C HCC

14. Anatomical Resection of HCC: Offer a Chance for a Cure BCLC stage B BCLC stage C

15. Treatment Option for BCLC B/C HCC

16. Recently, an increasing number of studies have focused on the indication of hepatic resection in HCC patients with BCLC stages B and C. • Whether liver resection can yield better survival outcomes in BCLC B HCC? • Is there a role for liver resection in patients with BCLC C HCC?

17. Chang WT, et al. Hepatic resection can provide long-term survival of patients with non-early-stage hepatocellular carcinoma: extending the indication for resection? Surgery 2012;152:809. • Hsu CY, et al. Surgical Resection is Better than Transarterial Chemoembolization for Patients with Hepatocellular Carcinoma Beyond the Milan Criteria: A Prognostic Nomogram Study. Ann Surg Oncol 2015 Oct 20 • Liu PH, et al. Surgical resection versus transarterial chemoembolization for BCLC stage C hepatocellular carcinoma. J Surg Oncol 2015;111:404 • Liu PH, et al. Surgical resection is better than transarterial chemoembolization for hepatocellular carcinoma beyond Milan criteria independent of performance status. J Gastrointest Surg 2014;18:1623. • Liu PH, et al. Surgical resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis. Ann Surg Oncol 2014;21:1825.

18. 3 recently published articles on HCC 1) A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: Is it adherent to the EASL/AASLD recommendation? Torzilli G, et al. Ann Surgery 2013;257:929. 2) Development of Hong Kong Liver Cancer Staging System with treatment stratification for patients with hepatocellular carcinoma. Yau T, et al. Gastroenterology 2014;146:1691. 3) Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan criteria: A RCT. Yin L, et al. J Hepatology 2014;67:82

19. Ann Surgery 2013;257:929.

20. Torzilli G, et al. Ann Surgery 2013;257:929.

21. Torzilli G, et al. Ann Surgery 2013;257:929.

22. Conclusions • Liver resection is in current practice widely applied among HCC patients with BCLC B and C • Short-term and long-term results are acceptable in these patients • These justifying an update of the BCLC therapeutic guidelines Torzilli G, et al. Ann Surgery 2013;257:929.

23. A retrospective study on 3856 HCC patients • In BCLC B patients, radical therapies including resection was significantly better than TACE in 5-year overall survival (52% vs 19%) • In BCLC C patients, radical therapies including resection was significantly better than systemic therapy, 5-year survival (49% vs 0.07%) • In selected patients with BCLC B/C, liver resection can produce better survival than TACE or systemic therapy Gastroenterology 2014;146:1691

24. A randomized comparative study comparing HCC patients with BCLC B who underwent liver resection (n=88) or TACE (n=85) • Confined to patients with resectable multiple HCC outside of Milan Criteria J Hepatol 2014;61:82

25. Yin L, et al. J Hepatol 2014;61:82

26. Arguments persisted concerning the recommendation of hepatic resection for the treatment of BCLC stage B and C: • An unintentional selection bias in selecting better patients for liver resection • Staging of the patients undergoing resection should based in preoperative imaging rather than in examination of the resected specimens • RCT by Yin et al. can be criticized on the method of TACE and outcomes that were achieved • Argument concerning with a solitary HCC > 5 cm, to put patients either into BCLC A or B?

27. Recently, the BCLC team stresses that a single HCC above 5 cm should be classified as BCLC A - Forner A, et al. Nat Rev Clin Oncol 2014;11:525 - Bruix J, et al. Ann Surg 2015;262:e30

28. Chang et al. Surgery 2012;152:809

29. In this study, patients with single HCC >5 cm were included in stage B. • Recently the BCLC team emphasized that all single HCCs of any size with no satellites and/or vascular invasion should be classified as BCLC-A stage. • Stage reassignment is necessary (a single HCC above 5 cm was classified as BCLC A and not B).

30. Stage Reassignment of BCLC Stage A and B Patients 47% 41% BCLC A (n=659) BCLC A (n=533) BCLC B(n=221) BCLC B (n=347) BCLC C (n=194) BCLC C (n=194) Single HCC > 5 cm as BCLC B Single HCC > 5 cm as BCLC A

31. 1074 HCC patient undergoing hepatic resection, Taipei VGH, from 1991-2005 Patients with long-term (> 10 years) disease-free survival, still alive at the time of this analysis BCLC B total (n=221) Disease-free (n=32) (14.5%) BCLC C total (n=194) Disease-free (n=26) (13.4%)

32. Beyond the AASLD Guidelines… Recent Strategies in the Treatment of BCLC B and C HCC:In favor of Hepatic Resection as the First-line of Treatment • NCNN guidelines • The APASL recommendation • 台灣肝癌醫學會2014肝癌診療共識

33. NCCN Guidelines for the Treatment of HCC (version 1.2016) • Tumor size is not a determinant of hepatic resection • Resection can be considered in patients with • Limited and resectable multifocal disease • In HCC with major vascular invasion National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. 2016

34. 台灣肝癌醫學會2014肝癌診療共識: Surgery (2)

35. 台灣肝癌醫學會2014肝癌診療共識:Surgery (3)

36. 台灣肝癌醫學會2014肝癌診療共識: Surgery (4)

37. 台灣肝癌醫學會2014肝癌診療共識: Surgery (5)

38. Treatment Option for BCLC B/C HCC

39. Treatment strategy for BCLC stage B and C HCC Torzilli G, et al. Ann Surg 2015;262:e31

40. Hepatic Resection for BCLC B/C HCCPractical and Ethical Consideration

41. We need properly designed randomized controlled trials with adequate sample size comparing hepatic resection with state of the art TACE procedures in BCLC B and C patients • Potential confounding factors • Tumor staging • Liver function • Tumor location • Surgical margin • Need of extensive liver resection • Co-morbidities

42. Some issues • Very poor outcome for TACE • Ill-defined inclusion criteria • Patients in the TACE group had slightly larger tumors and slightly poorer liver function than those in the surgical cohort • No report on performance status • Only 7% of the patients screened met the inclusion criteria for being randomized J Hepatol 2014;61:82 Roayaie S. J Hepatol 2014;61:3 Metussin A, et al. J Heptal 2015;62:739 Pang Q, et al. J Hepatol 2015;62:748

43. Questions Remain Unanswered • To differentiate patients who are more likely to benefit from hepatic resection from those who are unlikely to benefit in such a heterogeneous BCLC stage B and C HCC population • To know which proportion these patients represent among the whole population of patients at BCLC stage B or C • We have to recognize that most patients with HCC in the world are treated at less specialized centers, and whether a more conservative approach might be reasonable

44. “You ask, what is our aim? I can answer in one word: Victory. Victory at all costs — Victory, however long and hard the road may be, for without victory there is no survival.” Sir Winston Churchill, (1874 – 1965)

45. “You ask, what is our aim? I can answer in one word: Survival. Survival at all costs — Survival, however long and hard the road may be, for without survival there is no victory.” • In the fighting against HCC… Simplicity Less suffering Quality of life Disease clearance (+) Safety Survival

46. Conclusions • In the treatment of BCLC B and C patients, many centers have offered liver resection to selected HCC patients • Evidence is appearing that liver resection produces better survival than TACE and sorafenib • Additional trials and data analysis are needed to demonstrate a clear benefit with resection over the normally recommended treatments, and to redefine the role of surgery in the treatment algorithm of HCC