Unmet needs in intermediate HCC. Korea University Guro Hospital Ji Hoon Kim

Transcription

1 Unmet needs in intermediate HCC Korea University Guro Hospital Ji Hoon Kim

2 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:

3 Is BCLC optimal staging? LR χ²(p-value) AIC CLIP (<.0001) JIS (<.0001) CUPI (<.0001) BCLC (<.0001) Tokyo (<.0001) muicc (<.0001) Cammà C, Aliment Pharmacol Ther Jul;28(1):62-75 Jae JE, Kim JH et al. KASL 2014 PO-69

4 A lack of clarity in BCLC B Torzilli G, Ann Surg. Ann Surg May;257(5): Mazzaferro V, Ann Surg Dec 23

5 BCLC B = Intermediate stage Performance 0 Child-Pugh A and B >5cm >3c m

6 Heterogeneity in BCLC B Bolondi L et al., Seminars in Liver Disease, 2012 Nov;32(4):

7 BCLC B subclassification BCLC Sub-Stage B1 B2 B3 B4 Child-Pugh Score b Beyond Milan and within Ut-7 IN OUT OUT ANY ECOG (tumor related) PS 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):

8 BCLC B subclassification - validation N=391, BCLC B in Italian Liver Cancer database B1 B2 B3 B4 P value Number yr OS (%) Median survival (mo) <0.001 Piscaglia F, EASL 2013 abstarct 109

9 BCLC B subclassification - TACE N=466, BCLC B receiving TACE Ha Y et al. J Gastroenterol Hepatol 2014.

10 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

11 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:

12 HCC treatment in Europe Pre-BCLC era Retrospectively enrolled 359 HCC patients in single center 45% Ann Surg Oncol (2011) 18:

13 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

14 Survival benefit in TACE Lancet 2002;359: Hepatology 2002;35: Hepatology Feb;37(2):

15 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 Feb;37(2): EASL

16 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)

17 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 ;58(6):1181-7

18 Response decrease with size J Vasc Interv Radiol Apr;24(4):509-17

19 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.

20 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:

21 What are alternative Rx Liver transplantation Surgery Ablation Other locoregional Rx(DEB-TACE/TARE) Systemic therapy (Sorafenib) Combination treatment

22 Survival in LT in BCLC B Metroticket Model 1112 HCC with exceeding Milan who receiving LT during The graph showed the 5 yr survival estimates considering the presence of microvascular invasion Exceeding Milan was defined by pathologically Mazzaferro V, Lancet Oncol Jan;10(1):35-43

23 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 BCLC A BCLC B, C BCLC D Vitale A, Lancet Oncol Jul;12(7):654-62

24 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 May;257(5):

25 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 Mar;19(3):842-9.

26 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 Mar 17

27 DC Beads TACE Overall 6 months Tumor response in advanced disease All, p < 0.05 Cardiovasc Intervent Radiol 2010;33:41 52

28 Radioembolization Retrospective study (n=245) BCLC B (~50%) In BCLC B : 17.5 vs mo Salem R, Gastroenterology : Salem R, J Hepatol ;56:464-73

29 Radioembolization Systemic review of literatures Monte Carlo case-based simulation BCLC B Median survival (mo) IECR ($) BCLC C Median survival (mo) IECR ($) TARE TACE P value <0.001 <0.001 ICER : incremental cost-effectiveness ratio Rostambeigi N, J Vasc Interv Radiol May 23

30 Sorafenib 105 BCLC B patients Median OS: 14.5 vs months (HR = 0.72, CI: ) Bruix J, et al. J Hepatol. 2012;57:821 9.

31 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) ( ) ( ) ( ) P value NS NS Median TTP : 5.54 vs 5.53 months (S vs P) No unexpected safety findings J Clin Oncology 2012:30: LBA154

32 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 Feb;44(2

33 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 Dec;269(3):927-37

34 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 Dec;57(6):

35 Failure/refractory to TACE Authors Definition Kudo et al 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 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 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: Yamanaka K, et al. J Gastroenterol. 2012;47: Raoul JL, et al. Cancer Treat Rev. 2011;37:

36 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 P-value (Cox regression) + 2 points <0.001 Radiologic tumor response Present <0.001 Present 1 Absent Sieghart W, et al. Hepatology Jun;57(6):

37 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 Jun;57(6):

38 Is ART useful? Kudo M, et al. Hepatology Jun;59(6): Yoo YJ, Kim JH, et al. KSAL 2014 Abstarct

39 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 < Pre-2nd <200 1 TACE AFP Tumor Single 1 number Multiple BCLC stage A 1 B Pre-2nd A 1 TACE CTP B class AABCN Score* P-value Yoo YJ, Kim JH, et al. KSAL 2014, PO-67

40 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 Apr;34(4):612-20

41 Sorafenib 176 Previous TACE failure Median OS: 11.9 vs. 9.9 months (HR = 0.75, CI: ) Bruix J, et al. J Hepatol. 2012;57:821 9.

42 The strategy for improving prognosis BCLC B Patients selection TACE Patients selection TACE LT Resection RFA DEB-TACE TARE Sorafenib Combination

43 Thank you for your attention!