Falk Symposium 167 Current Concepts in the Treatment of HCC Peter R. Galle I. Medical Department Johannes Gutenberg-University Mainz Germany
Liver cancer: sixth most common cancer worldwide Most common cancers 1 Lung Breast Colon/rectal Stomach Prostate Liver Cervix uteri Oesophagus Non-Hodgkin lymphoma Bladder Ovary Corpus uteri Oral cavity Other Liver cancer is the third most common cause of cancer-related death 1 HCC is the most common primary liver malignancy in adults 2 1. Parkin DM, et al. CA Cancer J Clin 2005;55:74 108 2. Pons-Renedo F, Llovet JM. Med Gen Med 2003;5:11
Incidence of liver cancer worldwide: regional variation Eastern Asia Middle Africa Eastern Africa South-Eastern Asia World Western Africa Southern Europe Caribbean Southern Africa Western Europe Eastern Europe Northern America Central America Western Asia Northern Africa Australia/New Zealand South America Northern Europe South Central Asia Region Incidence of liver cancer in different regions of the world (2002) *Age standardised 0 5 10 15 20 25 30 35 40 Incidence rate per 100,000 population* Males Females GLOBOCAN 2002 database. Available at http://www-dep.iarc.fr/
Risk factors for HCC worldwide, by geographical region (2000) Risk factors associated with development of HCC Hepatitis C 20% 50 70% 70% 70% Asia/Africa* Europe/N America Japan All Hepatitis B 10 20% 10 20% Alcohol Other 10 20% 10% 0 20 40 60 80 Cases (%) *Excluding Japan Llovet JM, et al. Lancet 2003;362:1907 17
Incidence of HCC is increasing in economically developed countries Year Incidence /100,000 Year Incidence /100,000 Australia 1 (men) 1983 85 2.1 1995 96 4.0 France* 2 (men) 1976 79 7.5 1992 95 10.2 Japan 3 1980 10.0 2000 40.0 UK 4 1975 1.4 2003 3.6 USA 5 1975 77 1.4 1996 98 3.0 *Primary liver cancer 1. Law MG, et al. Med J Aus 2000;173:403 5 2. Benhamiche AM, et al. J Hepatol 1998; 29:802 6 3. Yoshizawa H, et al. Oncology 2002;62:8 17 4. http://info.cancerresearchuk.org/cancerstats/types/liver/incidence/?a=5441 5. El Serag HB, et al. Ann Intern Med 2003;139:817 23
Molecular Clock of Hepatitis C Virus Infection Effective population size of HCV infections 5000 4000 3000 2000 1000 1882 1910 Japan (Genotype 1b) 1930 1960 20 years USA (Genotype 1a) 0 1880 1900 1920 1940 1960 1980 2000 2020 Tanaka et al., PNAS 2002
HCC - in 90% with Cirrhosis Liver cirrhosis = precancerous lesion HCC
Poor prognosis for patients with advanced HCC 70 80% of patients with intermediate/ advanced disease at diagnosis 1 OS among 102 patients randomised to no treatment in two RCTs 2 OS (%) 2 Disease stage 1 year 2 years 3 years Intermediate 80 65 50 Advanced 29 16 8 OS = overall survival RCT = randomised controlled trial 1. Llovet JM. J Gastroenterology 2005;40:225 35 2. Llovet JM. Hepatology 1999;29:62 7
Treatment for early HCC: surgical resection Surgical resection: survival in retrospective studies Authors, year n 1-year survival (%) 5-year survival (%) Fong et al, 1999 100 83 42 Llovet et al, 1999 77 85 51 Takayama et al, 2000 * 74 100 62 Wayne et al, 2002 249 83 41 *Randomised study of resection adjuvant therapy Llovet JM. J Gastroenterol 2005;40:225 35
Resection in HCC - Survival Survival (%) 100 80 60 40 20 74% 50% 25% Best candidates for resection Solitary HCC Child-Pugh A Absence portal hypertension Normal bilirubin 0 0 12 24 36 48 60 72 84 96 No portal hypertension (n= 35) Portal hypertension and normal bilirubin (n=15) Portal hypertension and Bilirubin >1 mg/dl (n=27) months Llovet et al. Hepatology, 1999
Perioperative Lethality after partial Hepatectomy in Patients with Cirrhosis Child A 10-20 % > 60% with Decompensation Child B 30-40 % Child C 70-80 % Garrison 1984 Mansour 1997
Intrahepatic Recurrence after HCC Resection in Patients with Cirrhosis % Interval (ys) Belghiti J et al. 1991 80 5 Chen MF et al. 1994 80 5 Koike Y et al. 2000 64 5 Yamamoto J et al. 2001 71 5 Metachrone HCC in Cirrhosis
HCC: local Therapy Technique Percutaneous Ethanol Injection (PEI) Radio Frequency Thermo Ablation (RFTA) Indication: Child A/B Patients with 1 nodule < 5 cm, or max. 3 nodules < 3 cm Goal: complete Tumor Necrosis in curative intention
Treatment for early HCC: percutaneous ablation Percutaneous ethanol injection: survival in retrospective studies Authors, year Disease characteristics n 1-year survival (%) 5-year survival (%) Livraghi et al, 1995 Child Pugh A, HCC 5cm 293 98 47 Child Pugh B, HCC 5cm 149 93 29 Arii et al, 2000 Stage I HCC <2cm 767 96 54 Stage I HCC 2 5cm 587 95 38 Stage II HCC <2cm 426 92 33 Stage II HCC 2 5cm 483 87 28 Llovet JM. J Gastroenterol 2005;40:225 35
Treatment for early HCC: percutaneous ablation (cont d) Radiofrequency ablation: single-arm studies and a randomised trial Authors, year Trial design n 1-year survival (%) 5-year survival (%) Rossi et al, 1996 Single arm 39 94 40 Buscarini et al, 2001 Single arm 88 89 33 Lencioni et al, 2003 RCT: Radiofrequency 52 100 ND vs Percutaneous ethanol 50 96 ND ND = not described Llovet JM. J Gastroenterol 2005;40:225 35
PEI vs. Resection in HCC with Cirrhosis Yamamoto et al. Hepatology 2001; 34:707-13
HCC HCC - Coeliacography
Transarterial Chemoembolisation (TACE) Llovet et al.; Lancet 2002; 359: 1734-9
Two-year survival with chemoembolisation or embolisation versus supportive care for unresectable HCC Study Number of patients Odds ratio (95% CI) in random effects model Lin et al, 1988 63 GETCH, 1995 96 Bruix et al, 1998 80 Pelletier et al, 1998 73 Lo et al, 2002 79 Llovet et al, 2002 112 Overall 503 p=0.017 0.01 0.1 0.5 1 2 10 100 Heterogeneity p=0.14 Favours treatment Favours control Adapted from Llovet JM, et al. Lancet 2003;362:1907 17 Copyright 2003, reproduced with permission from Elsevier
Survival after LTX 01/1988-06/2002 (%) 100 80 60 Total Log Rank test p = 0.0001 82 75 74 71 61 59 65 58 Cirrhosis : 24227 Cancers : 4608 Acute hepatic failure : 4026 66 63 56 55 40 20 p Log Rank : Acute Hepatic Failure vs Cirrhosis : 0.0001 Cancers vs Cirrhosis : 0.0001 Acute Hepatic Failure vs Cancers : 0.0001 (Wilcoxon test) 49 44 41 0 1 2 3 4 5 6 7 8 9 10 Yrs
HCC - Selection criteria for LTX IN Milano criteria 8.5 cm 5 cm Single Multiple 3 nodules 3 cm OUT > 8.5 cm HCC > 3 nodules > 3 cm
Treatment for early HCC: liver transplantation Liver transplantation: survival in retrospective studies Authors, year n 1-year survival (%) 5-year survival (%) Mazzaferro et al, 1996 48 84 74 Bismuth et al, 1999 45 82 74 Llovet et al, 1999 87 84 69 Jonas et al, 2001 120 90 71 Llovet JM. J Gastroenterol 2005;40:225 35
Systemic Chemotherapy - Summary Response rates 0-20% (Doxorubicin) no survival benefit significant side effects Simonetti et al. Ann Oncol 1997 Nowak et al. EJO 2004 Schwartz et al. Anti-Cancer Drugs 2004 Multi-Drug Resistance (MDR1 gene) Huang et al. J Natl. Cancer Inst. 1992 HCC
HCC: a complex pathogenesis The pathogenesis of HCC is multifactorial 1 5 Cirrhosis/fibrosis Infection (e.g. hepatitis virus) Toxins (e.g. alcohol, aflatoxins) Mutation/deletion/amplification of genes 1 4 Mitogenic oncogenes Tumour suppressor genes Chronic liver damage Hepatocyte regeneration Cirrhosis Genetic alterations I N F L A M M A T I O N HCC 1. Marotta F, et al. Clin Ter 2004;155:187 93; 2. Thorgeirsson S, Grisham JW. Nat Genet 2002;31:339 46 3. Wiesenauer CA, et al. J Am Coll Surg 2004;198:410 21. 4. Wang XW, et al. Toxicology 2002;181:43 7 5. Feitelson MA, et al. Surg Clin N Am 2004;84:339 54
Key Concepts in Oncogenesis Oncogenic transformation -growth stimulation -apoptosis inhibition Primary event Escape from senescence Angiogenesis Secondary events Invasion and metastasis
Potential Therapeutic Pathways Apoptotic stimulus Oncogenic transformation Growth pathway Survival pathway Secondary events Anti-angiogenesis Anti-invasive Anti-metastatic
Targeting molecular signalling pathways The inhibition of signalling pathways that play an important role in the development of HCC may provide a promising treatment strategy for HCC These pathways include: Wnt/ -catenin PI3K/Akt mammalian target of rapamycin (mtor) Raf/MEK/ERK growth factor-mediated angiogenic pathways
Angiogenesis and HCC In HCC, a net excess of pro-angiogenic factors are secreted, including vascular endothelial growth factor (VEGF) platelet derived-growth factor (PDGF) placental growth factor transforming growth factors and basic fibroblast growth factor epidermal growth factor (EGF) hepatocyte growth factor angiopoietins interleukin (IL)-4, IL-8 Semela D, Dufour JFl. J Hepatol 2004;41:864 80
Serum VEGF levels predict prognosis Cumulative survival (%) 100 80 60 40 20 VEGF >240pg/mL n=80; p<0.007 VEGF <240pg/mL 0 0 12 24 36 48 Months after chemoembolisation Median overall survival 19.2 months for VEGF <240pg/ml 6.8 months for VEGF >240pg/ml Poon RT, et al. Oncol Rep 2004;11:1077 84
Agents that target the VEGF signalling pathway Thalidomide anti-inflammatory and anti-angiogenic agent that downregulates production of VEGF, TNF- and COX-2 Bevacizumab monoclonal antibody targeting VEGF Sunitinib receptor tyrosine kinase inhibitor of VEGF-receptor (VEGFR) and PDGF-receptor (PDGFR) Sorafenib multi-kinase inhibitor of VEGFR, PDGFR and Raf kinase
Sorafenib inhibits proliferation and angiogenesis Tumour cell proliferation Tumour angiogenesis Paracrine stimulation PDGF- VEGF KIT/Flt-3/ RET Raf Ras Apoptosis PDGFR- Ras Raf VEGFR-2 MEK ERK EGF PDGF Apoptosis MEK ERK Nucleus VEGF Proliferation Nucleus Angiogenesis Survival Sorafenib Wilhelm SM, et al. Cancer Res 2004;64:7099 109
Sorafenib inhibits tumour growth and Raf/MEK/ERK signalling in the PLC/PRF/5 HCC xenograft model 750 Tumour growth inhibition Untreated Vehicle Sorafenib 10mg/kg Sorafenib 30mg/kg Mean tumour weight (mg) 600 450 300 150 0 10 15 20 25 30 Days after implant perk 1/2 Total ERK 1/2 Raf/MEK/ERK pathway inhibition perk levels measured in tumours from individual mice MEK DMSO Sorafenib (µm) inhibitor 1 5 10 Liu L, et al. Cancer Res 2006;66:11851 8
Sorafenib: phase I data in advanced tumours Objective responses* Evaluable patients* (n) PR (n) SD (n) PD (n) Median TTP (days) 7 days on/7 days off 100 800mg b.i.d. 1 19 5 14 42 21 days on/7 days off 50mg every 5 days 800mg b.i.d. 2 32 1 16 15 69 28 days on/7 days off 50mg every 4 days 800mg b.i.d. 3 41 9 32 63 Continuous dosing 50mg q.d. 800mg b.i.d. 4 45 1 25 18 83 Overall 136 2 55 (40.4%) 79 64.2 *136/173 patients were evaluable for antitumour activity across the four phase I studies; In a patient with renal cell carcinoma In a patient with HCC q.d. = once daily PD = progressive disease 1. Clark JW, et al. Clin Cancer Res 2005;11:5472 80 2. Awada A, et al. Br J Cancer 2005;92:1855 61 3. Moore M, et al. Ann Oncol 2005;16:1688 94 4. Strumberg D, et al. J Clin Oncol 2005;23:965 72
Sorafenib in HCC Phase II study in advanced HCC 137 patients with advanced HCC 1 TTP 5.5 Month OS 9.2 Month 1.00 1.00 Survival Distribution Function 0.75 0.50 0.25 Survival Distribution Function 0.75 0.50 0.25 0 HCC 0 100 200 300 400 500 Time (days from start of study treatment) 0 n = 106 Child A 0 100 200 300 400 500 600 700 800 Time (days from start of study treatment) 1. Abou-Alfa GK et al. J Clin Oncol 2006;24:4293-300
Phase III Trial of Sorafenib in HCC (SHARP): Study Design Eligibility Advanced HCC ECOG PS 0-2 Child-Pugh Class A No prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECOG PS (0 vs 1/2) Geographic region R A N D O M I Z E 1:1 n=299 n=303 Sorafenib 400 mg bid Placebo Primary end points: OS, TTSP (assessed by FHSI-8) Secondary end points: TTP (independent assessment) FHSI-8 = Functional Assessment of Cancer Therapy-Hepatobiliary Symptom Index-8. SHARP = Sorafenib HCC Assessment Randomized Protocol; OS = overall survival; TTSP = time to symptomatic progression; TTP = time to progression. Llovet JM, et al. NEJM 2008
Phase III SHARP Trial Overall survival (Intention-to-treat) Survival Probability 1.00 0.75 0.50 0.25 0 Patients at risk Sorafenib: 299 Placebo: 303 Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88). P=0.00058* Sorafenib Median: 46.3 weeks (10.7 mo) (95% CI: 40.9, 57.9) Placebo Median: 34.4 weeks (7.9 mo) (95% CI: 29.4, 39.4) 0 8 16 24 32 40 48 56 64 72 80 274 241 205 161 108 67 38 12 0 276 224 179 126 78 47 25 7 2 *O Brien-Fleming threshold for statistical significance was P=0.0077. 0 0 Weeks
Phase III SHARP Trial Time to Progression (Independent central review) 1.00 Probability of progression 0.75 0.50 0.25 Sorafenib Median: 24.0 weeks (5.5 mo) (95% CI: 18.0, 30.0) Placebo Median: 12.3 weeks (2.8 mo) (95% CI: 11.7, 17.1) 0 Hazard ratio (S/P): 0.58 (95% CI: 0.44, 0.74) P=0.000007 0 6 12 18 24 30 36 42 48 54 Weeks Patients at risk Sorafenib: 299 Placebo: 303 196 126 80 50 28 14 8 2 192 101 57 31 12 8 2 1 0 0
SHARP: Maximum Percentage Change in Tumor Size From Baseline Change in target lesion from baseline (%) 100 50 0-50 -100 Placebo 27% 51% Sorafenib *Reported for each individual.
The problem of Radiologic Assessment - What Does RECIST Tell us? 10x6 cm 11x7 cm Baseline : AFP 219 8 weeks : AFP 36
Phase III SHARP Trial Response assessment (RECIST; Independent review) Time to Symptom Progression (FSHI8-TSP)* Sorafenib N=299 Placebo N=303 Overall response Complete response (CR) 0 0 Partial response (PR) 7 (2.3%) 2 (0.7%) Stable disease (SD) 211 (71%) 204 (67%) Progressive disease (PD) 54 (18%) 73 (24%) Progression-free rate at 4 mo 62% 42% Duration of treatment (median; weeks) 23 19 * FSHI8-TSP: No significant differences between treatment groups (P=0.77)
SHARP: Adverse Events Patients (%) Treatment-related SAEs Drug-related SAEs Sorafenib (n=299) 52 13 Placebo (n=302) 54 9 Grade Drug-Related AEs Any 3 / 4 Any 3 / 4 Diarrhea 39 8 / 0 11 2 / 0 HFSR 21 8 / 0 3 <1 / 0 Anorexia 14 <1 / 0 3 <1 / 0 Alopecia 14 0 / 0 2 0 / 0 Nausea 11 <1 / 0 8 1 / 0 Weight loss 9 2 / 0 <1 0 / 0 Pain (abdomen) 8 2 / 0 3 <1 / 0 Bleeding 7 <1 / 0 4 <1 / <1 Vomiting 5 1 / 0 3 <1 / 0 Liver dysfunction <1 <1 / 0 0 0 / 0 Llovet JM, et al. J Clin Oncol. 2007;25(suppl 18):LBA1. Updated from oral presentation at ASCO; Chicago, IL; June 2007.
Hand-Foot Skin Reaction Maculopapular rash Facial rash Body rash *Incidence reported from the SHARP trial; data on file, BayerHealthCare. Photos courtesy of Elizabeth Manchen, RN, MS, OCN.
Hand-Foot Skin Reaction by Grade Grade 1 Incidence: 8%* Grade 3 Incidence: 8%* Grade 2 Incidence: 6%* *Incidence reported from the SHARP trial; data on file, BayerHealthCare. Photos courtesy of Elizabeth Manchen, RN, MS, OCN.
Sorafenib in patients with HCC In a phase II trial, sorafenib 400mg b.i.d. demonstrated efficacy in patients with advanced HCC (n=137) 1 PR or minor response (MR) in 8% of patients, SD for 16 weeks in 34% of patients median independently assessed TTP of 5.5 months median investigator-assessed OS of 9.2 months grade 3 4 toxicities included fatigue, diarrhoea and HFSR In a phase III trial (SHARP) sorafenib 400mg b.i.d. significantly prolonged OS versus placebo in patients with advanced HCC (n=602) 2 10.7 months with sorafenib versus 7.9 months with placebo (p=0.0006) the most frequent grade 3 4 adverse events were diarrhoea, HFSR, fatigue and bleeding Sorafenib is the first systemic therapy to show a survival advantage over placebo in patients with advanced HCC SHARP = Sorafenib HCC Assessment Randomized Protocol 1. Abou-Alfa GK, et al. J Clin Oncol 2006 2. Llovet JM, et al. NEJM 2008
BCLC Treatment Overview: Linking Staging to Treatment HCC Early Stage Intermediate Stage Advanced Stage End Stage Surgical Treatment Local Ablation TACE Sorafenib (30%) Potentially Curative Treatments 5-y Survival: 40%-70% (50%-60%) Randomized Trials Median Survival If Untreated: 6-16 mo (10%) BSC Survival <3 mo TACE = transarterial chemoembolization; BSC = best supportive care. Adapted from Bruix J and Sherman M. Hepatology. 2005;42:1208-1236; Llovet JM, et al. Lancet. 2003;362:1907-1917.
Confirmation from the Asia-Pacific phase III study
Study Schema Eligibility Advanced HCC ECOG 0-2 Child-Pugh A No prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECOG PS Geographic region R A N D O M I Z E 2:1 n=150 n=76 Sorafenib 400 mg bid Placebo End points: Overall survival, time to symptomatic progression (FSHI8-TSP), time to progression, response (RECIST), and safety No primary end point defined Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 30-June 3, 2008; Chicago, IL.
Overall Survival Survival Probability 1.00 0.75 0.50 0.25 0 0 HR (S/P): 0.68 95% CI: 0.50-0.93 P=0.014 Months Sorafenib Median: 6.5 months (95% CI: 5.6-7.6) Placebo Median: 4.2 months (95% CI: 3.7-5.5) 2 4 6 8 10 12 14 16 18 20 22 Placebo Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 30-June 3, 2008; Chicago, IL.
Phase II Trial of Doxorubicin Sorafenib in HCC: Study Design Eligibility Advanced HCC ECOG PS 0-2 Child-Pugh Class A No prior systemic therapy No prior chemoembolization No history of organ allograft R A N D O M I Z E 1:1 n=47 n=49 Period 1 Period 2* Doxorubicin 60 mg/m 2 + sorafenib 400 mg bid q3w Doxorubicin 60 mg/m 2 + placebo q3w Sorafenib 400 mg bid Placebo Primary objective TTP (independent assessment) Secondary objectives ORR, PFS, OS, safety *Sorafenib or placebo continued until withdrawal, PD, or death in period 2. q3w = once every three weeks. Abou-Alfa GK, et al. Eur J Cancer Suppl. 2007;5(4):259. Updated from abstract 128. Poster and oral presentation at ASCO-GI; Orlando, FL; January 2008.
Overall survival Survival probability 1.00 0.75 0.50 0.25 0 Hazard ratio (sorafenib/doxorubicin): 0.45 (95% Cl: 0.24 0.84) p=0.004931 Sorafenib + doxorubicin (n=47) Median: 13.7 months (95% Cl: 10.4 NA) Placebo + doxrubicin (n=49) Median: 6.5 months (95% Cl: 4.9 9.5) 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Months From randomisation Definitive analysis (data from March 2007 cut-off, 50 events) NA = value can not be estimated due to censored data
Targeted agents in development for HCC: overview Agent Anti-angiogenic targets Antiproliferative targets VEGF VEGFR PDGFR EGFR Raf mtor Bevacizumab Brivanib Cediranib Erlotinib Gefitinib Lapatinib RAD001 Sorafenib* Sunitinib* Thalidomide TSU-68 Developmental status Phase II ongoing Phase II recruiting Phase II recruiting Phase II complete Phase II complete Phase II ongoing Phase I/II recruiting Phase III complete Phase II ongoing Phase III recruiting Phase I/II recruiting *Sunitinib and sorafenib also have antiproliferative effects through multi-tyrosine kinase inhibition Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IDdB3, BioPharm Insight, MedTrack