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
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

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

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
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

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

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

12. 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

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

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
Resection
TACE
Sorafenib
Simplicity - ++
+++
Safety +
Oncological efficacy
Curability
To prolong survival
Treatment priority B C

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.
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%

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

21. 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.

22. 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.

23. 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

24. 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

25. 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

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. 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

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) 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

35. 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

36. 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

37. 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

38. 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

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 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 -

41. 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

42. 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

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
“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. 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

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