Changing epidemiology of HCC in Italy

Changing epidemiology of HCC in Italy G. Svegliati-Baroni Clinica di Gastroenterologia SOS Epatopatie Croniche-Trapianto di Fegato Università Politecnica delle Marche, Ancona

Worldwide estimated new PLC cases and mortality (2012) Incidence 782,000 new PLCs worldwide 5th most common cancer in men (554,000 cases, 7.5% of total) and 9th in women (228,000 cases, 3.4%) Mortality 2nd most common cause of death from cancer worldwide, responsible for nearly 746,000 deaths HCC is the main cause of mortality in compensated cirrhosis Globocan, IARC 2012

Liver cancer 2016 Hepatocellular carcinoma (HCC) accounts for >90% of primary liver cancers. Liver cancer is the fifth most common cancer among men, the ninth most common cancer among women; Liver cancer is the second most common cause of cancer death for men and women combined; Ratio of mortality to incidence: 0.95 Ferlay et al., Int J Cancer 2015

Annual Report to the Nation on the Status of Cancer 2003-2012 overall cancer incidence rates decreased 0.7%/year; death rates declined by 1.5%/year overall; deaths from liver cancer increased at the highest rate of all cancer sites for both sexes; CDC recommends a 1-time HCV test for persons born during 1945 through 1965. ACS, CDC, NCI, NAACCR Ryerson et al., Cancer 2016

Incidence rates of primary liver cancer according to geographical distribution in Europe EASL-EORTC CPG, J Hepatol 2012

Worldwide estimated new PLC cases and deaths Male Female Demographic risk factors: - male gender - geographic area Globocan, 2012 IARC

Rete AIRTUM COVERAGE: NORTH-WEST 41% NORTH-EAST 69% CENTRE 26% SOUTH/ISLAN DS 32% Copertura: 50% territorio nazionale

Primary Liver Cancer Italian epidemiological data From 1996 to 2014 incidence and mortality have shown a trend to slow progressive reduction Incidence:Mortality = 1.3 Males. Estimation of trends of cancer incidence ( ) and mortality ( ). Standardized rates to the European population. I-APC: 1996-2014: 0,9* ( 1,5; 0,4) M-APC: 1996-2014: 1,3 ( 2,1; 0,5) Incidence:Mortality = 1.0 Females. Estimation of trends of cancer incidence ( ) and mortality ( ). Standardized rates to the European population. I-APC: 1996-2003: 1.5 ( 0,7; 4,8) 2003-2014: -4,4* (-8,2; -0,5) M-APC: 1996-2014: 1,* ( 2,7; 0,8) APC = Annual Percent Change; I = Incidence; M = Mortality AIOM-CCM-AIRTUM, 2014

MORTALITY RATES FOR LIVER DISEASE POTENTIALLY CURED WITH LIVER TRANSPLANTATION AISF Libro Bianco dell Epatologia Italiana - Istituto Superiore di Sanità

Temporal trends of complications in patients with initially compensated cirhosis Child-Pugh class A patients (n = 312), median follow-up: 93 months - HCC is the most frequent complication - HCC is most frequently the first complication HCC Benvegnù et al. Gut 2004

The long-term outcome of HCV compensated cirrhosis: a 17-yr follow-up of 214 Pts Cumulative probability of events 100 Pts still at risk 50 25 0 Annual Incidence rate HCC 3.9% Ascites 2.9% Jaundice 2.0% GI bleeding 0.7% EPS 0.1% HCC Ascites Jaundice GI bleeding 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 EPS 214 196 186 168 153 142 129 116 110 96 89 74 66 57 48 36 214 197 182 163 151 142 133 114 105 92 86 74 68 60 55 39 214 196 184 164 152 144 134 122 114 100 89 75 69 60 54 40 214 198 188 171 160 151 142 129 122 105 94 81 73 64 58 42 214 198 190 173 162 152 146 129 122 108 98 84 77 66 59 43 Years Sangiovanni A et al Hepatology 2006

Geographical distribution of risk factors >80% HCC associated with HBV or HCV

Annual risk of HCC in treated HBV patients Weighted mean annual incidence of HCC Entecavir Untreated Non-cirrhosis 0.7% 2.9% Cirrhosis 3.8% 5.0% Papatheodoridis GV et al., J Hepatol 2015; 62: 956-67

Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided. Bruno S et al., Hepatology 2007; Cardoso AC et al., J Hepatol 2010; Morgan et al., Hepatology 2010; van der Meer AJ, JAMA 2012

Effects of Viral Eradication in Patients With Hepatitis C Virus and Cirrhosis Differ With Stage of Portal Hypertension 444 patients, 218 stage 1 226 stage 2, mena follow-up 7.5 yrs HCC development Stage 1 (without EV) Stage 2 (with EV) 7 SVR patients, mean time 6.5 years, 87% BCLC-A 92 non-svr patients, mean time 4.7 years, 68% BCLC-A 2.9% year 0.7% year 3.6% year 0.9% year Di Marco et al., Gastroenterology 2016

Death or OLTx Effects of Viral Eradication in Patients With Hepatitis C Virus and Cirrhosis Differ With Stage of Portal Hypertension 444 patients, 218 stage 1 226 stage 2, mena follow-up 7.5 yrs Di Marco et al., Gastroenterology 2016

Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population (Bruno et al., J Hep 2016)

Risk factors of HCC >80% associated with HBV o HCV ( viral cancer) Pisani et al., Cancer Epidemiol Biomarkers Prev 1997 Western society HCC is becoming an addiction-environmental cancer: Drugs Alcohol Food Tobacco smoking Environmental contaminants

8.200.000 adulti 24.500 HCC

ITAlian.LIver.CAncer network 2015 (since 1998): 6597 pts. GE MI Treviglio PR PI PD 1,2 BO 1,2,3,4 FI Roma 1,2 BZ Seriate Negrar Faenza VT NA 1,2 PA 1,2 AN 1. Benvegnù L. (PD) 2. Borzio F. (MI) 3. Cammà C. (PA) 4. Caturelli E. (VT) 5. Ciccarese F. (Treviglio) 6. Colecchia A (BO) 7. Di Marco M. (Seriate) 8. Farinati F. (PD) 9. Giannini E. (GE) 10. Masotto A. (Negrar) 11. Nardone G (NA) 12. Felder M. (BZ) 13. Foschi G.F. (Faenza) 14. Gasbarrini A. (Roma) 15. Missale G. (PR) 16. Morisco F. (NA) 17. Piscaglia F. (BO) 18. Rapaccini G.L. (Roma) 19. Sacco R. (PI) 20. Svegliati-Baroni G. (AN) 21. Trevisani F. (BO) 22. Virdone R. (PA) 23. Zoli M. (BO) Database ITA.LI.CA 2015

The changing scenario of hepatocellular carcinoma in the new century in Italy Patients (%) Mean age (±SD) years Total n. 5192 2000-2004 n. 1147 2005-2009 n. 1624 2010-2014 n. 2421 66.8 ± 9.5 67.4 ± 10.2 68.3 ± 10.6 <0.001 P 30 25 HCC Cirrhosis Ageing 20 15 10 5 0 Age (years) Bucci L et al., in revision Database ITA.LI.CA 2015

Percentage Etiology of HCC in Italy: observed and expected temporal trends 11 centers, 3027 patients, recruitment period 1987 2008 Subject to PATH Program Disclaimer Santi V. et al., for ITA.LI.CA, J Hepatol 2012;56:397-405

The changing scenario of hepatocellular carcinoma in the new century in Italy 80 77.5 72.2 67.6 60 p < 0.001 40 22.5 27.8 32.4 Viral Non viral 20 0 2000-2004 2005-2009 2010-2014 Bucci L et al., in revision Database ITA.LI.CA 2015

Percentage Etiology of HCC: observed regional differences in Italy HCV prevalence (2010-2014) 80 p<0.001 p<0.001 60 p=0.191 40 20 0 North Center South Bucci L et al., in revision Database ITA.LI.CA 2015

Percentage Etiology of HCC: observed regional differences in Italy 100 80 60 40 HBV HCV Multietiology No viruses 20 0 1 2 3 North Centre South Bucci L et al., in revision Database ITA.LI.CA 2015

Percentage The changing scenario of hepatocellular carcinoma in the new century in Italy 60 50 40 30 20 10 HBV HCV Multietiology No viruses 0 1 2 3 2000-2004 2005-2009 2010-2015 Bucci L et al., in revision Database ITA.LI.CA 2015

Percentage Virus-free HCC in ITA.LI.CA: temporal trends in the new century 20 16.7 18.1 15 12.6 13.5 Alcohol 10 NAFLD 5 4.5 1.1 6.1 2.7 4.9 1.4 Multietiology Others 0 0.2 0.9 2000-2004 2005-2009 2010-2014 Bucci L et al., in revision Database ITA.LI.CA 2015

Emerging protective factors for HCC: mediterranean diet Case-control study: 518 HCC vs 772 controls Report 2015 0= lowest adherence to MD 9= highest adherence to MD Model adjusted for: center, age, sex, education, body mass index, smoking, diabetes, non-alcohol energy intake, and HBsAg and/or anti-hcv positivity. Turati F et al., J Hepatol 2015;60:606-11

Percentage (%) The changing scenario of hepatocellular carcinoma in the new century in Italy Total n. 5038 2000-2004 n. 1105 2005-2009 n. 1567 2010-2014 n. 2366 Cirrhosis 94.3% 94.6% 90.4% <0.001 P 100 Prevalence of cirrhosis by aetiology Viral p < 0.001 Non viral Proportion of HCC patients with a non cirrhotic liver 80 60 40 20 0 Bucci L et al., in revision Database ITA.LI.CA 2015

145 NAFLD-HCC vs 611 HCV-HCC from January 2010 to December 2012 Cirrhosis was detected in 78 of 145 NAFLD patients (53.8%)

Risk of HCC development in cirrhosis Social alcohol intake compared with no alcohol intake Ascha et al., Hepatology 2010

Percentage The changing scenario of hepatocellular carcinoma in the new century in Italy Percentage Type of diagnosis 100 80 60 p = 0.030 p <0.001 p <0.001 B 100 p <0.001 p = 0.017 Surveillance interval 40 p = 0.049 p = 0.013 80 20 60 0 Surveillance Incidental Symptoms 40 p <0.001 Modality of HCC diagnosis 20 p =0.006 0 3-7 8-13 >13 Interval (months) Bucci L et al., in revision Database ITA.LI.CA 2015

% patients Surveillance for HCC by aetiology in ITA.LI.CA Percentage of cases diagnosed during regular surveillance 68% 37% 39% HCV n. 2342 Alcohol n. 864 NASH/ Crypt. n. 271 Bucci L et al., in revision Database ITA.LI.CA 2015

Hepatocellular Carcinoma in Patients With Cryptogenic Cirrhosis Database ITA.LI.CA 1987-2006, 2042 HCC Giannini et al., CGH 2009

Hepatocellular Carcinoma in Patients With Cryptogenic Cirrhosis Database ITA.LI.CA 1987-2006, 2042 HCC HCV CC Giannini et al., CGH 2009

HCC Tumor Characterists: NAFLD vs HCV HCC on NAFLD n=145 HCC on HCV n=611 Crude mean overall survival NAFLD = 27.2 months HCV = 34.4 months (P = 0.015). Survival rates at 1 year and 3 years NAFLD = 76.4% and 48.7% HCV = 84.2% and 61.1% Piscaglia et al., Hepatology 2016

HCC Tumor Characterists: NAFLD vs HCV HCC on NAFLD n=145 HCC on HCV n=611 Mean overall survival lead time adjusted NAFLD = 25.5 months HCV = 33.7 months (P = 0.015). Survival rates at 1 year and 3 years NAFLD = 76.4% and 48.7% HCV = 84.2% and 61.1% Piscaglia et al., Hepatology 2016

HCC in NAFLD vs HCV after propensity score matching Mean overall survival NAFLD = 30.2 months HCV = 36.9 months (P = 0.33). Survival rates at 1 year and 3 years NAFLD = 87.4% and 72.6% HCV = 91.9% and 63.3% Mean overall survival of HCC on NAFLD NAFLD with cirrhosis = 28.5 m NAFLD without cirrhosis = 34.9 m (P = ns). No significant impact of cirrhosis Piscaglia et al., Hepatology 2016

HCC in NAFLD vs HCV: only Milan-in submitted to curative therapies Mean overall survival NAFLD = 38.6 months HCV = 41.0 months (P = ns). NAFLD HCC patients die more of non liver related causes than HCV HCC patients Piscaglia et al., Hepatology 2016

These results highlight the need to focus future research on identifying those patients with NAFLD who require surveillance in order to establish earlier diagnosis and offer them treatment, which in our series appeared to be as effective as that provided for patients with HCV at an early stage.

EASL CPG 2016 Screening for HCC-NAFLD

The changing scenario of hepatocellular carcinoma in the new century in Italy BCLC Total n. 4238 2000-2004 2005-2009 2010-2014 P <0.001 Stage 0 245 1.8% 5.4% 7.9% ( ) Stage A 1649 42.6% 37.2% 38.3% ( ) Stage B 714 22.8% 15.6% 14.9% ( ) Stage C 1235 23.9% 30.8% 30.5% ( ) Stage D 395 9.3% 11.0% 8.4% Tumor size 4562 <0.001 2 cm 1300 25.0% 30.1% 29.1% ( ) 2.1-5 cm 2336 57.4% 51.4% 48.1% ( ) > 5 cm 926 17.6% 18.5% 22.8% ( ) Database ITA.LI.CA 2015

Primary Liver Cancer Italian epidemiological data (AIRTUM 2015) 21% nel 2009

The changing scenario of hepatocellular carcinoma in the new century in Italy Survival probability (%) Survival probability (%) Overall survival at 5-yrs: 39.2% 100 80 All patients (n. 5118) Viral patients (n. 3622) Non-viral patients (n. 1444) G1: median OS (95% CI) 30.7 (27.7-33.7) G2: median OS (95% CI) 32.2 (28.9-35.6) G3: median OS (95% CI) 40.4 (34.3-46.5) G1: median OS (95% CI) 31.5 (28.2-34.7) G2: median OS (95% CI) 33.2 (29.4-37.0) G3: median OS (95% CI) 40.4 (33.4-47.4) G1: median OS (95% CI) 24.8 (18.4-31.2) G2: median OS (95% CI) 27.5 (20.5-34.5) G3: median OS (95% CI) 35.3 (25.5-45.2) 60 40 p<0.001 p=0.001 p=0.041 20 0 100 80 BCLC 0+A (n.1884) G1: median OS (95% CI) 45.8 (40.6-51.0) G2: median OS (95% CI) 57.5 (47.6-67.4) G3: median OS (95% CI) nd BCLC B (n. 704) BCLC C (n. 1223) G1: median OS (95% CI) 20.8 (15.4-26.2) G2: median OS (95% CI) 27.2 (19.8-34.6) G3: median OS (95% CI) 30.6 (21.0-40.3) G1: median OS (95% CI) 14.2 (10.5-17.9) G2: median OS (95% CI) 17.5 (14.6-20.3) G3: median OS (95% CI) 15.9 (11.8-20.0) 60 40 p<0.001 p=0.004 p=0.136 20 0 Bucci L et al., in revision Months Database ITA.LI.CA 2015

Epidemiology of HCC in ITALY: take home messages The incidence and mortality of HCC is decreasing, particularly in men. The etiologic scenario is changing, with a reduction in HCV-related tumors and a progressive rise of non-viral tumor, particularly of metabolic HCCs. The proportion of HCCs detected during a correct surveillance is moderately increasing, being this trend curbed by the spreading out of non-viral tumors. In clinical series, almost 50% of HCC are diagnosed at early stages, with an increase of very early tumors. Nevertheless, large tumors (>5 cm) are increasing. The treatment distribution and outcome are changed in all HCC stages, likely reflecting a more appropriate selection of candidates and technical refinements for each approach. Overall survival is improving both in viral and non-viral patients. However, in population-based registries the 5-year survival rate remains dismal.

Mr. ITA.LI.CA