Si Hyun Bae, 1,2,3 Do Seon Song, 1,2,3 Myeong Jun Song, 1,4 Woo Jin Chung, 1,5

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1 Comparison of efficacy between hepatic arterial infusion chemotherapy and sorafenib in advanced hepatocellular carcinoma with portal vein tumor thrombosis 1,2,3 Si Hyun Bae, 1,2,3 Do Seon Song, 1,2,3 Myeong Jun Song, 1,4 Woo Jin Chung, 1,5 Jae Young Jang, 1,5 Young Seok Kim, 1,6 Jun Yong Park, 1,7 Hyung Joon Yim, 1,8 Sung Bum Cho, 1,9 Soo Young Park 1 The Korean Liver Cancer Study Group, 2 The Catholic University Liver Research Center, 3 College of Medicine, The Catholic University of Korea, 4 Keimyung University School of Medicine, 5 Soonchunhyang University College of Medicine, 6 Yonsei University College of Medicine, 7 Korea University, 8 Hwasoon Chonnam National University Hospital, 9 Kyungpook National University

2 Introduction

3 Introduction Hepatic arterial infusion chemotherapy (HAIC) Used for the treatment of HCC for decades Theoretically more effective against HCC than systemic chemotherapy Increased local concentration Lower systemic toxicity Lack of randomized studies Not standard practice in many countries for patients with advanced HCC

4 Introduction Treatment with sorafenib may achieve a similar survival rate to that achieved by HAIC in advanced HCC Kudo M et al. Dig Dis 2011 Hiramine et al. Experimental and Therapeutic Medicine 2011

5 Aim To compare the efficacy of HAIC and sorafenib in advanced HCC with portal vein tumor thrombosis

6 Patients Advanced HCC patients (n=110) HAIC treatment group : 50 patients Sorafenib treatment group : 60 patients From Feb 2008 to Jan 2013, 7 Korean centers, retrospectively HAIC regimen 60 mg/m 2 cisplatin for 2 h on day mg/m 2 5-FU for 5 hours on days 1 3 with or without 35mg/m 2 epirubicin on day 1 Sorafenib (Nexavar, Bayer HealthCare, Leverkusen, Germany) 400mg, twice a day Inclusion criteria 1) Advanced HCC with portal vein tumor thrombosis 2) Child Pugh score 5-7 3) ECOG performance status 0-1 4) WBC 3,000 cells/mm 3 or ANC 1,000 cells/mm 3 5) Platelet count 50,000 cells/mm 3

7 Endpoint Primary endpoint Overall survival (OS) and time to progression (TTP) Secondary endpoint Treatment response Objective response : CR + PR Disease control : CR + PR + SD

8 Baseline characteristics Total Sorafenib HAIC (n=110) (n=60) (n=50) P value Mean age ± SD (yr) 55.1 ± ± ± Sex Male 82 (74.5) 44 (73.3) 38 (76) Femal 28 (25.5) 16 (26.7) 12 (24) Etiology HBV/HCV/Alcohol/Others 85/7/11/7 41/5/8/6 44/2/3/ Tumor maximal diameter (cm) <10cm >10cm Child-Pugh class A/B 92/18 47/13 45/ Portal vein thrombosis Vp2/Vp3/Vp4 12/30/68 5/16/39 7/14/ Extrahepatic metastasis Yes/No 33/77 21/39 12/ Stage AJCC (III/IV) 60/50 34/26 35/ Previous treatment Yes/No 40/70 21/39 19/ Combined locoregional treatment Yes/No 27/83 9/51 18/ Serum AFP (ng/dl) <200/ /73 20/38 15/

9 Treatment response mrecist CR PR SD PD p-value Sorafenib <0.001 HAIC P< % 90% 10 80% 70% 60% 50% 40% 30% 20% 10% 0% PD SD PR CR Sorafenib HAIC By χ 2 -test

10 Response rate Objective response Nonresponse Disease control Progressive disease Sorafenib HAIC p-value <0.001 P=0.214 P< % 90% 100% 90% 10 80% 70% % 70% 55 60% 60% 50% 40% 30% 20% Non-response Objective response 50% 40% 30% 20% Progress disease Disease control 10% 0% 10% % Sorafenib HAIC Sorafenib HAIC Objective response Disease control rate By χ 2 -test

11 Overall survival HAIC Sorafenib Median survival (P=0.011) Sorafenib: 5.5 months HAIC: 7.1 months No. at risk Sorafenib HAIC By Kaplan-Meier method

12 Time to progression HAIC Sorafenib Median TTP (P=0.034) Sorafenib: 2.1 months HAIC: 3.3 months No. at risk Sorafenib HAIC By Kaplan-Meier method

13 Prognostic factor (Survival and TTP) Variables Age <50/ 50 Gender Male/Female Tumor diameter <10cm/ 10cm Child-Pugh A/B Portal vein thrombosis Vp2/Vp3/Vp4 Extrahepatic spread Yes/No Treatment group Sorafenib/HAIC Previous treatment Yes/No Combined locoregional treatment Yes/No Serum AFP level (ng/dl) <200/ 200 Univariate (p-value) Overall survival Multivariate HR (p-value) 95% CI Univariate (p-value) Tumor progression Multivariate HR (p-value) 95% CI < By Cox-proportional hazard model

14 Adverse effect % Adverse effect Any grade Grade 1 Grade 2 Grade 3 Grade 4 HAIC Leukopenia (Overall AE Neutropenia : 100%) Anemia Thrombocytopenia Bilirubin ALT GI toxicity Sorafenib HFSR (Overall AE Alopecia :83.3%) Rash Diarrhea Fatigue Hypertension (%) Grade 1 Grade 2 Grade 3 Grade 4 Pre-HAIC Leukopenia 12 4 Neutropenia 8 14 Anemia Thrombocytopenia 48 8 Bilirubin 10 ALT 44 Assessed by CTCAE v. 4.0

15 Conclusion HAIC treatment is comparable with sorafenib treatment in terms of overall survival and time to progression in advanced HCC patients with PVTT. HAIC showed higher response rate than sorafenib treatment. Therfore, HAIC treatment can be an alternative to sorafenib treatment in advanced HCC with PVTT.

16 Thank you for your attention!

17 Option of Treatment (Catholic Univ.) - HCC stage C or refractory to TACE- HCC + PVT, N? M? Disease control (CR, PR, SD) HAIC Repeat HAIC control progression Repeat HAIC Op/LT TACE+RFA, RT etc 2 nd line systemic option Disease progression Sorafenib Disease control TACE+ etc.(rt) progression 2 nd line systemic option