HCC with Intrahepatic Portal vein Tumour Should Be Treated by Systemic Therapy Rather Than Transarterial Therapy (Pros)

Transcription

1 HCC with Intrahepatic Portal vein Tumour Should Be Treated by Systemic Therapy Rather Than Transarterial Therapy (Pros) Yi-Hsiang Huang, MD, Ph.D. Professor, Division of Gastroenterology & Hepatology, Taipei Veterans General Hospital; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 2016 APPLE HK 1

2 Vp, staging in HCC by Liver Cancer Study Group of Japan Vp0: no tumor in portal vein Vp1: <2 nd order segmental branch invasion Vp2: 2 nd order segmental branch invasion Vp3: 1 st order (right/left main portal vein ) No Branch Vp4: main portal trunk or contralateral portal vein Main Portal vein tumor thrombosis (PVTT) of HCC is usually associated with a poor prognosis and is found in approximately % of patients at diagnosis. World J Hepatol 2015 June 18; 7(11): ; Liu PH, et al. Ann Surg Oncol 2014;21:

3 Sorafenib is the standard treatment for pt with PVT (BCLC guideline) HCC PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh C Very early stage (0) Single < 2 cm Carcinoma in situ Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Large, Multinodular, PS 0 Advanced stage (C) Portal invasion, EHS, CP-A/B, PS 1-2 Terminal stage (D) Single 3 nodules 3 cm Portal pressure/bilirubin Increased Associated diseases Normal No Yes Resection Liver transplantation RFA/PEI Curative treatments (30%); 5-yr survival: 40%-70% TACE Sorafenib RCTs (50%); 3-yr survival: 10%-40% Symptomatic (20%); survival < 3 mos Llovet JM, et al. AASLD; The Lancet

4 Sorafenib is the standard treatment for unresectable HCC with PVT (APASL guideline) Hepatol Int 2010; 4:

5 HONG KONG LIVER CANCER STAGING SYSTEM EVM, extrahepatic vascular invasion/metastasis. Early tumor: 5 cm, 3 tumor nodules and no intrahepatic venous invasion; Intermediate tumor: 1) 5 cm, either >3 tumor nodules or with intrahepatic venous invasion, or 2) >5 cm, 3 tumor nodules and no intrahepatic venous invasion; Locally-advanced tumor: 1) 5 cm, >3 tumor nodules and with intrahepatic venous invasion, or 2) >5 cm, >3 tumor nodules or/and with intrahepatic venous invasion, or 3) diffuse tumor. Poon RT. Gastroenterology 2014;146(7):

6 Phase III trial of sorafenib in advanced HCC (SHARP): Study design Eligibility Advanced HCC* ECOG PS 0-2 Child-Pugh A No prior systemic therapy Stratification Macrovascular invasion and/or extrahepatic spread (present vs absent) ECOG PS (0 vs 1/2) R A N D O M I S E Sorafenib 400 mg bid (n=299) Placebo (n=303) Primary endpoints OS TTSP Secondary endpoints TTP DCR Safety Geographic region 1 : 1 *Not eligible for, or had disease progression after surgical or locoregional therapies. Assessed by the Functional Assessment of Cancer Therapy-Hepatobiliary Symptom Index-8 (FSHI-8). Assessed using USA National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). MVI = macroscopic vascular invasion; EHS = extrahepatic spread; TTSP = time to symptomatic progression. 6 Llovet JM, et al. N Engl J Med 2008;359:378 90

7 Survival probability Probability of progression SHARP: Sorafenib prolonged OS by 44% and TTP by 74% Overall survival Time-to-progression Sorafenib (n=299) = 10.7 months Placebo (n=303) = 7.9 months 0.25 Sorafenib (n=299) = 5.5 months Placebo (n=303) = 2.8 months Time from randomisation (months) Time from randomisation (months) HR = 0.69 (95% CI: ; p < 0.001) HR = 0.58 (95% CI: ; p < 0.001) HR = hazard ratio CI = confidence interval Llovet JM, et al. N Engl J Med 2008;359:

8 Median Overall Survival (months) SHARP: Sorafenib prolonged OS irrespective of patient characteristics Sorafenib Placebo HR=0.69 HR=0.79 HR=0.75 HR=0.68 HR=0.71 HR=0.52 HR=0.77 HR=0.47 HR=0.59 HR=0.58 HR=0.76 Llovet JM et al. N Engl J Med 2008;359:378 90; Galle P et al. EASL 2008; Bolondi L et al. ASCO-GI 2008; Craxi A et al. ASCO 2008; Raoul J et al. ASCO 2008; Sherman M et al. ASCO 2008; Bruix J et al. EASL

9 SHARP:subanalyses Bruix J, et al. J Hepatol 2012;57:821 9

10 Survival probability Probability of progression Asia-Pacific study: Sorafenib prolonged OS by 47% and TTP by 74% Overall survival Time-to-progression 1.00 Sorafenib (n=150) = 6.5 months Placebo (n=76) = 4.2 months 1.00 Sorafenib (n=150) = 2.8 months Placebo (n=76) = 1.4 months Time from randomisation (months) HR = 0.68 (95% CI: ; p = 0.014) Time from randomisation (months) HR = 0.57 (95% CI: ; p < 0.001) HR = hazard ratio CI = confidence interval Cheng A-L, et al. Lancet Oncol 2009;10:

11 Median OS (months) Asia Pacific trial: exploratory subanalysis Exploratory subanalysis of the Asia Pacific trial Nexavar Placebo HR = % CI: HR = % CI: HR = % CI: HR = % CI: HR = % CI: Study overall Prior TACE ECOG PS 1/2 No MVI/ EHS MVI and/or EHS Cheng A-L, et al. Eur J Cancer. 2012;48:

12 SHARP+AP Analysis To identify prognostic factors for HCC and predictive factors of response to sorafenib treatment, a pooled analysis of 827 randomized patients in the SHARP (N=601) and AP (N=226) phase 3 trials was performed SHARP study To identify prognostic factors To assess consistency of the efficacy of sorafenib or identify predictive factors for treatment response Pooling Univariate analysis* Multivariate analysis* HR* Median OS** Interaction test* AP study *Using the Cox proportional hazard regression model; **based on Kaplan-Meier Methodology. Cheng AL, at al. Slides presented at: APPLE; July 3-5, 2015; Osaka, Japan. 4 12

13 Identification of Potential Predictive Factors OS by Tumor-Related Variables (Multivariate Analysis) Baseline Covariate * n (PBO; Sorafenib ) Events, n Median OS, months PBO Sorafenib HR (Sorafenib/PBO) [95% CI] Treatment Interaction P Value BCLC Stage B Stage C 113 (55; 58) 714 (324; 390) [ ] 0.69 [ ] Tumor burden Absent Present 229 (107; 122) 598 (272; 326) [ ] 0.77 [ ] MVI No Yes 515 (230; 285) 310 (148; 162) [ ] 0.69 [ ] EHS No Yes 365 (178; 187) 462 (201; 261) [ ] 0.84 [ ] MVI without EHS No Yes 689 (307; 382) 136 (71; 65) [ ] 0.53 [ ] Number of target lesions >3 208 (99; 109) 165 (79; 86) 147 (70; 77) 295 (130; 165) [ ] 0.59 [ ] 0.49 [ ] 0.85 [ ] Analyses of all tumor-related variables showed beneficial trends in the efficacy of sorafenib vs placebo (PBO). Patients with less tumor burden and no extrahepatic spread (EHS) appeared to have a greater magnitude of benefit. * Intent-to-treat population; in the sorafenib group, 1 patient with BCLC stage D was excluded; assessed using the Wald test of individual effects. 13 Cheng AL, at al. Slides presented at: APPLE; July 3-5, 2015; Osaka, Japan. 5

14 Comparison of treatment outcomes among SHARP, AP and real-world studies (Taiwan) Outcome TPE-VGH (n=149) Asian-Pacific study SHARP study Overall survival (mo) Median (95% CI) 8.0 ( ) 6.5 ( ) 10.7 ( ) Estimated 6-mo survival rate (%) NA Estimated 1-yr survival rate (%) 36.1 NA 44 Progression-free survival (mo) Median (95% CI) 2.5 ( ) 2.8 ( ) 5.5 ( ) Post-progression survival (mo) Median (95% CI) 4.6 ( ) - - Level of response, n (%) Complete response 3 (2.0) 0 0 Partial response 5 (3.4) 3.3% 2% Stable disease 59 (39.6) 54% 71% Progressive disease 63 (42.3) 30.7% NA Not assessable 19 (12.8) 12% NA 1. Llovet J, et al. N Engl J Med. 2008;359: Cheng A-L, et al. Lancet Oncol. 2009;10: Lee IC, et al. Medicine 2015 Apr;94(14):e688 14

15 Sorafenib treatment outcomes Outcome Overall survival, month (95% CI) Estimated 6-month survival rate (%) Estimated 1-year survival rate (%) Progression-free survival, month (95% CI) Post-progression survival month (95% CI) Overall, n=149 Vascular invasion (VI) only, n=57 (38.3%) Extrahepatic metastasis (Mets) only, n=50 (33.6%) 8.0 ( ) 7.4 ( ) 11.7 ( ) Concurrent VI and Mets, n=42 (28.2%) p 5.3 ( ) ( ) 2.6 ( ) 3.4 ( ) 1.8 ( ) ( ) 3.8 ( ) 7.7 ( ) 3.0 ( ) Level of response, n (%) Complete response 3 (2) 1 (1.8) 2 (4) 0 (0) Partial response 5 (3.4) 4 (7) 1 (2) 0 (0) Stable disease 60 (40.3) 22 (38.6) 23 (46) 15 (35.7) Progressive disease 62 (41.6) 21 (36.8) 22 (44) 19 (45.2) Not assessable 19 (12.8) 9 (15.8) 2 (4) 8 (19) Lee IC, et al. Medicine 2015;;94(14):e688 15

16 Sorafenib for HCC with PVTT Studies Group N OS in months Cheng AL, 2012 PVT and/or EHS ( ) Bruix J, 2012 PVT Pinter M, 2012 PVT and/or EHS Lee IC, 2015 PVT and/or EHS Zhang Y, 2015 Main PVT ( ) Song DS, 2015 PVT ( ) Edeline J, 2016 PVT de la Torre M, 2016 PVT ( ) Lee JM, 2016 PVT Cheng AL, et al. Eur J Cancer 2012;48: Bruix J, et al. J Hepatol 2012;57: Pinter M, et al. Radiology 2012;26:590 (Sor vs TACE) 4. Lee IC, et al. Medicine 2015;;94(14):e688 (real-world data) 5. Zhang Y, et al. The Oncologist 2015;20: (Sor vs Sor+TACE) 6. Song DS, et al. J Gastroenterol 2015;50: (Sor vs HAIC) 7. Edeline J, et al. Eur J Nucl Med Mol 2016; 43: (Sor vs Y90) 8. De la Torre M, et al. Liver Int doi: /liv (Sor vs Y90) 9. Lee JM, et al. Clinical and Molecular Hepatology 2016;22: (Sor vs TACE vs HR) 16

17 Transarterial Therapy 17

18 Recommendations for TACE in Patients with Hepatocellular Carcinoma -Clinical Practice Guidelines jointly issued by the EASL and the EORTC TACE is recommended for patients with intermediate-stage HCC (multinodular asymptomatic tumors without vascular invasion or extrahepatic spread) (GR: 1A) TACE is discouraged in patients with decompensated liver disease, advanced liver dysfunction, macroscopic invasion, or extrahepatic spread (GR: 1B) The use of drug-eluting beads has shown similar response rates than Gelfoam-lipiodol particles associated with less systemic adverse events (GR: 2B) Selective intra-arterial chemotherapy, bland embolization, and lipiodolization are not recommended for the management of HCC (GR: 2B) 18

19 Percent survival TACE vs Supportive Tx for unresectable HCC: a multi-center study in Taiwan TACE (n=425) VI+:80 (18.8%) - Supportive (n=51) VI+:8 (15.7%) P= Median OS TACE Supportive 16.5 mo 9.1 mo VI- VI mo 9.2 mo Months Huang YH, et al. Aliment Pharmacol Ther 2005;21:687 Huang YH 19

20 Cumulative survival of HCC patients with extra-hepatic metastasis in the TACE or control groups P<0.001 Median survival: 6.6 vs 3.2 mon. Before propensity analysis Lee IC, et al. Hepatol Int 2011 P=0.029 Median survival: 4.0 vs 3.0 mon. After propensity analysis mos: VI- (n=38) 8.5 mo ( ) VI+(n=67) 3.2 mo ( ) Huang YH 20

21 HCC with PVTT: TACE/TACI 281 patients were newly diagnosed to have HCC with PV invasion Repeated TACE/TACI, retrospective Median survival of 5.2 months Median OS Main PVT: 3.9 mo Branch PVT: 7.0 mo Kim KM, et al. Journal of Gastroenterology and Hepatology 2009;24:

22 TACE for Unresectable HCC with Portal Vein Tumor Thrombosis: A Prospective Comparative Study Between July 2007 and July 2009, a prospective two-arm nonrandomized study was performed TACE (n=84) vs Conservative tx (n=80) Segmental PVTT mos 10.2 m mos 7.1 months for TACE Major PVTT mos 5.3 m Luo J, et al. Ann Surg Oncol 2011;18:

23 TACE for Unresectable HCC with Portal Vein Tumor Thrombosis: A Prospective Comparative Study Variable TACE group (n = 82) Conservative group (n = 61) segmental PVTT (n = 39) major PVTT (n = 43) segmental PVTT (n = 19) major PVTT (n = 42) CR PR 9 (23.1%) 7 (16.3%) 0 (0%) 0 (0%) SD 21 (53.8%) 15 (34.9%) 7 (36.8%) 6 (14.3%) PD 9 (23.1%) 21 (48.8%) 12 (63.2%) 36 (85.7%) Only 16.3~23.1% of the cases with PVTT had partial response to TACE Survival factors: Treatment type TACE vs Conservative (OR, 2.113; 95% CI, ; P <0.001), PVTT extent (OR, 0.427; 95% CI, ; P <0.001), serum bilirubin (OR, 0.626; 95% CI, ; P = 0.009), and tumor size (OR, 0.678; 95% CI, ; P = 0.024) Luo J, et al. Ann Surg Oncol 2011;18:

24 TACE for the Treatment of HCC with PVTT (HR vs TACE) Between December 2002 and December 2007, 201 resectable HCC with PVTT received HR. 402 case-matched controls received TACE. PVTT was classified to 4 types: Type I, PVTT involves segmental branches of the portal vein Type II, PVTT extending to involve the right/left portal vein Type III, the main portal vein Type IV, the superior mesenteric vein TACE Tumor response Type I (n=54) Type II (n=136) Type III (n=166) Type IV (n=46) CR PR 6 (11.1) 32 (23.5) 28 (16.8) 4 (8.7) SD PD Peng ZW, et al. Cancer 2012;118:

25 TACE for the Treatment of HCC with PVTT (HR vs TACE) Type I PVTT Type II PVTT Type III PVTT Type IV PVTT Peng ZW, et al. Cancer 2012;118:

26 Efficacy of TACE Targeting Portal Vein Tumor Thrombus in Patients with HCC Retrospectively examine the tolerability and efficacy of TACE in patients with advanced HCC with portal vein tumor thrombus (PVTT). A total of 33 HCC patients with PVTT were analyzed Extent of PVTT: First-order branch 17 Second-order branch 12 Main portal vein 4 Parenchymal response In the peripheral PVTT (second-order portal branches) subgroup, MSTs of PVTT responsepositive and -negative patients were 18.2 and 5.9 months, respectively (p=0.04). In the major PVTT (main portal vein or first-order portal branches) subgroup, MSTs of PVTT response-positive and negative patients were 11.1 and 5.5 months, respectively (p=0.04). Tawada A, et al. Anticancer Research 2014;34: PVTT response p- CR+PR SD+PD Value CR+PR 12 8 <0.01 SD+PD

27 Adverse events after TACE Any [no. (%)] Grade 3/4 [no. (%)] Elevated ALT level 30 (90.9) 18 (54.5) Hyperbilirubinemia 25 (75.8) 1 (3.0) Hyponatremia 14 (42.4) 2 (6.1) Fever 20 (60.6) 0 Anemia 26 (78.8) 1 (3.0) Thrombocytopenia 20 (60.6) 2 (6.1) Tawada A, et al. Anticancer Research 2014;34:

28 TACE for Advanced HCC with PVTT -ctace vs DEB-TACE Retrospective analysis included a total of 133 patients, treated without cross-over and compared head-to-head by means or propensity score weighting Treatment ctace (n=95) DEB-TACE (n=38) Age>65 years 28 (27.4 %) 16 (42.1 %) BCLC class C 77 (81.1 %) 32 (84.2 %) D 18 (18.9 %) 6 (15.8 %) Portal Venous Thrombosis peripheral 22 (23.2 %) 13 (34.2 %) main 33 (34.7 %) 12 (31.6 %) extrahepatic 40 (42.1 %) 13 (34.2 %) The survival was 5.00 months (95 % CI, ) vs months (95 % CI, ) for ctace and DEB-TACE, respectively (p =0.153). The subgroup survival analysis according to the SHARP criteria demonstrated a mos of 8.1 months vs. 5.3 months in the ctace and DEB-TACE group, respectively (p = 0.053) Gorodetski B,.. Geschwind J-F. Eur Radiol 2016 DOI /s

29 TACE for Advanced HCC with PVTT -ctace vs DEB-TACE SHARP criteria ctace DEB-TACE Clinical Toxicity N=190 N=62 PES 57 (30.0 %) 38 (61.3 %) encephalopathy 11 (5.8 %) 2 (3.2 %) 30-Day-Mortality 11 (5.7 %) 4 (6.3 %) The survival was not satisfactory with potential life-threatening AE by TACE Gorodetski B,.. Geschwind J-F. Eur Radiol 2016 DOI /s

30 BCLC stage B-C: TACE for Unresectable Advanced HCC (>10cm) Larger tumor size is an independent prognostic factor in both resectable and unresectable HCC. Median OS.: 9.1m vs 2.1m TACE is the only treatment option for unresectable HCC larger than 10cm in diameter. 31 TACE ( cm), 26 control ( cm) Child A/B: 74%/26% vs 77%/23% TACE-related mortality: 2 in TACE group (7%) Huang YH, et al. Aliment Pharmacol Ther 2006;23:129 Huang YH 30

31 BCLC stage B-C: TACE for Unresectable Advanced HCC (>10cm) Larger tumor size is an independent prognostic factor in both resectable and unresectable HCC. TACE is the only treatment option for unresectable HCC larger than 10cm in diameter. 31 TACE ( cm), 26 control ( cm) Child A/B: 74%/26% vs 77%/23% VI+ TACE: 10 (32.3%) Control: 14 (53.8%) Median OS: VI mo ( ) VI mo ( ) Huang YH, et al. Aliment Pharmacol Ther 2006;23:129 Huang YH 31

32 Sorafenib vs TACE for PVTT TACE+Sorafenib vs Sorafenib TACE+Sorafenib vs TACE 32

33 Cancer 1997; 79: Huang YH 33

34 Sorafenib+TACE vs Sorafenib in HCC with PVTT Between January 2009 and June 2013, consecutive patients with advanced HCC and Main PVTT were retrospectively reviewed. Of these, 89 patients with advanced HCC and MPVTT were enrolled: 45 sorafenib-tace group, 44 sorafenib group. mos:7 vs 6 mo TACE could not provide additional beneficial effect in HCC with main PVTT Zhang Y, et al. The Oncologist 2015;20:

35 Sorafenib Combined with TACE versus TACE Alone for Advanced-Stage HCC (subgroup) Advanced HCC with PVTT, retrospective Main PVT: Combo n=20, TACE mono n=35 Branch PVT: Combo n=21, TACE mono n=45 mos:5.8 VS 4.7 mo P=0.06 mos:7.5 VS 5.0 mo P=0.032 Main PVT Branch PVT Hu H, et al. PLoS ONE 2014;9(5): e96620 SOR+TACE >> TACE 35

36 TACE+Sorafenib vs TACE in HCC with PVTT Consecutive patients with HCC and PVTT who underwent TACEsorafenib or TACE alone from January 2010 to December 2012 were retrospectively evaluated. PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C) 46 patients underwent TACE-sorafenib and 45 underwent TACE. Characteristic TACE-Sorafenib TACE Group (n = 45) Group (n = 46) Location of PVTT Main portal vein 10 (22) 11 (24) First-order portal vein 19 (41) 21 (47) branch Second- or lower-order portal vein branches 17 (37) 13 (29) Zhu K, et al. Radiology 2014;272:

37 TACE+Sorafenib vs TACE in HCC with PVTT Disease control rate for TACE-sorafenib group: 57% vs TACE-alone group: 13%, p<0.001 Zhu K, et al. Radiology 2014;272:

38 TACE+Sorafenib vs TACE in HCC with PVTT TACE-sorafenib may improve overall survival in patients with HCC with first-order or lower-branch PVTT when compared with TACE alone. SOR+TACE >> TACE OS 11 vs 6 mo Type A OS 3 vs 3 mo OS 13 vs 6 mo Type B Type C OS 15 vs 10 mo Zhu K, et al. Radiology 2014;272:

39 Summary of TACE for HCC with PVTT Median Survival Luo J, et al. Ann Surg Oncol 2011 Segmental PVTT Main PVTT Response Rate 10.2 mo 5.3 mo % Kim KM, et al. JGH mo 3.9 mo Peng ZW, et al. Cancer 2012 Niu ZJ, et al. Med Oncol Tawada A, et al. Anticancer Research mo % mo mo mo mo 36.3% Hu H, et al. PLoS ONE mo 4.7 mo Zhu K, et al. Radiology mo 3.0 mo 13% Gorodetski B, et al. Eur Radiol mo Only responders have the survival benefit from TACE, but there are high risk of AE from the procedure. 39

40 Radioembolization for HCC with PVTT HAIC for PVTT 40

41 TARE with yttrium-90 microspheres in HCC patients with PVTT Study PVTT status Number OS, months Salem et al. (2010) (glass) Hilgard et al. (2010) (glass) PVTT (mixed) First-order Main PVTT (mixed: 12 main, 12 second- and first-order, 9 unknown) Sangro et al. (2011) (resin) Inarrairaegui et al. (2010) (resin) PVTT (mixed: 32 main, 44 first-order) PVTT (mixed: 6 main, 19 second- and first-order) Tsai et al. (2010)(glass and resin) Kulik et al. (2008) (glass) First-order 12 7 Main First-order Main

42 Radioembolization for HCC with portal vein thrombosis 63 patients with HCC and PVT (CP-A:35, CP-B7:27) underwent 90 Y radioembolization. CP-A CP-B Lobar PVT 15.7 ( ) 6.5 ( ) Main PVT 9.0 ( ) 5.8 ( ) Of the 29 CP-A patients who progressed, 45% maintained their CP status at progression (55% decompensated to CP-B). Of the 15 CP-B7 patients who progressed, 20% improved to CP-A, 20% maintained their CP score and 60% decompensated. Memon K, et al. J Hepatol 2013;58:

43 RCTs to Compare Radioembolization vs Sorafenib in HCC with PVTT: Still Ongoing SorAfenib Versus RADIOEMBOLIZATION (SIR-Spheres) in Advanced Hepatocellular Carcinoma (SARAH) NCT Efficacy Evaluation of TheraSphere to Treat Inoperable Liver Cancer With Blockage of the Portal Vein (YES-P) NCT (BTG) Data from prospective RCTs are not available now! 43

44 Sorafenib and hepatic arterial infusion chemotherapy for advanced HCC with PVTT A total of 110 patients were observed between February 2008 and May 2013 in seven Korean centers. 50 HAIC, 60 sorafenib No significant difference in the objective response rate (p = 0.214). The median overall survival (OS) HAIC vs sorafenib group: 7.1 vs. 5.5 months, p = HAIC is comparable with sorafenib in terms of OS and TTP in advanced HCC patients with PVTT Song DS, et al. J Gastroenterol 2015;50:

45 Conclusions TACE is not recommended in HCC patients with PVTT, especially with Main PVTT. Only small portion of the cases with PVTT respond to TACE, potential life-threatening AE should be aware of when performing the procedure. Determinants of response to TACE before the procedure are not yet identified. Further data from prospective studies or RCT are required for TARE with Yttrium-90 or HAIC. Systemic therapy with sorafenib is still the standard of care as the 1 st line treatment for unresectable advanced HCC with PVTT 45

46 46