Unmet needs in intermediate HCC Korea University Guro Hospital Ji Hoon Kim
BCLC HCC Stage 0 PST 0, Child Pugh A Stage A C PST 0 2, Child Pugh A B Stage D PST > 2, Child Pugh C Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PST 0 Intermediate stage (B) Large, multinodular, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1 2 End stage (D) 1 HCC 3 nodules 3 cm Portal pressure/ bilirubin Increased Associated diseases Normal No Yes Resection Liver transplantation (CLT/LDLT) RF/PEI TACE Sorafenib Best supportive care Curative treatments (30 40%) Median OS > 60 months; 5-year survival 40 70% Target 20% OS: 20 months (45 14) Target 40% OS: 11 months (6 14) Target 10% OS: < 3 months EASL EORTC. J Hepatol. 2012;56:908 43.
Is BCLC optimal staging? LR χ²(p-value) AIC CLIP 319.541(<.0001) 7789.566 JIS 320.356(<.0001) 7792.751 CUPI 308.659(<.0001) 7800.448 BCLC 295.324(<.0001) 7817.783 Tokyo 262.502(<.0001) 7848.605 muicc 227.819(<.0001) 7883.288 Cammà C, Aliment Pharmacol Ther. 2008 Jul;28(1):62-75 Jae JE, Kim JH et al. KASL 2014 PO-69
A lack of clarity in BCLC B Torzilli G, Ann Surg. Ann Surg. 2013 May;257(5):929-37 Mazzaferro V, Ann Surg. 2013 Dec 23
BCLC B = Intermediate stage Performance 0 Child-Pugh A and B >5cm >3c m
Heterogeneity in BCLC B Bolondi L et al., Seminars in Liver Disease, 2012 Nov;32(4):348-59.
BCLC B subclassification BCLC Sub-Stage B1 B2 B3 B4 Child-Pugh Score 5-6-7 5-6 7 8-9 b Beyond Milan and within Ut-7 IN OUT OUT ANY ECOG (tumor related) PS 0 0 0 0-1 PVT NO NO NO NO 1st Option Alternative TACE LT TACE + Ablation TACE or TARE SOR CT TACE SOR BSC a This figure was redrawn to combine Figures 3 and 4 from the Bolondi publication b with severe/refractory ascites and/or jaundices c only if up-to-7 and PS 0 BSC, best supportive care; LT, liver transplantation; SOR, sorafenib; TARE, transarterial radioembolization LT c Bolondi L et al., Seminars in Liver Disease, 2012 Nov;32(4):348-59.
BCLC B subclassification - validation N=391, BCLC B in Italian Liver Cancer database B1 B2 B3 B4 P value Number 162 136 28 65 5 yr OS (%) 39.5 32.4 10.7 13.8 Median survival (mo) 34 24 15 12 <0.001 Piscaglia F, EASL 2013 abstarct 109
BCLC B subclassification - TACE N=466, BCLC B receiving TACE Ha Y et al. J Gastroenterol Hepatol 2014.
BCLC B subclassification - Validation N=375, BCLC B N=262, BCLC B receiving TACE Original New: - Compensated LC - Size - Number - AFP Jung HJ et al. KASL 2014, FP-106
BCLC HCC Stage 0 PST 0, Child Pugh A Stage A C PST 0 2, Child Pugh A B Stage D PST > 2, Child Pugh C Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PST 0 Intermediate stage (B) Multinodular, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1 2 End stage (D) 1 HCC 3 nodules 3 cm Portal pressure/ bilirubin Increased Associated diseases Normal No Yes Resection Liver transplantation (CLT/LDLT) RF/PEI TACE Sorafenib Best supportive care Curative treatments (30 40%) Median OS > 60 months; 5-year survival 40 70% Target 20% OS: 20 months (45 14) Target 40% OS: 11 months (6 14) Target 10% OS: < 3 months EASL EORTC. J Hepatol. 2012;56:908 43.
HCC treatment in Europe Pre-BCLC era Retrospectively enrolled 359 HCC patients in single center 45% Ann Surg Oncol (2011) 18:1964 1971
HCC treatment in Europe Post-BCLC era 15 trials in BCLC B; 9 - yttrium 90, capecitabine, irinotecan 6 - sorafenib Leoni S, Dig Liver Dis 2014
Survival benefit in TACE Lancet 2002;359:1734-9. Hepatology 2002;35:1164-71. Hepatology. 2003 Feb;37(2):429-42.
Limit of TACE in BCLC B TACE BCLC B with Child-Pugh A - AASLD BCLC B with Child-Pugh A & B7 Lancet 2002;359:1734-9, Hepatology. 2003 Feb;37(2):429-42. - EASL
Unresolved issue in TACE Anticancer drugs/dose (cisplatin/epi or doxorubicin/mitomycin/combination) Procedures (TACE/TOCE/TAE) Lipiodol Embolizing agents (gelfoam/pva/deb) Frequency (scheduled/on demand)
Objective response of TACE EASL or mrecist CR PR SD PD EASL 34% 34% 25% 7% mrecist 34% 28% 31% 7% Jung ES, Kim JH. J Hepatol. 2013 ;58(6):1181-7
Response decrease with size J Vasc Interv Radiol. 2013 Apr;24(4):509-17
Side effect of TACE Irreversible deterioration of liver function : 3-5.7% Treatment related mortality (within 30days) : 2.4% Radiology 1996;198:33 40 Cardiovasc Intervent Radiol. 2007;30(1):6-25.
Prognosis prediction in TACE Variable Score Albumin > 3.6 g/dl 1 Total bilirubin > 1mg/dl 1 AFP > 400ng/ml 1 Tumor size > 7cm 1 HAP A = 0 HAP B = 1 HAP C = 2 HAP D = 3, 4 Kadalayil L et al. Ann Oncol 2013;24:2565-2570
What are alternative Rx Liver transplantation Surgery Ablation Other locoregional Rx(DEB-TACE/TARE) Systemic therapy (Sorafenib) Combination treatment
Survival in LT in BCLC B Metroticket Model 1112 HCC with exceeding Milan who receiving LT during 2006-2007 The graph showed the 5 yr survival estimates considering the presence of microvascular invasion Exceeding Milan was defined by pathologically Mazzaferro V, Lancet Oncol. 2009 Jan;10(1):35-43
Survival benefit of LT in BCLC B Potential LT candidate In ITA.LI.CA HCC cohort (n=1328) (No vascular invasion, EHM, comorbidity) Monte Carlo simulation analysis 5 yr survival benefit in LT (months) BCLC 0 11.19 BCLC A 13.49 BCLC B, C 17.36 BCLC D 28.46 Vitale A, Lancet Oncol. 2011 Jul;12(7):654-62
Surgery Resected HCC (n=2046) in Europe Median 25 months f/u 5 yr OS BCLC 0-A : 61% BCLC B : 57% BCLC C : 38% BCLC B with Child A Receiving TACE in KUMC (n=120) Median survival 29 months 5 yr OS 23% Ann Surg. 2013 May;257(5):929-37.
Surgery Surgery and TACE N= 146, respectively - Propensity score model - Variables Surgery TACE P value CTP class A (%) 131 (90) 136 (93) NS Single tumor (%) 86 (59) 90 (62) NS Vascular invasion (%) 79 (54) 77 (53) NS 68% 29% BCLC stage B/C/D (%) 38/61/1 33/67/0 NS Ann Surg Oncol. 2012 Mar;19(3):842-9.
Surgery RCT of Partial hepatectomy (n=88) vs. TACE (n=85) Outside Milan without vascular invasion and EHM Child-Pugh A and B (n=1 and 5, respectively) 5 yr OS: 51.5% Median survival :41 months In TACE patients, LT or PH were allowed in case of CR. Repeated TACE or combined RFA were allowed in case of non-cr 5 yr OS: 18.1% Median survival :14 months Yin L, J Hepatol. 2014 Mar 17
DC Beads TACE Overall 6 months Tumor response in advanced disease All, p < 0.05 Cardiovasc Intervent Radiol 2010;33:41 52
Radioembolization Retrospective study (n=245) BCLC B (~50%) In BCLC B : 17.5 vs. 17.2 mo Salem R, Gastroenterology. 2011 140:497-507 Salem R, J Hepatol. 2012 ;56:464-73
Radioembolization Systemic review of literatures Monte Carlo case-based simulation BCLC B Median survival (mo) IECR ($) BCLC C Median survival (mo) IECR ($) TARE 16-338 17 +360 TACE 23-13 - P value <0.001 <0.001 ICER : incremental cost-effectiveness ratio Rostambeigi N, J Vasc Interv Radiol. 2014 May 23
Sorafenib 105 BCLC B patients Median OS: 14.5 vs. 11.4 months (HR = 0.72, CI: 0.38 1.38) Bruix J, et al. J Hepatol. 2012;57:821 9.
Sorafenib with DEB TACE SPACE trial Sorafenib + DEB-TACE vs. Placebo + DEB-TACE n=154 n=153 Child-Pugh A, BCLC B Variables TTP Time to VI/EHS OS HR (95% CI) 0.797 (0.588-1.08) 0.621 (0.321-1.20) 0.898 (0.606-1.330) P value 0.076 NS NS Median TTP : 5.54 vs 5.53 months (S vs P) No unexpected safety findings J Clin Oncology 2012:30: LBA154
TACE with RFA BCLC B TACE + RFA vs. BSC n=34 n=24 5 yr OS : 27% vs. 0% (p<0.0001) Median survival : 41 months vs. 9.3 months Tanaka M, Hepatol Res. 2014 Feb;44(2
TACE with RFA Within Milan with Child A or B Surgery vs. TACE + RFA n=154 n=176 - Propensity score model - N= 76, respectively 5 yr OS : 75% vs. 70% (p=0.393) 5 yr DFS :32% vs. 17% (p=0.048) Takuma Y. 2013 Dec;269(3):927-37
Flow of TACE in practice 1 died 47.7% 42.3% 9.6%* 72.2% 65% 41% 42.2%* 22% (33/151) Full progression /Liver function deterioration after 1 st TACE 29% (43/151) Full progression /Liver function deterioration until 2nd TACE * : Full progression/ Liver function deterioration J Hepatol. 2012 Dec;57(6):1258-67.
Failure/refractory to TACE Authors Definition Kudo et al. 2011 1 Intrahepatic lesion (>2 consecutive incomplete necrosis; >2 consecutive appearances of a new lesion (recurrence)) Appearance of vascular invasion Appearance of EHS Continuous elevation of tumor markers Yamanaka et al. 2012 2 TACE Failure Inability to select the feeding artery of the HCC because of arterial devastation Deterioration of liver function and/or Tumor thrombosis of the portal vein TACE Refractory Repetitive tumor recurrence in the liver Appearance of vascular invasion Appearance of distant metastasis Continuous increase in tumor marker levels after TACE Raoul et al. 2012 3 Patients with no response of treated tumor after 2 sessions of TACE Patients who experience serious toxicity 1. Kudo, et al. Dig Dis. 2011;29:339-364. 2. Yamanaka K, et al. J Gastroenterol. 2012;47:343-346. 3. Raoul JL, et al. Cancer Treat Rev. 2011;37:212-220.
ART (Assessment for Retreatment with TACE) BCLC A and B and received at least 2 TACE session within 90 days Training (n=107), Validation (n=115) Variables Overall survival ART-score points Child-Pugh score increase Absent 1 AST increase > 25% Absenct 1 HR 95% CI β +1 point 2.0 1.2-3.5 0.71 1.5 P-value (Cox regression) + 2 points 4.4 2.0-9.6 1.49 3 <0.001 Radiologic tumor response Present 8.4 4.5-15.5 2.13 4 <0.001 Present 1 Absent 1.7 1.1-2.6 0.51 1 0.026 Sieghart W, et al. Hepatology. 2013 Jun;57(6):2261-73.
ART (Assessment for Retreatment with TACE) BCLC A and B and received at least 2 TACE session within 90 days Training (n=107), Validation (n=115) Sieghart W, et al. Hepatology. 2013 Jun;57(6):2261-73.
Is ART useful? Kudo M, et al. Hepatology. 2014 Jun;59(6):2424-5 Yoo YJ, Kim JH, et al. KSAL 2014 Abstarct
ART or other prediction score BCLC A and B and received at least 2 TACE session within 90 days Training (n=182), Validation (n=94) Overall Survival (OS) Variable HR B Age <65 1 65 1.549 0.437 Pre-2nd <200 1 TACE AFP 200 2.071 0.728 Tumor Single 1 number Multiple 1.628 0.488 BCLC stage A 1 B 1.542 0.433 Pre-2nd A 1 TACE CTP B 1.988 0.687 class AABCN Score* P-value - 2.0 0.018-3.5 0.003-2.5 0.008-2.0 0.016-3.5 0.004 Yoo YJ, Kim JH, et al. KSAL 2014, PO-67
Subsequent Rx after TACE 1516 BCLC B receiving TACE as initial Rx 5 yr OS and median survival 52%, 61.8 mo 29%, 33.6 mo 12%, 25.1 mo 10%, 17.4 mo Other Rx include systemic Rx and BSC Heng-jun G, Liver Int. 2014 Apr;34(4):612-20
Sorafenib 176 Previous TACE failure Median OS: 11.9 vs. 9.9 months (HR = 0.75, CI: 0.49 1.14) Bruix J, et al. J Hepatol. 2012;57:821 9.
The strategy for improving prognosis BCLC B Patients selection TACE Patients selection TACE LT Resection RFA DEB-TACE TARE Sorafenib Combination
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