Hepatocellular Carcinoma: Can We Slow the Rising Incidence?

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1 Hepatocellular Carcinoma: Can We Slow the Rising Incidence? K.Rajender Reddy M.D. Professor of Medicine Director of Hepatology Medical Director of Liver Transplantation University of Pennsylvania

2 Outline Epidemiology Etiology Hepatitis B and HCC Hepatitis C and HCC Metabolic Syndrome and HCC

3 Hepatocellular Carcinoma Represents 5 % of all cancers Estimated annual numbers of cases 500,000 Rising incidence 2 3 times higher in developing countries Southeast Asia and sub-saharan Africa account for 85% of HCC More common in men Survival rates for untreated symptomatic HCC: approximately 1% at 2 years

4 El-Serag HB, et al. NEJM 2011;365:

5 Racial/Ethnic Distribution of HCC in the United States El Serag HB, et al. NEJM 1999;340:745-50

6 Etiology of Hepatocellular Carcinoma in the US Marrero JA, et al. Hepatology 2002;36:

7 Hepatitis B

8 Percent per Year HBV DNA and Natural History Incidence of HCC 1 Incidence of Cirrhosis HBV DNA (copies/ml) 3.0 HBV DNA (copies/ml) <300 ~1000 ~10,000 ~100,000 >1,000, <300 ~1000 ~10,000 ~100,000 >1,000, Chen CJ et al. JAMA. 2006;295: Iloeje UH et al. Gastroenterology. 2006;130:

9 Quantitative Serum Levels of HBV DNA and HBsAg Are Independent Risk Predictors of HCC Study examined the effects of HBV DNA and HBsAg levels on the development of hepatocellular carcinoma (HCC) (N=3,411) Correlation between HBV DNA and HBsAg (r=0.59) HBV DNA and HBsAg levels were significantly associated with HCC risk HCC risk associated with increasing serum HBV DNA and HBsAg levels remained, even in HBeAg(-) participants without cirrhosis Cumulative incidence of hepatocellular carcinoma by HBV DNA/HBsAg levels at study entry HBeAg(-) without Cirrhosis (N=2,840) Entire Cohort (N=3,411) 17.2% 15.3% 13.6% 17.2% P < % 5.3% 3.7% 3.0% 2.2% 1.1% P < % 10.7% 5.8% 4.9% 3.8% 3.1% 2.2% 1.1% Chen C, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

10 Odds ratio Risk of HCC/cirrhosis increases in patients with family history of HCC In Asian families with a history of HCC, there is an increased risk for both HCC and cirrhosis for mothers and siblings but not for fathers of case subjects 8 HCC Cirrhosis Mother Father Brother Sister Case subjects: HBV carriers with recently diagnosed HCC (n=553) Control subjects: HBV carriers without HCC (n=4,684) Yu M-W, et al. JNCI 2000;92:

11 HCC recurrence (%) Recurrence of hepatocellular carcinoma (HCC) in the 115 patients surviving >1 year without recurrence after resection There is a significantly low recurrence of HCC in the sustained low viraemia group than the other groups (log-rank test, p<0.001) Sustained high viraemia Fluctuating HBV DNA Sustained low viraemia p< Time (Months) An HJ, et al. J Gastroenterol Hepatol 2010;25:

12 Impact of Surveillance, HBV Vaccination, and Therapy on HCC

13 Survival Probability (%) Surveillance for HCC Reduces Mortality: A Randomized Controlled Trial.8.6 Control Screening Time (Years) Zhang BH, et al. J Cancer Res Clin Oncol 2004

14 Rate (%) Rate of HCC in Children 6-14 years old Taiwan introduced a universal HBV vaccination program in 1984 Since then, incidence of HCC in children 6-14 years old has fallen by 65-75% Introduction of HBV Vaccine Year Chang MH, et al. NEJM 1997;336:1855-9

15 Approved HBV Treatments First-line agents: Pegylated interferon alpha 2a (Pegasys) Injectable Entecavir (Baraclude) Oral Tenofovir (Viread) Oral Second-line agents: Interferon alpha 2b (Intron) Injectable Lamivudine (Epivir) Oral Adefovir dipivoxil (Hepsera) Oral Telbivudine (Tyzeka) Oral

16 Lamivudine significantly reduced the incidence of hepatic decompensation and HCC Multicenter, DB-RCT in Asian populations, N=651 P=0.001 P=0.047 Liaw YF, et al. N Engl J Med 2004;351:

17 Hepatitis C

18 Number of Cases Projected Prevalence of Chronic HCV, Cirrhosis, and Complications Projected Number of Patients With Decompensated Cirrhosis and Hepatocellular Carcinoma 160, , , ,000 80,000 60,000 40,000 20,000 Hepatocellular Carcinoma (HCC) Decompensated Cirrhosis Year Davis GL, et al. Gastroenterology. 2010;138(2): e516.

19 Milestones in Therapy of CHC Average SVR Rates from Clinical Trials Direct Acting Antivirals Peginterferon 2011 Standard Interferon 1991 Ribavirin IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m Peg-IFN 12m Peg-IFN/ RBV 12m Peg-IFN/ RBV/ DAA Adapted from US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.

20 Impact of HCV Therapy on HCC

21 Bruno S, et al. Hepatology 2007;45:

22 Bruno S, et al. Hepatology 2007;45:

23 Sustained virologic response to interferon is associated with improved survival in hepatitis C patients with hepatocellular carcinoma Cohort 1: 307 Cohort 2: IFN-treated Compensated cirrhosis Untreated: 307 SVR: 71 (20%) Non-SVR: 281 (80%) HCC: 11 (15%) HCC: 94 (33%) 2 Decompensated at diagnosis 16 9 (13%) HCC on Study 78 (28%) Bruno S, et al 2011 AASLD Meeting, 7-9 November 2011

24 Incidence of Liver Related Decompensation Following HCC Development According to IFN Virological Response Time since HCC diagnosis Patients at risk Non SVR SVR

25 Mortality Following HCC Development According to IFN Virological Response Time since HCC diagnosis Patients at risk Non SVR SVR

26 Veldt BJ, et al. Ann Intern Med. 2007;147:

27 Singal AK, et al. Clin Gastro Hepat 2010;8:

28 Sustained Virologic Response Improves Overall Survival in Chronic HCV with Advanced Fibrosis 5 large centers from Europe and Canada , advanced fibrosis. Treated with interferon based regimens 529 patients followed for 20.2 years (median follow up 7.7 years) 191 ( 36.1%) achieved SVR Hazard Ratio of NR vs. SVR Liver Failure HCC Liver Related Death p<0.001 p<0.001 p<0.001 Death, Overall p< *Hazard Ratio s are adjusted for age, gender, center, fibrosis score, diabetes mellitus, heavy alcohol use treatment period. Van der Meer AJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, Abst. 165.

29 Metabolic Syndrome and HCC

30 Comparison of HCC Patients with Cryptogenic Cirrhosis versus other Etiologies Cryptogenic n= 30 Other Etiologies n=75 P Value Female(%) Mean age ±SD(yr) 57 ± ± 13 NS Non-Hispanic white(%) NS BMI > 30 (%) Diabetes(%) Hypertriglyceridemia(%) Hypercholesterolemia(%) Maximal tumor diameter Mean ± SD(cm) 7.6 ± ± 5.03 AFP < 20 ng/ml (%) NS Detected by surveillance(%) Marrero JA, et al. Hepatology 36; :2002

31 Obesity and Liver Cancer Calle EE, et al. NEJM 2003;348:

32 HCC Rate (%) Diabetes Is Associated with a Two-fold Increase in Risk of HCC Diabetes N=173,643 P< No Diabetes N=650, Years of Follow up El-Serag HB, et al. Gastroenterology 2004;126:

33 Probability of HCC Free Survival Impact of Diabetes and Overweight on Liver Cancer Occurrence in Cirrhosis P< Time (Years) BMI <23.9, diabetes - BMI <23.9, diabetes + BMI diabetes - BMI diabetes + BMI >27.3, diabetes - BMI >27.3, diabetes + N = 771 N Kontchou G, et al. Clin Gastro Hepatol 2005

34 Summary Rising Incidence of HCC HBV vaccination effectively reduces incidence of HCC Hepatitis B viral DNA correlates with HCCtreatment effectively decreases the incidence of HCC Rising incidence of HCV related HCC-SVR effectively decreases incidence of HCC Metabolic syndrome-a major cause for HCC; education and preventive strategies needed