Optimal management of HCC: in Asia Kwang-Hyub Han, MD Department - PowerPoint PPT Presentation

Optimal management of HCC: in Asia Kwang-Hyub Han, MD Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea

Newly diagnosed HCC : > 70% occur in Asia, > 75% of them are infected with HBV Regional mortality rates of HCC (per 100,000 persons) categorized by age-adjusted mortality rates Annual mortality per region: Europe: 54,000 55% of HCC USA: 19,000 Worldwide China – Korea – Japan: 390,000

Challen Challenge ge: sur : surveillanc eillance e & Dx & Dx Screening and surveillance program are not implemented successfully in many Asian countries. The majority of HCC patients in Asia still presents with intermediate and advanced stage HCC at diagnosis

HCC HCC sur surveillance: eillance: Recommenda ecommendations tions in in dif differ erent Asian ent Asian countries countries Korea Japan Taiwan Interval 6 mo Cirrhosis: 3 mo Cirrhosis: 3-6 mo HBV/HCV carrier: 6 mo Non-cirrhosis: 6-12 mo Test US+AFP Cirrhosis: US+AFP US+AFP+DCP+AFP-L3, every 3-4 mo (dynamic CT/MR, every 6-12 mo) HBV/HCV carrier: US+AFP+DCP+AFP-L3, every 6 mo

Optimal managements of HCC in Asia

How to win( 知彼知己 , 百戰百勝 ) ( 孫子兵法 ) 1. Know enemy( 知彼 ); 2. Know myself( 知己 ); 3. Establish good strategy ( 必勝戰略 , roadmap)

Know enemy( 知彼 ); Characteristics of HCC • Tumor neovasculature and frequent vascular invasion with intra-and extra-hepatic metastasis • Great heterogeneity with respect to tumor behavior • Frequent association with different status of the underlying liver cirrhosis and viral hepatitis

Know myself( 知己 ); Tre reatment Opti tions fo for r H HCC • Radical therapies (40%) • Surgical resection • Liver Transplantation (CLT/LDLT) • Local ablation therapy • Palliative therapies (40-50%) • Transarterial embolization/ Chemoembolization • Molecular target therapy(sorafenib) • Hormonal treatments/ Immunotherapy • Antiproliferative agents • HAIC • Others; pilot therapy; Radiotherapy;external, internal RT,etc • Combination therapy • Symptomatic treatment (10-20%) www.themegallery. Company Logo com

Staging Systems of HCC • To predict the prognosis • To stratify the patients according to prognostic variables in the setting of clinical trials • To guide therapeutic approach

AASLD Practice Guideline: BCLC Staging and Treatment Strategy (30-40 %) (20%) (40%) (10%) 50%-70% 5 years 10%-40% 3 years Lovett et al, 2008

APASL Guidelines HCC Confined to the liver Extrahepatic metastasis Main portal vein patent Main portal vein tumor thrombus Child – Pugh A/B Child – Pugh C Resectable Sorafenib or systemic therapy trial Yes No Solitary tumor < 5 cm Tumor > 5 cm Resection/RFA < 3 tumors < 3 cm > 3 tumors (for < 3 cm HCC) No venous invasion Invasion of hepatic / portal vein branches Child – Pugh A Child – Pugh B Child – Pugh C Child – Pugh A/B Child – Pugh C Local Transplantation TACE Supportive care ablation APASL recommendations on HCC, Omata M, et al. Hepatol Int. 2010;4:439 – 474

Nation-wide Survey of HCC in Korea - Frequency of 1 st Treatment Methods in real CP- 1.1 100% 4.4 RT 2 3.5 4.1 1.3 6.3 OP 7.4 HAIC 90% 11.3 15.5 2 3.4 0.6 80% 8.7 RFA 24.3 70% 35.7 Radiation therapy 60% 52.4 Systemic Chemotherapy Local Chemotherapy 50% Surgery 53.8 TACE Local ablation 40% Embolotherapy 49 No treatment 30% 47.1 No 20% 33.7 Tx 10% 19.2 10.8 Also much discrepancy between 0% Total : 4444 Stage I Stage II Stage III Stage IV guidelines and real practice in Korea N 461 1911 1230 842

Practice Guideline : Early Stage (30%) (50%) (20%) Lovett et al, 2008

Curative treatment for early stage HCC • Surgery is the mainstay of curative treatment. • But, high recurrence rate after surgical resection is still a problem. 100 Recurrence (%) 80 70% 54% Predictors of recurrence : 60 Differentiation degree (p=.013) 40 19% Multinodular HCC (p=.045) 20 Satellites (p=.02) 0 months 0 12 24 36 48 60 72 No. at risk 53 34 22 17 11 16

Emerging Trends of Management in Early Stage • Resection; Classic or Minimal invasive surgery (laparoscopic or Robot surgery) • Liver transplantion; expansion of criteria • Local ablation therapy; RFA, PEIT or Holmium • Adjuvant therapy after curative tx.; molecular target therapy(phase III; STORM, PATRON), Curative efficacy

Practice Guideline; Intermediate Stage

TACE; Effective but incomplete

Degree of lipiodol uptake determines survival in conventional TACE Kim DY, et al. Aliment Pharmacol Ther 2012

Incomplete TACE; Nonresponder Responder Responder Nonresponder Before TACE-3d TACE-4 wk  Incomplete TACE induces angiogenesis Sergio et al., Am J Gastroenterol 2007

TACE: ineffective for large or multiple (≥4) HCC Kim DY, et al. Aliment Pharmacol Ther 2012

Sorafenib in Combination with TACE for Intermediate HCC Inclusion Criteria Imaging • Unresectable, multinodular, HCC TACE • Child-Pugh A Primary Endpoint without ascites or (optional) • Time to progression n=307 encephalopathy Cycle no (by central review) • ECOG PS of 0 (=4 weeks) 1 3 5 7 9 11 13 15 17 19 R Secondary Endpoints A Exclusion Criteria • Overall survival N n=154 Sorafenib 400mg bid • Vasc. invasion, extrahepatic D • Time to VI/EHS spread (VI/EHS) O • Time to untreatable • Planned liver transplantation M progression I Matching Placebo n=153 • Previous local therapy • Safety Z to target lesion E • Prior TACE, prior systemic therapy • First TACE with DEB performed 3-7 days after start of treatment with sorafenib or placebo • Subsequent TACE with DEB performed on day 1 ( ± 4 days) of cycles 3, 7, and 13, and every 6 cycles thereafter • Patients allowed optional TACE with DEB sessions between cycles 7 and 13 and cycles 13 and 19, if deemed necessary by the investigator Adapted from Cheng presentation at AP BESTT 2012 Lencioni et al., ASCO GI 2012

TACE vs. TACE+RT: Survivals Response rate; 65.8% 100 TACE vs. TACE+RT P<0.01 80 SURVIVAL(%) 60 36% 40 postTACE preRT 20 14.3% 0 0 12 24 36 48 60 TIME (Months) postRT Shim and Seong et al .2005, Liver International

TACE vs. TACE+RT: Median survival-Tumor size 50 TACE alone TACE + RT 40 Survival (Months) 30 20 10 0 5-7 8-10 > 10 Tumor size (cm) Shim and Seong et al .2005, Liver International

Radioembolization with Yttrium-90 microsphere Ischemia Radiation

Advanced Stage

OS in the SHARP and AP Trials Sorafenib consistently increased overall survival in different global patient populations SHARP 1 Asia-Pacific 2 1.00 1.00 Sorafenib (n=299) Sorafenib (n=150) Median: 10.7 months Median: 6.5 months 95% CI: 9.4-13.3 95% CI: 5.6-7.6 Survival Probability Survival Probability 0.75 0.75 Placebo (n=303) Placebo (n=76) Median: 7.9 months Median: 4.2 months 95% CI: 6.8-9.1 95% CI: 3.7-5.5 0.50 0.50 0.25 0.25 HR (S/P): 0.69 HR (S/P): 0.68 95% CI: 0.55-0.87 95% CI: 0.50-0.93 P =0.00058 P =0.014 0 0 4 8 12 16 20 4 8 12 16 20 0 0 Months from Randomization Months from Randomization 1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-390. 2. Cheng AL, et al. Lancet Oncol . 2009;10:25-34. 30

Position of Sorafenib in advacned HCC; AP region Pros Cons • Only one approved drug • High cost to maintain therapy by large scaled indefinite tx prospected RCT • OS in Asian patients with • Less harmful oral drug for HCC is shorter than cirrhotic liver SHARP trial • Is able to manage in out- • SAE is more common patient clinic • Not enough data in clinical practice level Lee JM, Han KH: Positioning and indication of sorafenib in the treatment algorithm and real practice setting: Western and eastern approach--Asian perspective. Oncology; 2010

Emerging Trends; Treatment of Advanced HCC:  New molecular target agents  New combination treatment  Exploring alternative treatment

Beyond sorafenib: novel targeted therapies for advanced HCC • Antiangiogenic agents; Sunitinib, Brivanib, Linifanib(ABT-869), Bevacizumab, AZD2171 (cediranib), PTK787 (Vatalanib) • EGFR inhibitors; EGFR tyrosine kinase inhibitors (erlotinib (Tarceva), Lapatinib, Monoclonal antibodies against EGFR (Cetuximab) • mTOR inhibitors; (sirolimus, temsirolimus and everolimus) • Others; MEK inhibitors

Hepatic arterial infusion chemotherapy (HAIC) Media 1-yr survival Objective Therapeutic No. n OS rate Response Group Scheme DDP 7 mg/m 2 Ando et al. 5-FU 170 mg/m 2 2002 48 10.2 mo 45.0% 48% D1-D5, 4 consecutive weeks Itamoto et al. DDP 10 mg 5-FU 250 mg 2002 7 7.5 mo 33% D1-D5, 4 consecutive weeks DDP 10 mg Yamasaki et al. 5-FU 250 mg (+ LV) 2005 44 9.4 mo 39.0% 38% D1-D5, 4 consecutive weeks DDP 7 mg/m 2 , D1-D5 5-FU Tanioka et al. 170 mg/m 2 , D1-D7 2003 38 6.0 mo 17.8% 47% 4 consecutive weeks Llovett et al. Median OS was 10.7 vs 7.9 mos (Sor vs P). ASC0 2007

May 2008 Feb 2009