Portal Vein Invasion and the Role of Liver Directed Therapy. Matthew S Johnson MD FSIR Indiana University May 6, 2016

Transcription

1 Portal Vein Invasion and the Role of Liver Directed Therapy Matthew S Johnson MD FSIR Indiana University May 6, 2016

2 Matthew Johnson, M.D., FSIR Stock: Endoshape Consultant/Advisory Board: Bayer, BTG, Boston Scientific, CeloNova (now part of BSC), Cook, Scientia, Surefire Research Grants: I am national PI for the PRESERVE study, supported by ALN, Argon, B Braun, Bard, Cook, Cordis, and Volcano; I was site PI for the Novate SENTRY study, now completed; I was PI for a retrospective dosimetry study sponsored by BTG, now completed

3 Reference Unlabeled/Unapproved uses of drugs or products: SirSphere is approved only for the treatment of colorectal cancer metastatic to the liver when used in conjunction with intraarterial floxuridine. As such, it's use is almost always offlabel TheraSphere is approved only for the treatment of unresectable hepatocellular carcinoma. Its use for other types of tumors is off-label. No microsphere/drug combination is approved for use in the treatment of cancer. All such combinations are therefore off-label.

4 nexavar-us.com

5 BCLC C BCLC C Analysis of 582 BCLC patients (78.7% w HBV) with PVI and/or extrahepatic spread (EHS) PVI divided into non; type 1-seg/sectoral branch; type II- L and/or RPV; type III main PV Extent of PVI was independent predictor of survival (as was type of EHS) mos = 11.7 mo for PVI-0/I w/o distant (d) EHS; 5.7 mo for PVI-II/III w/o dehs; 4.9 mo for PVI-0/I with dehs, and 2.3 months for PVI-II/III w dehs Sinn et al. PLoS One April 29; 10(4):e

6 Portal Vein Involvement and Our Ability to Optimize Treatment Portal vein involvement (PVI) PVI Likely survival for patients with HCC and various extents of PVI is not well known Whether there is PVI is difficult to assess Whether PVI means PV tumor or bland thrombus is difficult to assess

7 Untreated HCC Meta-analysis of 30 RCT of HCC with placebo or no-treatment arms through 2009 Primary outcomes were 1 and 2 y OS, = 17.5% and 7.3% respectively Heterogeneity among studies was highly significant (p < ) and persisted when RCTs were stratified Impaired performance status, CP B-C class, and presence of PV thrombosis were all independently associated with shorter survival Cabibbo et al. Hepatology 2010; 51:

8 Discerning the Nature of PVI: Is PVI Malignant? 33 Italian pts w HCC + PVI considered for OLT PVI considered benign if No vascularization on CEUS, CT, or MR, and Absence of mass-forming features of thrombus, and Absence of disruption of the walls of the veins, and [If uncertainty persisted] biopsy showed no malignancy 14 pts w benign PVI had OLT w no PV malig on bx OLT contraindicated in 9 pts w confirmation or strong suspicion of malignant PVI Pscaglia et al. Liver Transpl 2010; 16:

9 Discerning the Nature of PVI: Is PVI Malignant? Review of diffusion weighted (DW) and conventional MRI in 36 patients w HCC + PVI 16 pts w PVI in size in 3 months despite anticoagulation considered to have malignant PVI 20 pts w stable or PVI over 12 months benign The only parameter to predict type of PVI was the size of HCC (p = 0.05) DWI (incl apparent diffusion coefficient) did not assist in ddx malignant from benign PVI Sandrasegaran et al. AJR 2013; 201:

10 Discerning the Nature of PVI: Is PVI Malignant? Review of diffusion weighted (DW) and conventional MRI in 36 patients w HCC + PVI The presence of 2 of the following had a sensitivity of 100% & specificity of 90% for malignant PVI Distance from tumor to PVI < 2 cm HCC size > 5 cm Arterial enhancement of PVT Sandrasegaran et al. AJR 2013; 201:

11 Hepatocellular Cancer with PVI: Treatment Options Conservative care Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy

12 Hepatocellular Cancer with PVI: Treatment Options Conservative care (± PVT, 17.5% 1 year OS) Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy

13 Sorafenib: The SHARP Trial Multicenter double-blind placebo-controlled RCT of 602 patients with advanced HCC Macroscopic vascular invasion in 36% in sorafenib group, in 41% in placebo group; extrahepatic spread in 53% and 50% 82 % 83% BCLC C mos 10.7 months in SOR vs 7.9 months in PLA (p < 0.001, data not powered for subgroup analysis) 1 year survival 44% in SOR versus 33% in PLA Llovet et al. N Engl J Med. 2008; 359:

14 Sorafenib in Patients with HCC + PVI Review of 30 Korean patients w advanced HCC + PVI treated with sorafenib All ECOG 1 or 2, Child-Pugh A or B 3 (10%) had PR w PV revascularization; 9 (30%) had stable disease Median PFS was 2 months Median OS was 3.1 months Jeong et al. Gut Liver 2013; 7:

15 Hepatocellular Cancer with PVI: Treatment Options Conservative care Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy

16 Surgical Resection Review of Chinese patients with HCC + PV tumor thrombus (PVTT) who underwent partial hepatectomy w or w/o portal thrombectomy PVTT divided into 1 segmental/sectoral branch(es) 2 Left and/or right portal vein 3 Main portal vein 4 Superior mesenteric vein Shi et al. Ann Surg Oncol 2010; 17:

17 Surgical Resection 406 patients Complication and in-hospital mortality rates of 32.8% and 0.2% respectively After median f/u of 6.4 months, 128 (31.5%) died 1 and 3 year OS 34.4% and 13% 1 and 3 year disease free survival 13.3 and 4.7% PVTT limited to R or L or smaller vein significantly longer OS than if more prox PVTT Shi et al. Ann Surg Oncol 2010; 17:

18 Surgical Resection Review of 89 Chinese patients with HCC and PVTT who underwent resection Excluded pts w extrahepatic disease, PVTT involving the SMV, and/or hepatectomy w + margin Post hoc division of pts into 3 groups 1 Ipsilateral PVTT resected w hepatectomy (72) 2 PVTT extending to main PV, resected en bloc (10) 3 PVTT extending to main PV, thrombectomy (7) Chok et al. World J Surg 2014; 38:

19 Surgical Resection OR times, in-hospital mortality, complications hours, 2/72 (2.8%), 23/72 (31.9%) hours, 1/10 (10%), 5/10 (50%) hours, 0/7 (0%), 5/7 (71.4%) Median disease free and overall survival months, 10.9 months months, 9.4 months months, 8.6 months Chok et al. World J Surg 2014; 38:

20 Surgery For PVI Not Extending to Main Portal Vein Review of 172 HCC patients with PVTT not extending to main PV 40 surgical resection; 80 TACE; 52 Sorafenib OS: surgery 19.9; TACE 6.6; Sor 6.2 months Surgery OS significantly longer (p < 0.001) Review of 62 HCC patients w (not main) PVTT who underwent resection and thrombectomy OS at 1, 3, 5 years: 53.3%, 30.1%, and 20% 1. Lee et al. Clin Mol Hepatol Mar; 22 (1): Pesi et al. Am J Surg. 2015; 210 (1):35-44.

21 Hepatocellular Cancer with PVI: Treatment Options Conservative care Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy

22 Radiation Therapy Phase 2 study of 60 pts w HCC & NO PVT 1 Review of 181 Chinese patients 2 with HCC + PVTT treated with EBRT to PVTT ± 1 tumor Median dose 50 Gy, range Gy mos 10.2 months for patients w PV branch tumor, 7.4 months for patients with main PV tumor One of the negative predictors for OS was inability to get TACE after EBRT 1. Andolino et al. Int J Radiat Oncol Biol Phys 2011; 81:e447-e Hou et al. Int J Radiat Oncol Biol Phys 2012; 84:

23 Radiation Therapy Korea 1 : 45 pts, med 61.2 Gy to PV ± 1, CR + PR (of portal vein tumor) in 62.3% Korea 2 : 35 pts, PVTT involved main PV in 51.4%, med 50 Gy, capecitabine given to all, CR + PR 43% Japan 3 : 57 pts, Gy, CR + PR in 45% 1. Rim et al. Japan J Clin Oncol 2012; 42: Kim et al. Radiat Oncol 2013; 8: Tanaka et al. J Gastroenterol Hepatol 2014; 29:

24 Radiation Therapy Canada 1 : 29 CP B/C (69% CPS 7) patients w HCC ± PVTT (present in 76%) treated w SBRT Median dose 30 Gy, median OS 7.9 months Japan 2 : review of 40 pts w HCC & PVTT Rx d w sorafenib & 57 w RT (med 50 Gy) no dif in OS Korea 3 : 46 pts, 30 w main or B PVTT, med dose 50 Gy, CR + PR (PVTT) in 32.6%, 1 year survival in 15 responders was 66.8% 1. Culleton et al. Radiother Oncol : Nakazawa et al. BMC Gastroenterol 2014; 14:84 3. Lee et al. Radiat Oncol J 2014; 32:

25 Radiation Therapy Review of 106 patients with HCC and PVTT referred for radiotherapy Complete Response in 10; PR in 55 patients RT allowed subsequent surgery in 12 TACE was performed in 19 patients after RT 1 and 2 OS rates of 34.7 and 11% respectively mos = 7 months Yeh et al. J Radiat Res. 2015; 56:

26 Hepatocellular Cancer with PVI: Treatment Options Conservative care Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy

27 Hepatic Artery Infusion 25 Japanese pts 1 w HCC & PVTT & no prior Rx treated with HAI (cisplatin) in a phase 2 trial HAI via PHA q4-6 weeks for max of 6 courses Med 3 (1-6) courses w CR in 1, PR in 6 28% RR Med PFS, OS, 1 y OS = 3.6 mo, 7.6 mo, 40.3% Review of 50 Korean pts 2 w HCC & PVTT Rx w HAI (epirubicin, cisplatin, 5-FU) q3-4 weeks 3 CR + 13 PR 32% RR Med PFS & OS = 2 months & 7 months 1. Ikeda et al. Cancer Chemother Pharmacol 2013; 72: Song et al. World J Gastroenterol 2013; 19:

28 HAI Versus Sorafenib Review of 110 Korean pts w HCC + PVTT, 50 Rx w HAI, 60 Rx w sorafenib mttp & mos both significantly longer in HAI gp mttp = 3.3 versus 2.1 months (p = 0.034) mos = 7.1 versus 5.5 months (p = 0.011) Absence of concomitant LRT was one of the significant prognostic factors Song et al. J Gastroenterol 2014 July 16 (Epub)

29 Hepatocellular Cancer with PVI: Treatment Options Conservative care Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy

30 Chemoembolization for HCC & PVTT 84 Chinese pts Rx d w TACE compared to 80 pts who had no Rx 1 1 y OS 30.9% vs 9.2% Not randomized; not matched populations 115 Chinese pts Rx d w TACE compared to 35 who refused TACE 2 mos 8.7 mo vs 1.4 mo Not randomized; not matched populations Meta-analysis of 5 prospective studies, 335 Rx w TACE vs 226 controls better OS w TACE, but several limitations to this analysis 1. Luo et al. Ann Surg Oncol 2011; 18: Niu et al. Med Oncol 2012; 29: Leng et al. ANZ J Surg 2014 Aug 3 (Epub)

31 Chemoembolization for HCC & PVTT Review of 188 consecutive Chinese CPS 5-7 pts (89% w HBV) Rx d w TACE mos was 6.1 months Extent of PVTT, number of tumors, CP class, and presence of metastases were independent predictors Liu et al. Biomed Res Int 2014;

32 TACE vs Resection for HCC & PVTT Case-control comparison (CCC) of resection (HR) in 201 Chinese pts compared to 402 pts Rx d w TACE, stratified for PVTT location 1 y OS 42% for HR group; 37.8% for TACE group HR OS better for type 1 and 2 PVTT, but not for type 3 or 4, multiple tumors, or tumors < 5 cm CCC of HR in 247, TACE in 181 Chinese patients HR pts sig younger, w better liver fxn, PS, & smaller tumors 1 y OS 85% for HR group; 60% for TACE group 1. Peng et al. Cancer 2012; 118: Liu et al. Ann Surg Oncol 2014; 21:

33 TACE For PVI Extending to Main Portal Vein Retrospective review of 418 HCC patients with tumor thrombus extending to the main PV 307 TACE; 54 Surgery; 15 sorafenib; 42 no Rx OS: TACE 10.4; OR 4.1; Sor 5.5; no Rx 2.8 months TACE OS significantly better than others (p < 0.05) Ye et al. World J Gastroenterol 2016 Apr 7; 22(13):

34 Hepatocellular Cancer with PVI: Treatment Options Conservative care Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy

35 Radioembolization for HCC + PVTT Safety demonstrated in report 1 of 15 pts w type 2 PVTT Rx d w glass microspheres (MS) Phase 2 study 2 of 108 pts (37 w PVTT, 12 involving main PV) Rx d with glass MS OS dependent upon location of PVTT Review of Y90 in 291 HCC pts ± PVTT CP A mos 17.2 months; CP B mos 7.7 months CP B w PVTT mos 5.6 months 1. Salem et al. JVIR 2004; 15: Kulik et al. Hepatology 2008; 47: Salem et al. Gastroenterology 2010; 138:52-64.

36 Radioembolization for HCC + PVI Review of 25 Spanish pts 1 w PVI (incl bland) Rx d w resin MS: mos = 10 months Review of 22 US pts2 w PVI (incl bland) Rx d w Y90: CP A mos = 7.7 mo; CP B/C = 2.7 mo Prospective study of Y90 in 52 Italian pts ECOG 0-1, CPS 7, lobar delivery targeting 120 Gy mttp 13 mo if no PVT, 7 mo if PVI (p = NS) mos 18 mo if no PVT, 13 mo if PVI (p = NS) 1. Iñarrairaegui et al. JVIR 2010; 21: Tsai et al. JVIR 2010; 21: Mazzafero et al. Hepatology 2013; 57:

37 Radioembolization for HCC + PVI Review of 291 US patients Rx d w Y90 Of them 63 CPS 7 pts had PVI mttp was dependent upon CP class CPS 5 & 6 mttp = 5.6 months CPS 7 mttp = 4.9 months mos was dependent upon CP class CPS 5 & 6 pt mos = 13.8 months CPS 7 mos = 6.5 months Memon et al. J Hepatolo 2013; 58:73-80.

38 Hepatocellular Cancer with PVI: Treatment Options Conservative care Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy

39 Combination Therapy for HCC + PVI RT + HAI vs HAI Interferon + HAI Sorafenib + HAI Sorafenib + RT Sorafenib + TACE TACE + RT TACE + RT vs OR + TACE TACE + RFA TACE + I125 stent No diff in OS Inadequate description Case report? Promising TACE/sor OS v T? in OS Suspect methodology Suspect methodology? Promising

40 Surgery for I-II; TACE (+) for III Review of 1580 patients with HCC & PVTT treated in 4 largest tertiary hospitals in China mos for 745 who had surgical resection for types I, II, and III were 15.9, 12.5, and 6 months Corresponding mos for TACE, TACE + sorafenib, and TACE + RT in PVTT types I, II, and III were 604 TACE: 113 TACE + sorafenib: 118 TACE + RT: 9.3, 4.9, and 4 months 12, 8.9, and 7 months 12.2, 10.6, and 8.9 months Concluded surgery was best for types I and II PVTT, and TACE + RT was best for type III Wang et al. Medicine (Baltimore) Mar; 95(11):e3015.

41 2015 Review of Reported Methods of Treating HCC + PVI In suitable patients, even surgical resection can be considered TACE can be performed effectively and safely in a carefully chosen population with reserved liver function and sufficient collateral blood flow TARE achieves QOL advantages and is as effective as TACE. A large proportion of HCC patients accompanying PVTT are considered to be proper for TARE Yu et al. World J Hepatol. 2015; 7:

42 Hepatocellular Cancer with PVI: Summary Conservative care Systemic treatment Surgical Resection Locoregional Therapies Radiation therapy (RT, radiotherapy, conformational radiotherapy, stereotactic body radiotherapy, etc.) Hepatic artery infusion Chemoembolization (TACE, DEB-TACE) Radioembolization (Y90) Combination Therapy