Systemic Cytotoxic Therapy in advanced HCC

Transcription

1 Systemic Cytotoxic Therapy in advanced HCC Yeul Hong Kim Korea University Anam Hospital Cancer Center

2 Hepatocellular Carcinoma : Overview Epidemiology Current Guideline : advanced HCC Cytotoxic Chemotherapy (excluding biologic, hormonal agents) Adjuvant Setting Palliative Setting Summary

3 Epidemiology

4 Epidemiology : HCC 694,000 deaths from liver cancer yearly worldwide In KOREA, ,936 new cases / year, 8.3% of all cancer 15.6 % of cancer deaths, 2 nd leading cause of cancer deaths

5 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 (?)

6 Current Guideline

7 Current Guideline - BCLC

8 Current Guideline - NCCN

9 Current Guideline KLCSG 2009

10 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

11 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

12 Cytotoxic Chemotherapy - Adjuvant

13 Cytotoxic Chemotherapy : Adjuvant Recurrence following resection Approximately 50% at 3 years Approximately 70% at 5 years Cytotoxic agents as Adjuvant therapy Oral FU, anthracylines

14 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 P=0.77 negative - negative P=0.38 negative Fail to demonstrate a survival benefit in the adjuvant setting

15 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

16 Cytotoxic Chemotherapy - Palliative

17 Cytotoxic Chemotherapy vs Best Supportive Care

18 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

19 Cytotoxic Chemotherapy vs BSC UFT vs. BSC (n=56), Phase II The median OS : months in UFT arm The median OS : 6.2 months in BSC arm

20 Monotherapy

21 Cytotoxic Chemotherapy : Monotherapy (Old) Study Type Agent N RR % Survival Sciarrino 1985 Retrospective Doxorubicin % at 1 year Gish, Yeo 2007, 2005 Phase III, control arm Doxorubicin M, 6.8 M Okada 1993 Phase II Cisplatin Hochster 1985 Phase II Epirubicin Zaniboni 1998 Phase II 5-FU M Chao 1998 Phase II Paclitaxel M Stuart 1999 Phase II Nolatrexed M

22 Cytotoxic Chemotherapy : Monotherapy (New) Study Type Agent N RR % Survival Patt 2004 O Reilly 2001 Leung 2002 Fuchs 2002 Phase II Capecitabine M Phase II Irinotecan M Phase II T M Phase II Gemcitabine M

23 Best Monotherapy Regimen? Doxorubicin (control) vs. Nolatrexed (experimental), Phase III Inclusion Criteria CLIP 3 Unresectable or metastatic disease Primary end point OS

24 Doxorubicin vs. Nolatrexed

25 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)

26 Combination therapy

27 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%

28 Combination therapy: Gemcitabinebased Gemcitabine (D 1, mg/m 2 ) + cisplatin (D1 70 mg/m 2 ): RR 20% Gemcitabine (D 1, mg/m 2 ) + cisplatin (D 1, 8 25 mg/m 2 ): RR 7.5% Gemcitabine + pegylated liposomal doxorubicin: RR 24%

29 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%

30 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

31 Doxorubicin vs. PIAF No difference for OS between doxorubicin and PIAF

32 Combination and Monotherapy Combination therapy Not any consistently improved activity over single agents Rare, randomized trial Heterogeneous study-population, Not stratified Statistically underpowered

33 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

34 JUN 02 JUL 02 DEC 02 MAY 03

35 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

36 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

37 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

38 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