The 44th Congress of the Korean Association of HBP Surgery Staged Partial Hepatectomy Versus Transarterial Chemoembolization for the Treatment of Spontaneous Hepatocellular Carcinoma Rupture: A Multicenter Analysis in Korea. Hyung Soon Lee, MD1, Gi Hong Choi, MD1, Jin Sub Choi MD1, Kwang-Hyub Han, MD2, Sang Hoon Ahn, MD2, Do Young Kim, MD2, Jun Yong Park, MD2, Seung Up Kim, MD2, Sung Hoon Kim, MD3, Yoon Dong Sup, MD4, Jae Keun Kim, MD4, Jong Won Choi, MD5 , Soon Sun Kim, MD6, Hana Park, MD7   1Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. 2Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. 3Department of Surgery, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea. 4Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. 5Department of Internal Medicine, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea. 6Department of Internal Medicine, Ajou University Medical Center, Ajou University School of Medicine, Suwon, Korea. 7Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.

AJCC cancer staging manual. 7th ed. Chicago: Springer; 2009. Background Spontaneous rupture of hepatocellular carcinoma (HCC) - Considered as T4 stage (AJCC 7th) - Evokes risk of peritoneal metastasis AJCC cancer staging manual. 7th ed. Chicago: Springer; 2009.

Background An Analysis of 1160 Cases From a Nationwide Survey in Japan Spontaneous tumor rupture had an additional negative impact on the baseline tumor status. This impact corresponded to an additional 0.5 to 2.0 TNM stages. Aoki T et al. Ann Surg. 2014 Mar;259(3):532-42.

Chan AC et al. Surgery. 2015 Aug 18 Background Spontaneous tumor rupture affects the outcome of partial hepatectomy for T1T2 disease or tumor ≤ 10 cm only. Assigning all resectable ruptured tumors to T4 may overestimate the severity of disease. Chan AC et al. Surgery. 2015 Aug 18

Lee HS et al. World J Surg. 2014 Aug;38(8):2070-8 Background Unmatched After propensity score-matching. Spontaneously ruptured HCC with staged hepatectomy shows comparable long-term survival and recurrence pattern versus non-ruptured HCC, with similar tumor characteristics and liver functional status. Lee HS et al. World J Surg. 2014 Aug;38(8):2070-8

Background Although recent studies have shown favorable long-term outcomes of staged partial hepatectomy in well-selected cases, the optimal treatment modality in patients with ruptured HCC remains unclear. Resection and TACE mainly performed treatment modality in patients with ruptured HCC. However, very few studies had specifically investigated the survival benefit between staged hepatectomy and TACE for patients with ruptured HCC.

Purpose Thus, we aimed to compare the long-term outcomes of treatment with staged hepatectomy or with TACE for patients with ruptured HCC. To identify prognostic factors for patients with ruptured HCC to select optimal candidates for staged partial hepatectomy.

Methods Retrospectively review with medical records Duration : from 2000 to 2014 Subject - Age : 18 ~ 80 - Newly diagnosed HCC as ruptured tumor Multicenter study involving 6 hospitals - Severance Hospital - Gangnam Severance Hospital - Wonju Severance Christian Hospital - National Health Insurance Corporation Ilsan Hospital - Ajou University Medical Center - CHA Bundang Medical Center

Results

Patients Number according to the Treatment Modality Center Total Number Surgery * TACE Supportive care Chemotherapy Radiotherapy Severance Hospital 60 (34.9%) 27 31 2 Gangnam Severance Hospital 25 (14.5%) 6 11 3 Wonju Severance Christian Hospital 32 (18.6%) 7 17 1 CHA Medical Center 15 (8.7%) 12 National Health Insurance Corporation Ilsan Hospital 20 (11.6%) 8 10 Ajou University Medical Center 5 172 (100%) 49 (28.5%) 90 (52.3%) 23 (13.4%) 5 (2.9%) * Staged partial hepatectomy + Bleeder ligation

Scheme of Patients Selection Spontaneous rupture of HCC (n=172) Child-Pugh A (n=117, 71.3%) Surgery (n=49) Staged hepatectomy (n=44) Bleeder ligation (n=5) TACE (n=61) *Conservative (n=7) Child-Pugh B (n=37, 22.6%) TACE (n=20) *Conservative (n=17) Child-Pugh C (n=10, 6.1%) TACE (n=4) *Conservative (n=6) Concomitant extrahepatic metastasis (n=8) *Conservative : Supportive care, Radiotherapy, Chemotherapy Duration : 2000-2014 Median follow-up time: 5 months (range, 0-162)

Staged Hepatectomy vs TACE Patient characteristics at diagnosis of tumor rupture Staged hepatectomy (n=44) TACE (n=61) P value Age (yrs) 51.5 (18 - 80) 61 (32 - 79) 0.009 Sex (M : F) 34:10 52:9 0.295 HBV (+) * 36 (81.8%) 42 (68.9%) 0.495 Shock on presentation* 13 (29.5%) 24 (39.3%) 0.300 Portal vein thrombosis* 4 (9.1%) 12 (19.7%) 0.137 Tumor size (cm) 6.7 (2.2-15.0) 8.4 (2.9-20.0) 0.012 Multiple tumor* 5 (11.4%) 26 (42.6%) 0.001 Pre-treatment transfusion* 21 (47.7%) 37 (60.7%) 0.189 Pre-treatment transfusion >1200 (mL) * 12 (27.3%) 0.199 AFP (ng/mL) 144.5 (1.1 - 83000) 62 (1.8-200000) 0.082 DCP (mAU/mL) 806.5 (13.0-23641) 2000 (20.0-69660) 0.249 Hemoglobin (g/dL) 11.6 (8.0-16.2) 10.7 (5.5-15.9) 0.045 Platelet (103/µL) 184k (69k-467k) 165k (65k-454k) 0.138 Creatinine (mg/dL) 0.8 (0.3-3.0) 1.0(0.5-4.1 ) 0.419 AST (IU/L) 52 (12-386) 67 (20-466) 0.061 ALT (IU/L) 45.5 (7-136) 43 (11-288 ) 0.084 Total bilirubin (mg/dL) 0.75 (0.2-1.7) 0.9 (0.2-2.8) 0.006 INR 1.06 (0.34-1.61) 1.13 (0.84-1.77) 0.078 *The data are presented as numbers and percentages.

Overall Survival according to the Main Treatment Modality Staged hepatectomy vs TACE

Type of Resection Rt. hemihepatectomy 11 (25.0%) Lt. hemihepatectomy Number (%) Rt. hemihepatectomy 11 (25.0%) Lt. hemihepatectomy 7 (15.9%) Lt. extended hemihepatectomy 2 (4.5%) Central bisectionectomy Lt. lateral sectionectomy 6 (13.6%) Anterior sectionectomy 1 (2.3%) Posterior sectionectomy Segmentectomy 8 (18.2%) Wedge resection 44 (100%)

Complication after Staged Hepatectomy Complication analysis by Clavien-Dindo classification† Complication Grade Number (%) Wound problem I 4 (3.8%) Pleural effusion 5 (4.8%) Ileus II 2 (1.9%) Fluid colllection * Acute renal failure # 1 (1.0%) 17 (16.2%) * Antibiotics change due to fever # Managed conservatively † Dindo D. et al. Ann Surg 2004;240:205–213.

Recurrence Pattern after Staged Hepatectomy Recurrence after staged hepatectomy (31/44, 70.5%) Number of patients 16 (51.6%) 7 (22.6%) 2 (6.5%) 4 (12.9%) 1 (3.2%) 1 (3.2%)

Univariate Cox Regression Analysis of Prognostic Factor Variable Categories Disease-free Survival Hazard Ratio 95% Confidence Interval P value Age 1-year increase 1.940 0.994-1.035 0.164 Gender Female vs Male 0.008 0.516-1.829 0.929 HBsAg positivity No vs Yes 1.095 0.367-1.356 0.295 Shock on presentation 0.140 0.531-1.537 0.708 Portal vein thrombosis 13.333 0.155-0.570 <0.001 Type of treatment Staged hepatectomy vs TACE 26.205 0.106-0.367 Pre-treatment transfusion >1200 mL 5.005 0.319-0.927 0.025 Hemoglobin , g/dL 1.271 0.821-1.055 0.260 Creatinine , mg/dL 2.109 0.371-1.159 0.146 Albumin, g/dL 0.776 0.483-1.318 0.378 AST, IU/L 2.225 0.999-1.005 0.136 ALT, IU/L 0.697 0.997-1.007 0.404 Platelet, mm3 0.006 0.997-1.003 0.940 Total bilirubin, mg/dL 3.598 0.986-2.402 0.058 INR 0.173 0.352-4.993 0.678 AFP, IU/mL 5.162 1.000-1.000 0.023 DCP, mAU/mL 0.415 0.519 Tumor size > 5cm 9.154 0.160-0.676 0.002 Multiple tumor Solitary vs Multiple 8.633 1.293-3.618 0.003

Multivariate Cox Regression Analysis of Prognostic Factor Variable Categories Disease-free Survival Hazard Ratio 95% Confidence Interval P value Type of treatment Staged hepatectomy vs TACE 17.027 0.126-0.478 <0.001 Pre-treatment transfusion >1200 mL No vs Yes 4.135 0.301-0.978 0.042 Portal vein thrombosis 10.485 0.143-0.620 0.001 Tumor size > 5cm 4.183 0.196-0.966 0.041

Comparison of Overall Survival between Staged Hepatectomy Group and TACE Group by using propensity score match

Comparison of Demographics in the Propensity Score Model Variable Categories Before Matching After Matching Staged hepatectomy (n = 44) TACE (n = 85) P value Staged hepatectomy (n = 16) (n = 16) Age (yrs) 53.43±12.70 59.63±12.07 0.0076 57.38±13.64 57.38±14.66 >.9999 Hemoglobin (g/dL) 11.01±2.16 10.55±2.27 0.2616 11.44±1.97 11.35±1.73 0.9023 Tumor size (cm) 6.98±3.23 9.25±4.51 0.0014 7.82±3.42 7.83±2.63 0.9942 Multiple Tumor * 5(11.4%) 38(44.7%) 0.0001 2(12.5%) Child-Pugh grade * A 44(100%) 61(71.8%) <.0001 16(100%) NA B 0(0%) 20(23.5%) C 4(4.7%) *The data are presented as numbers and percentages.

Staged Hepatectomy vs TACE Overall survival (after match)

Conclusion Our study indicates that staged partial hepatectomy may offer better long-term survival than TACE for HCC with recent tumor rupture. Multivariate analysis showed that type of treatment, pre-treatment transfusion above 1200mL, presence of portal vein thrombosis, and tumor size above 5cm were associated with poor prognosis of patients. Further clinical studies are required in the form of prospective randomized trials with adequate sample sizes and prolonged follow up.

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