Systemic Cytotoxic Therapy in advanced HCC Yeul Hong Kim Korea University Anam Hospital Cancer Center
Hepatocellular Carcinoma : Overview Epidemiology Current Guideline : advanced HCC Cytotoxic Chemotherapy (excluding biologic, hormonal agents) Adjuvant Setting Palliative Setting Summary
Epidemiology
Epidemiology : HCC 694,000 deaths from liver cancer yearly worldwide In KOREA, 2010-2011 15,936 new cases / year, 8.3% of all cancer 15.6 % of cancer deaths, 2 nd leading cause of cancer deaths
Epidemiology : HCC A majority of HCC patients (80%~) Advanced or Unresectable disease In resected disease The recurrence rate : 50% at 2 years Systemic Therapy Molecular targeted therapy Cytotoxic chemotherapy (?)
Current Guideline
Current Guideline - BCLC
Current Guideline - NCCN
Current Guideline KLCSG 2009
Cytotoxic Chemotherapy : HCC Pre-Era of targeted therapy At present No drug or regimen as standard for treating HCC Not be disregarded Strong rationale for combination with targeted agents Some benefit
Cytotoxic Chemotherapy : HCC relatively refractory High rate of expression of drug resistance gene Survival is often determined by the degree of hepatic dysfunction Diverse disease population Young vs. Old, Hep B, C vs. Alcoholic Many cytotoxic agents are detoxified or metabolized in the liver
Cytotoxic Chemotherapy - Adjuvant
Cytotoxic Chemotherapy : Adjuvant Recurrence following resection Approximately 50% at 3 years Approximately 70% at 5 years Cytotoxic agents as Adjuvant therapy Oral FU, anthracylines
Cytotoxic Chemotherapy : Adjuvant Authors, year Yamamoto et al, 1996 Ono Et al, 1997 Kohno Et al, 1996 Setting Study type Agent n Recurrence Adjuvant Phase II Carmofur 62 Adjuvant Adjuvant Phase II Phase II Epirubicin Carmofur Epirubicin UFT 57 101 P=0.77 negative - negative P=0.38 negative Fail to demonstrate a survival benefit in the adjuvant setting
Cytotoxic Chemotherapy : Adjuvant No standard of care adjuvant therapy for HCC patients undergoing resection Cytotoxic agents : No benefit At present Large, randomized, controlled trials of adjuvant therapy following resection ongoing Molecular agents Molecular agents + Cytotoxic agents
Cytotoxic Chemotherapy - Palliative
Cytotoxic Chemotherapy vs Best Supportive Care
Cytotoxic Chemotherapy vs BSC Doxorubicin vs. BSC (n=106), Phase III The median OS : 10.6 weeks in doxorubicin arm The median OS : 7.5 weeks in BSC arm (p=0.036) However, doxorubicin (60-75 mg/m 2 ) too toxic No ideal regimen
Cytotoxic Chemotherapy vs BSC UFT vs. BSC (n=56), Phase II The median OS : 12.13 months in UFT arm The median OS : 6.2 months in BSC arm
Monotherapy
Cytotoxic Chemotherapy : Monotherapy (Old) Study Type Agent N RR % Survival Sciarrino 1985 Retrospective Doxorubicin 109 10 13% at 1 year Gish, Yeo 2007, 2005 Phase III, control arm Doxorubicin 309 4.8 8.2 M, 6.8 M Okada 1993 Phase II Cisplatin 28 15 - Hochster 1985 Phase II Epirubicin 18 17 - Zaniboni 1998 Phase II 5-FU 25 28 3.3 M Chao 1998 Phase II Paclitaxel 20 0 3 M Stuart 1999 Phase II Nolatrexed 26 8 7 M
Cytotoxic Chemotherapy : Monotherapy (New) Study Type Agent N RR % Survival Patt 2004 O Reilly 2001 Leung 2002 Fuchs 2002 Phase II Capecitabine 37 11 10.1 M Phase II Irinotecan 14 7 8.2 M Phase II T138067 21 10 6 M Phase II Gemcitabine 30 0 6.9 M
Best Monotherapy Regimen? Doxorubicin (control) vs. Nolatrexed (experimental), Phase III Inclusion Criteria CLIP 3 Unresectable or metastatic disease Primary end point OS
Doxorubicin vs. Nolatrexed
Monotherapy and BSC Conventional cytotoxic therapy Undoubted activity against HCC However, Survival advantage.still not confirmed (Small heterogenous studies, various non-stratified patients population, Too short survival, Toxicity, QoL)
Combination therapy
Combination therapy: Cisplatin-based Higher objective response rates than non-cisplatincontaining regimens Cisplatin + doxorubicin: RR 18-49% Cisplatin + mitoxantrone + 5-FU CI: RR 24-27% Cisplatin + epirubicin + 5-FU inf: RR 15% Cisplatin + doxorubicin + xeloda: RR 24% Sequential low-dose cisplatin inf + 5-FU inf: RR 47% Cisplatin + xeloda: RR 6-20%
Combination therapy: Gemcitabinebased Gemcitabine (D 1, 8 1250 mg/m 2 ) + cisplatin (D1 70 mg/m 2 ): RR 20% Gemcitabine (D 1, 8 1000 mg/m 2 ) + cisplatin (D 1, 8 25 mg/m 2 ): RR 7.5% Gemcitabine + pegylated liposomal doxorubicin: RR 24%
Combination therapy: Oxaliplatinbased GEMOX: lacks renal and hepatic toxicity Gem fixed rate D1 + oxaliplatin D2: RR 18%, SD 58% More effective in non-alcoholic XELOX: RR 6% (3/50), additional 25 pts SD, DCR 72% FOLFOX: mfolfox4 vs. doxorubicin (371 pts) mos: 6.5 vs. 4.9 mo PFS: 3 vs. 1.8 mo DCR: 53 vs. 33%
Combintion vs. Monotherapy Doxorubicin (control) vs. CDDP/IFN-2a/Doxorubicin/FU (PIAF) (experimental), Phase III Inclusion Criteria ECOG PS 0-2 Unresectable or metastatic disease Primary end point OS
Doxorubicin vs. PIAF No difference for OS between doxorubicin and PIAF
Combination and Monotherapy Combination therapy Not any consistently improved activity over single agents Rare, randomized trial Heterogeneous study-population, Not stratified Statistically underpowered
Case M/61 JAN 98: Chronic Hepatitis B Dx MAY 01: Elevation of AFP > 1,500 TACE 5 times until FEB 02 multiple lung metastasis Start EPUL chemotherapy MAR 02 NOV 02, 8 cycles Date 09/01 10/01 11/01 01/02 03/02 04/02 05/02 07/02 10/02 11/02 AFP 272 1428 3641 5610 17442 6630 1734 521 284 127
JUN 02 JUL 02 DEC 02 MAY 03
Case M/61 MAY 03: 3 new lesions in Rt lobe of liver JUN 03: TACE, Holmium, PEI AUG 03: TACE, RFA, PEI TACE, PEI, RFA, RT until MAR 2008 Date 05/03 07/03 09/03 11/03 01/04 02/04 05/04 09/04 02/05 03/05 AFP 1815 322 418 308 216 5 17 103 407 4
Problems - Clinical Trial for HCC The lack of consensus regarding Standard chemotherapy Drug activity RECIST Poorly correlation Not translate (Response Survival) Heterogenous patients population Cause, Function, Race and Sex
Problems- Clinical Trial for HCC Heterogeneous tumor Tumor biology, intrinsic or acquired resistance Topoisomerase Iia MDR-1 doxorubicin resistance MRP (multidrug resistance protein) P-gp (p-glycoprotein) H19 gene, p53
Futures (Era of targeted therapy) - Cytotoxic therapy in HCC The addition of chemotherapy to biologic agent may provide a significant survival advantage for patients with advanced HCC (bevacizumab, cetuximab, aflibercept, regorafenib in mcrc, advance NSCLC) However, additional insight is required to ensure optimal use of biomarkers in clinical practice duration of treatment Several ongoing studies of existing and new therapies have the potential to further improve clinical practice