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

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

Barcelona Clinic Liver Cancer (BCLC) Staging Performance status Tumor characters Liver function Very early stage Single tumor < 2 cm CTP A or B Early stage Single tumor, or 3 tumors, all < 3 cm Intermediate stage Large multinodular Advanced stage 1 or 2 Vascular invasion or extrahepatic spread Terminal stage 3 or 4 Any CTP C A B C D

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

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

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

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

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

Hepatic Resection as the First-line Treatment for BCLC B/C Patients: Pros and Cons In favor of Against Resection had a low mortality and manageable morbitidy Resection is a maximally invasive procedure Resection can cure the disease Resection may be effective only initially Recurrence in the early postoperative period was frequently observed Rapid liver function deterioration with massive ascites formation after resection Resection offers better palliative effects than TACE Selection bias may exist in surgical group

Treatment Option for BCLC B/C HCC Resection TACE Sorafenib Simplicity - ++ +++ Safety Oncological efficacy Curability To prolong survival Treatment priority B C

Mortality Following Resection or TACE for HCC Patients (Taipei VGH) Resection TACE n 992 933 Mortality 7 (0.7%) 2 (0.2%)

BCLC B/C HCC: Treatment-related Mortality Author Resection TACE n Mortality Torzilli G (2013)1 1034 3.0% Zhong JH (2014)2 908 3.1% 351 2.8% Lei Y (2014)3 88 1.1% 85 0% Chang WT (2012)4 478 2.7% 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

Treatment Option for BCLC B/C HCC Resection TACE Sorafenib Simplicity - ++ +++ Safety + Oncological efficacy Curability To prolong survival Treatment priority B C

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

Treatment Option for BCLC B/C HCC Resection TACE Sorafenib Simplicity - ++ +++ Safety + Oncological efficacy Curability To prolong survival Treatment priority B C

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?

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.

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

Ann Surgery 2013;257:929. A retrospective study on 2046 HCC patients who underwent liver resection in 10 renowned centers BCLC 0-A 1012 50% BCLC B 737 36% BCLC C 297 14% 90-day mortality: 2.7%

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

Disease-free Survival Overall Survival Disease-free Survival 1 yr 3 yr 5 yr BCLC A 95% 80% 61% 77% 41% 21% BCLC B 88% 71% 57% 63% 38% 27% BCLC C 76% 49% 46% 28% 18% Torzilli G, et al. Ann Surgery 2013;257:929.

Short-term and long-term results are acceptable in these patients 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.

A retrospective study on 3856 HCC patients Gastroenterology 2014;146:1691 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

J Hepatol 2014;61:82 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

Overall Survival 1 yr 3 yr 5 yr median Liver resection 76.1% 63.5% 51.5% 41 m TACE 51.8% 34.8% 18.1% 14 m Yin L, et al. J Hepatol 2014;61:82

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?

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

n 5-year survival BCLC B 318 46% BCLC C 160 29% Operative mortality 13 2.7% As the overall surgical mortality is very low, resection can be considered as an option even in intermediate stage HCC. Chang et al. Surgery 2012;152:809

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).

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

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%)

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

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

台灣肝癌醫學會2014肝癌診療共識: Surgery (2) Contents Agree (6 voters) If agree, please give score of E and R 2. 多發性肝癌若侷限於單一肝葉，仍可有機會給予治癒性切除。若多發性肝癌發生於兩側肝葉， >3顆病灶，且位於肝深部或肝門侵犯，則不適合切除。(E-2, R-B) 6/6 (100%) E-2 : 6 (100%) R-B: 5 (83%) A: 1 (17%) Ref (1) Ho MC, et al. Ann Surg Oncol 2009;16:848 (2) Ishizawa T, et al. Gastroenterology 2008;134:1908 (3) Yau T, et al. Gastroenterology 2014;146:1691

If agree, please give score of E and R 台灣肝癌醫學會2014肝癌診療共識: Surgery (3) Contents Agree (6 voters) If agree, please give score of E and R 3. 肝癌單側門脈侵襲，仍可有機會給予治癒性切除。若發生門脈主幹侵襲或對側分支侵襲，則不適合切除。(E-2, R-B) 6/6 (100%) E-2 : 6 (100%) R-B: 5 (83%) C: 1 (17%) Ref (1) Liu PH, et al. Ann Surg Oncol 2014;21:1825 (2) Wu CC, et al. Arch Surg 2000;135:1273 (3) Chen XP, et al. Ann Surg Oncol 2006; 13:940 (4) Pawlik TM, et al. Surgery 2005; 137: 403

If agree, please give score of E and R 台灣肝癌醫學會2014肝癌診療共識: Surgery (4) Contents Agree (6 voters) If agree, please give score of E and R 4. 肝癌發生單枝肝靜脈侵襲，仍可有機會給予治癒性切除。若發生下腔靜脈或右心室侵襲，則不適合切除。(E-2, R-B) 6/6 (100%) E-2 : 5 (83%) 3: 1 (17%) R-B: 5 (83%) C: 1 (17%) Ref (1) Wu CC, et al. Surgery 2012;151:223 (2) Kokudo T, et al. J Hepatology 2014;61:583

If agree, please give score of E and R 台灣肝癌醫學會2014肝癌診療共識: Surgery (5) Contents Agree (6 voters) If agree, please give score of E and R 5. 肝癌發生單一器官肝外轉移，仍可有機會給予治癒性切除。若發生多處轉移或肝癌肝內病灶進展中，則不適合切除。(E-3, R-B) 6/6 (100%) E-2 : 3 (50%) 3: 3 (50%) R-B: 4 (67%) C: 2 (33%) Ref (1) Chan KM, et al. World J Gastroenterol 2009;15:5481 (2) Jung SM, et al. 2012;27:684 (3) Lin CC, et al. J Gastroenterol Hepatol 2009;24:815

Treatment Option for BCLC B/C HCC Resection TACE Sorafenib Simplicity - ++ +++ Safety + Oncological efficacy Curability To prolong survival Treatment priority B 1 2 3 C

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

Hepatic Resection for BCLC B/C HCC Practical and Ethical Consideration Ascites T.Bil > 2 (mg/dL) Alb<3 (g/dL) Technical curability Remnant <40% (LC+) Severe co-morbidities Patient reluctant Resection + No -

Potential confounding factors 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

Very poor outcome for TACE Ill-defined inclusion criteria J Hepatol 2014;61:82 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 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

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

“You ask, what is our aim. I can answer in one word: Victory “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)

In the fighting against HCC… “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.” Simplicity Less suffering Quality of life Disease clearance (+) Safety Survival

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