EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma

Abstract

EASL–EORTC Clinical Practice Guidelines (CPG) on the management of hepatocellular carcinoma (HCC) define the use of surveillance, diagnosis, and therapeutic strategies recommended for patients with this type of cancer. This is the first European joint effort by the European Association for the Study of the Liver (EASL) and the European Organization for Research and Treatment of Cancer (EORTC) to provide common guidelines for the management of hepatocellular carcinoma. These guidelines update the recommendations reported by the EASL panel of experts in HCC published in 2001 [[1]Bruix J. Sherman M. Llovet J.M. Beaugrand M. Lencioni R. Burroughs A.K. et al.EASL Panel of Experts on HCC. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.J Hepatol. 2001; 35: 421-430Abstract Full Text Full Text PDF PubMed Scopus (2365) Google Scholar]. Several clinical and scientific advances have occurred during the past decade and, thus, a modern version of the document is urgently needed. The purpose of this document is to assist physicians, patients, health-care providers, and health-policy makers from Europe and worldwide in the decision-making process according to evidence-based data. Users of these guidelines should be aware that the recommendations are intended to guide clinical practice in circumstances where all possible resources and therapies are available. Thus, they should adapt the recommendations to their local regulations and/or team capacities, infrastructure, and cost–benefit strategies. Finally, this document sets out some recommendations that should be instrumental in advancing the research and knowledge of this disease and ultimately contribute to improve patient care. The EASL–EORTC CPG on the management of hepatocellular carcinoma provide recommendations based on the level of evidence and the strength of the data (the classification of evidence is adapted from National Cancer Institute [[2]National Cancer Institute. PDQ® levels of evidence for adult and pediatric cancer treatment studies. Bethesda, MD: National Cancer Institute. Date last modified 26/August/2010. <http://cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/healthprofessional/>; 2011 [accessed 01.03.11].Google Scholar]) (Table 1A) and the strength of recommendations following previously reported systems (GRADE systems) (Table 1B).Table 1ALevels of evidence according to study design and end-points National Cancer Institute: PDQ Levels of Evidence for Adult and Pediatric Cancer Treatment Studies. Bethesda [2]National Cancer Institute. PDQ® levels of evidence for adult and pediatric cancer treatment studies. Bethesda, MD: National Cancer Institute. Date last modified 26/August/2010. <http://cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/healthprofessional/>; 2011 [accessed 01.03.11].Google Scholar¶.¶National Cancer Institute: PDQ® Levels of Evidence for Adult and Paediatric Cancer Treatment Studies. Bethesda, MD: National Cancer Institute. Date last modified 26/August/2010. Available at: http://cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/HealthProfessional. Accessed <March 1st, 2011>.∗The randomized, double-blinded controlled clinical trial (1i) is the gold standard of study design. Meta-analyses of randomized studies are placed in the same category of strength of evidence as are randomized studies.∗∗This category includes trials in which treatment allocation was made by birth date, chart number (so-called quasi randomized studies) or subset analyses of randomized studies (or randomized phase II studies).∗∗∗All other prospective (cohort studies) or retrospective studies (case–control studies, case series).#These end-points may be subjected to investigator interpretation. More importantly, they may, but do not automatically, translate into direct patient benefit such as survival or quality of life. Nevertheless, it is rational in many circumstances to use a treatment that improves these surrogate end-points while awaiting a more definitive end-point to support its use. Open table in a new tab Table 1BGrading evidence and recommendations (adapted from GRADE system). Open table in a new tab ¶National Cancer Institute: PDQ® Levels of Evidence for Adult and Paediatric Cancer Treatment Studies. Bethesda, MD: National Cancer Institute. Date last modified 26/August/2010. Available at: http://cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/HealthProfessional. Accessed <March 1st, 2011>. ∗The randomized, double-blinded controlled clinical trial (1i) is the gold standard of study design. Meta-analyses of randomized studies are placed in the same category of strength of evidence as are randomized studies. ∗∗This category includes trials in which treatment allocation was made by birth date, chart number (so-called quasi randomized studies) or subset analyses of randomized studies (or randomized phase II studies). ∗∗∗All other prospective (cohort studies) or retrospective studies (case–control studies, case series). #These end-points may be subjected to investigator interpretation. More importantly, they may, but do not automatically, translate into direct patient benefit such as survival or quality of life. Nevertheless, it is rational in many circumstances to use a treatment that improves these surrogate end-points while awaiting a more definitive end-point to support its use. The clinical practice guidelines below will give advice for up to date management of patients with HCC as well as providing an in-depth review of all the relevant data leading to the conclusions.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) The burden of cancer is increasing worldwide. Each year there are 10.9 million new cases of cancer and 6.7 million cancer-related deaths. The most commonly diagnosed cancers are lung, breast, and colorectal while the most common causes of cancer death are lung, stomach, and liver [3Parkin D.M. Bray F. Ferlay J. Pisani P. Global cancer statistics, 2002.CA Cancer J Clin. 2005; 55: 74-108Crossref PubMed Google Scholar, 4IARC. <http://www-dep.iarc.fr/>; 2011 [accessed 01.11.11].Google Scholar]. Liver cancer is the sixth most common cancer (749,000 new cases), the third cause of cancer-related death (692,000 cases), and accounts for 7% of all cancers [[4]IARC. <http://www-dep.iarc.fr/>; 2011 [accessed 01.11.11].Google Scholar]. HCC represents more than 90% of primary liver cancers and is a major global health problem. The incidence of HCC increases progressively with advancing age in all populations, reaching a peak at 70 years [[5]El-Serag H.B. Mason A.C. Rising incidence of hepatocellular carcinoma in the United States.N Engl J Med. 1999; 340: 745-750Crossref PubMed Scopus (2305) Google Scholar]. In Chinese and in black African populations, the mean age of patients with the tumor is appreciably younger. This is in sharp contrast to Japan, where the incidence of HCC is highest in the cohort of men aged 70–79 years [[6]Tanaka H. Imai Y. Hiramatsu N. Ito Y. Imanaka K. Oshita M. et al.Declining incidence of hepatocellular carcinoma in Osaka, Japan from 1990 to 2003.Ann Intern Med. 2008; 148: 820-826Crossref PubMed Google Scholar]. HCC has a strong male preponderance with a male to female ratio estimated to be 2.4 [[4]IARC. <http://www-dep.iarc.fr/>; 2011 [accessed 01.11.11].Google Scholar]. The pattern of HCC occurrence has a clear geographical distribution, with the highest incidence rates in East Asia, sub-Saharan Africa, and Melanesia, where around 85% of cases occur [3Parkin D.M. Bray F. Ferlay J. Pisani P. Global cancer statistics, 2002.CA Cancer J Clin. 2005; 55: 74-108Crossref PubMed Google Scholar, 4IARC. <http://www-dep.iarc.fr/>; 2011 [accessed 01.11.11].Google Scholar]. In developed regions, the incidence is low with the exception of Southern Europe where the incidence in men (10.5 age-standardized incidence rates per 100,000) is significantly higher than in other developed regions [[7]Bosetti C. Boffetta P. Lucchini F. Negri E. La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, 1980–2004.Hepatology. 2008; 48: 137-145Crossref PubMed Scopus (129) Google Scholar] (Fig. 1). There is a growing incidence of HCC worldwide. Overall, the incidence and mortality rates were of 65,000 and 60,240 cases in Europe and 21,000 and 18,400 cases in the United States in 2008, respectively. It is estimated that by 2020 the number of cases will reach 78,000 and 27,000, respectively [[4]IARC. <http://www-dep.iarc.fr/>; 2011 [accessed 01.11.11].Google Scholar]. People infected with HCV in Europe during the period 1940–60 and in the United States of America (USA) one decade later led to the current increase of HCC incidence. In Europe, the incidence and mortality rates reported are heterogeneous. HCC mortality during the last decades increased in males in most of the countries (i.e. Austria, Denmark, Germany, Greece, Ireland, Portugal, Norway, Spain, Switzerland, and United Kingdom), but decreased in others (Finland, France, Italy, Netherlands, and Sweden) [[7]Bosetti C. Boffetta P. Lucchini F. Negri E. La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, 1980–2004.Hepatology. 2008; 48: 137-145Crossref PubMed Scopus (129) Google Scholar]. In the United States, the rate of HCC deaths appears to have increased by about 40% over the period 1990–2004, whereas the overall rate of cancer deaths has declined by about 18% during this same period [[8]Jemal A. Siegel R. Ward E. Hao Y. Xu J. Murray T. et al.Cancer statistics, 2008.CA Cancer J Clin. 2008; 58: 71-96Crossref PubMed Scopus (7675) Google Scholar]. Besides the emergence of liver disease due to hepatitis C, this growth in incidence may be also due to an increase in HBV-related HCC, particularly among immigrants from endemic countries. Conversely, in Japan, a country where the impact of HCV-related HCC was first noticed after World War II, there has been an apparent decline in the incidence of this neoplasm for the first time since 1990 [[6]Tanaka H. Imai Y. Hiramatsu N. Ito Y. Imanaka K. Oshita M. et al.Declining incidence of hepatocellular carcinoma in Osaka, Japan from 1990 to 2003.Ann Intern Med. 2008; 148: 820-826Crossref PubMed Google Scholar]. Finally, the impact of universal infant vaccination against HBV has decreased the rate of HBV-related HCC in endemic countries. So far, this has been observed among children in Taiwan, but it is expected to become more apparent as these vaccinated children grow into adults [[9]Chang M.H. You S.L. Chen C.J. Liu C.J. Lee C.M. Lin S.M. et al.Taiwan Hepatoma Study Group. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study.J Natl Cancer Inst. 2009; 101: 1348-1355Crossref PubMed Scopus (219) Google Scholar]. Approximately 90% of HCCs are associated with a known underlying risk factor (Table 2). The most frequent factors include chronic viral hepatitis (types B and C), alcohol intake and aflatoxin exposure. In Africa and East Asia, the largest attributable fraction is due to hepatitis B (60%) whereas in the developed Western world, only 20% of cases can be attributed to HBV infection, while chronic hepatitis C appears to be the major risk factor [[3]Parkin D.M. Bray F. Ferlay J. Pisani P. Global cancer statistics, 2002.CA Cancer J Clin. 2005; 55: 74-108Crossref PubMed Google Scholar]. Worldwide, approximately 54% of cases can be attributed to HBV infection (which affects 400 million people globally) while 31% can be attributed to HCV infection (which affects 170 million people), leaving approximately 15% associated with other causes.Table 2Geographical distribution of main risk factors for HCC worldwide.∗∗Updated from Llovet et al. [99]Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (2475) Google Scholar, according to IARC data [4]IARC. <http://www-dep.iarc.fr/>; 2011 [accessed 01.11.11].Google Scholar. AAIR, age-adjusted incidence rate. Open table in a new tab ∗Updated from Llovet et al. [99]Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (2475) Google Scholar, according to IARC data [4]IARC. <http://www-dep.iarc.fr/>; 2011 [accessed 01.11.11].Google Scholar. AAIR, age-adjusted incidence rate. Cirrhosis is an important risk factor for HCC, and may be caused by chronic viral hepatitis, alcohol, inherited metabolic diseases such as hemochromatosis or alpha-1-antitrypsin deficiency, and non-alcoholic fatty liver disease. All etiologic forms of cirrhosis may be complicated by tumor formation, but the risk is higher in patients with hepatitis infection. Overall, one-third of cirrhotic patients will develop HCC during their lifetime [[10]Sangiovanni A. Prati G.M. Fasani P. Ronchi G. Romeo R. Manini M. et al.The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients.Hepatology. 2006; 43: 1303-1310Crossref PubMed Scopus (234) Google Scholar]. Long-term follow-up studies have demonstrated that approximately 1–8% per year of patients with cirrhosis develop HCC (e.g. 2% in HBV-infected cirrhotic patients and 3–8% in HCV-infected cirrhotic patients) [[11]Ioannou G. Splan M. Weiss N. McDonald G. Beretta L. Lee S. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.Clin Gastroenterol Hepatol. 2007; 5: 938-945Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. In general, features of liver disease severity (low platelet count of less than 100 × 103, presence of esophageal varices), in addition to older age and male gender, correlate with HCC development among patients with cirrhosis [[12]Lok A.S. Seeff L.B. Morgan T.R. Di Bisceglie A.M. Sterling R.K. Curto T.M. et al.Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.Gastroenterology. 2009; 136: 138-148Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar]. Recent studies have shown that liver cancer incidence increases in parallel to portal pressure as directly measured [[13]Ripoll C. Groszmann R.J. Garcia-Tsao G. Bosch J. Grace N. Burroughs A. et al.Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis.J Hepatol. 2009; 50: 923-928Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar] or in parallel to the degree of liver stiffness as measured by transient elastography [14Masuzaki R. Tateishi R. Yoshida H. Goto E. Sato T. Ohki T. Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography.Hepatology. 2009; 49: 1954-1961Crossref PubMed Scopus (138) Google Scholar, 15Jung K.S. Kim S.U. Ahn S.H. Park Y.N. Kim do Y. Park J.Y. et al.Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan).Hepatology. 2011; 53: 885-894Crossref PubMed Scopus (105) Google Scholar]. Several studies have identified HBV-related factors as key predictors of HCC development in patients with chronic hepatitis B infection [[16]Lok A.S. Prevention of hepatitis B virus-related hepatocellular carcinoma.Gastroenterology. 2004; 127: S303-S309Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. Hepatitis B virus e antigen (HBeAg) seropositivity [[17]Yang H.I. Lu S.N. Liaw Y.F. You S.L. Sun C.A. Wang L.Y. et al.Taiwan Community–Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med. 2002; 347: 168-174Crossref PubMed Scopus (743) Google Scholar], high viral load [[18]Chen C.J. Yang H.I. Su J. Jen C.L. You S.L. Lu S.N. et al.REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (1443) Google Scholar], and genotype C [[19]Yu M.W. Yeh S.H. Chen P.J. Liaw Y.F. Lin C.L. Liu C.J. et al.Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men.J Natl Cancer Inst. 2005; 97: 265-272Crossref PubMed Scopus (345) Google Scholar] are independent predictors of HCC development. In addition, hepatitis B viral load correlates with the risk of progression to cirrhosis [[20]Iloeje U.H. Yang H.I. Su J. Jen C.L. You S.L. Chen C.J. Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer–In HBV (the REVEAL–HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.Gastroenterology. 2006; 130: 678-686Abstract Full Text Full Text PDF PubMed Scopus (853) Google Scholar]. Similarly, in a recent meta-analysis, HCV genotype 1b is claimed to increase the risk of HCC development [[21]Raimondi S. Bruno S. Mondelli M.U. Maisonneuve P. Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis.J Hepatol. 2009; 50: 1142-1154Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. Dietary exposure to aflatoxin B1, derived from the fungi Aspergillus flavus and A. parasiticus, is an important co-factor for HCC development in some parts of Africa and Asia. These molds are ubiquitous in nature and contaminate a number of staple foodstuffs in tropical and subtropical regions. Epidemiologic studies have shown a strong correlation between the dietary intake of aflatoxin B1, TP53 mutations and incidence of HCC, specifically in HBV-infected individuals [[22]Hsu I.C. Metcalf R.A. Sun T. Welsh J.A. Wang N.J. Harris C.C. Mutational hotspot in the p53 gene in human hepatocellular carcinomas.Nature. 1991; 350: 427-428Crossref PubMed Scopus (885) Google Scholar]. Regarding other risk factors, patients with hemochromatosis develop HCC in up to 45% of cases [[23]Deugnier Y.M. Guyader D. Crantock L. Lopez J.M. Turlin B. Yaouanq J. et al.Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases.Gastroenterology. 1993; 104: 228-234Abstract PubMed Scopus (0) Google Scholar], most often with a background of cirrhosis, and HCC is well documented as a complication of cirrhosis associated with alpha-1-antitrypsin deficiency [[24]Perlmutter D.H. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency.Pediatr Res. 2006; 60: 233-238Crossref PubMed Scopus (51) Google Scholar]. HCC develops occasionally in patients with Wilson’s disease, but only in the presence of cirrhosis [[25]Polio J. Enriquez R.E. Chow A. Wood W.M. Atterbury C.E. Hepatocellular carcinoma in Wilson’s disease. Case report and review of the literature.J Clin Gastroenterol. 1989; 11: 220-224Crossref PubMed Google Scholar]. Obesity, diabetes and fatty liver disease have come to be recognized as a cause of HCC [26El-Serag H.B. Richardson P.A. Everhart J.E. The role of diabetes in hepatocellular carcinoma: a case–control study among United States Veterans.Am J Gastroenterol. 2001; 96: 2462-2467Crossref PubMed Google Scholar, 27Marrero J. Fontana R. Fu S. Conjeevaram H. Su G. Lok A. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.J Hepatol. 2005; 42: 218-224Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar], although the mechanisms by which these overlapping conditions contribute to cancer development remain elusive. Cirrhosis due to non-alcoholic steatohepatitis may give rise to HCC but it appears that these factors may also be additive to chronic viral hepatitis [[27]Marrero J. Fontana R. Fu S. Conjeevaram H. Su G. Lok A. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.J Hepatol. 2005; 42: 218-224Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar]. Epidemiologic evidence of a link between cigarette smoking and the occurrence of HCC was traditionally conflicting [[26]El-Serag H.B. Richardson P.A. Everhart J.E. The role of diabetes in hepatocellular carcinoma: a case–control study among United States Veterans.Am J Gastroenterol. 2001; 96: 2462-2467Crossref PubMed Google Scholar], but recent evidence support that smoking is a clear co-factor [[28]Trichopoulos D. Bamia C. Lagiou P. Fedirko V. Trepo E. Jenab M. et al.Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested case–control study.J Natl Cancer Inst. 2011; 103: 1686-1695Crossref PubMed Scopus (66) Google Scholar]. Heavy smokers have a higher risk than non-smokers. In the general population, the incidence of HCC is increased among patients with HIV infection compared to controls, and HIV appears to be an additive co-factor, exacerbating the risk of HCC in patients with chronic viral hepatitis [[29]Marcellin P. Pequignot F. Delarocque-Astagneau E. Zarski J.P. Ganne N. Hillon P. et al.Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption.J Hepatol. 2008; 48: 200-207Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. Identification of mutations in germline DNA that define patients at high risk of developing cancer has become a challenge for surveillance programs and chemopreventive strategies. This is the case of mutations in BRCA1 or BRCA2 and increased risk of breast or ovarian cancer [[30]Miki Y. Swensen J. Shattuck-Eidens D. Futreal P.A. Harshman K. Tavtigian S. et al.A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.Science. 1994; 266: 66-71Crossref PubMed Google Scholar] or in genes involved in DNA mismatch repair and hereditary colon cancer [[31]Marra G. Boland C.R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives.J Natl Cancer Inst. 1995; 87: 1114-1125Crossref PubMed Google Scholar]. In HCC, a recent case–control study found a significant association between an epidermal growth factor (EGF) gene polymorphism and the risk of HCC [[32]Tanabe K.K. Lemoine A. Finkelstein D.M. Kawasaki H. Fujii T. Chung R.T. et al.Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis.JAMA. 2008; 299: 53-60Crossref PubMed Scopus (124) Google Scholar], while another study suggests genetic predisposition of SNPs at loci involved in immune response [[33]Clifford R.J. Zhang J. Meerzaman D.M. Lyu M.S. Hu Y. Cultraro C.M. et al.Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma.Hepatology. 2010; 52: 2034-2043Crossref PubMed Scopus (48) Google Scholar]. These findings require validation by independent investigators. Primary prevention of HCC can be achieved with universal vaccination against HBV infection [[9]Chang M.H. You S.L. Chen C.J. Liu C.J. Lee C.M. Lin S.M. et al.Taiwan Hepatoma Study Group. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study.J Natl Cancer Inst. 2009; 101: 1348-1355Crossref PubMed Scopus (219) Google Scholar]. Vaccination against hepatitis B is recommended to all newborns and high risk groups, following the recommendations of the World Health Organization [[34]World Health Organization. Hepatitis B vaccines. Weekly epidemiological record of the World Health Organization 2009;84;405–420.Google Scholar]. Since perinatal or early postnatal transmission is an important cause of chronic HBV infections globally, the first dose of hepatitis B vaccine should be given as soon as possible after birth, even in low-endemicity countries (those with prevalence of HBsAg carriers <2%). Vaccination is also recommended in age-specific cohorts (young adolescents) and people with risk factors for acquiring HBV infection (i.e. health workers, travellers to areas where HBV-infection is prevalent, injecting drug users, and people with multiple sex partners). Antiviral treatment for patients with chronic hepatitis B and C infection should follow the recommendations from existing EASL guidelines [35European Association for the Study of the Liver EASL Clinical Practice Guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1189) Google Scholar, 36European Association for the Study of the Liver EASL Clinical Practice Guidelines: management of hepatitis C virus infection.J Hepatol. 2011; 55: 245-264Abstract Full Text Full Text PDF PubMed Scopus (749) Google Scholar]. Interferon, lamivudine, adefovir, entecavir, telbivudine and tenofovir are now available for HBV treatment, but long-term follow-up data assessing their effect in secondary prevention are only available with interferon and lamivudine. Observational studies assessing the effect of interferon showed a potential effect in reduction of HCC incidence [[37]Niederau C. Heintges T. Lange S. Goldmann G. Niederau C.M. Mohr L. et al.Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.N Engl J Med. 1996; 334: 1422-1427Crossref PubMed Scopus (702) Google Scholar], but this was not confirmed by Asian case-controlled studies [[38]Yuen M.F. Sablon E. Hui C.K. Yuan H.J. Decraemer H. Lai C.L. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy.Hepatology. 2001; 34: 785-791Crossref PubMed Scopus (322) Google Scholar]. Similarly, a randomized controlled trial (RCT) assessing the effect of lamivudine showed a significant reduction in HCC incidence. Nonetheless, there are some concerns regarding the effects obtained in this study as prevention of HCC occurrence was not the primary end-point of the study, and because the marginal effect obtained disappeared once adjusted for co-variables [[39]Liaw Y.F. Sung J.J. Chow W.C. Farrell G. Lee C.Z. Yuen H. et al.Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Crossref PubMed Scopus (1308) Google Scholar]. As a result, it appears prudent to conclude that surveillance for HCC should be maintained in those patients who already qualified before starting the treatment. In hepatitis C viral infection, the results of a meta-analysis of retrospective studies suggest that the risk of HCC is reduced among patients with HCV who achieve a sustained virological response (SVR) with antiviral therapy with interferon–ribavirin [[40]Singal A.G. Volk M.L. Jensen D. Di Bisceglie A.M. Schoenfeld P.S. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus.Clin Gastroenterol Hepatol. 2010; 8: 280-288Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. Once cirrhosis is established, there is no conclusive evidence that anti-viral therapy can prevent or delay the occurrence of HCC [41Nishiguchi S. Kuroki T. Nakatani S. Morimoto H. Takeda T. Nakajima S. et al.Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis.Lancet. 1995; 346: 1051-1055Abstract Full Text PDF PubMed Scopus (781) Google Scholar, 42Valla D.C. Chevallier M. Marcellin P. Payen J.L. Trepo C. Fonck M. et al.Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment.Hepatology. 1999; 29: 1870-1875Crossref PubMed Scopus (192) Google Scholar]. Maintenance therapy with PEG–interferon in cirrhotic patients has not significantly decreased the incidence of HCC according to the HALT-C [43Lok A.S. Everhart J.E. Wright E.C. Di Bisceglie A.M. Kim H.Y. Sterling R.K. et al.HALT-C Trial Group. Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C.Gastroenterology. 2011; 140: 840-849Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 44Di Bisceglie A.M. Stoddard A.M. Dienstag J.L. Shiffman M.L. Seeff L.B. Bonkovsky H.L. et al.HALT-C Trial Group. Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon.Hepatology. 2011; 53: 1100-1108Crossref PubMed Scopus (33) Google Scholar] and EPIC studies [[45]Bruix J. Poynard T. Colombo M. Schiff E. Burak K. Heathcote E.J. et al.EPIC3 Study Group. Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C.Gastroenterology. 2011; 140: 1990-1999Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. Additional studies are required to test the potential preventive effect of combination with new protease inhibitors (boceprevir, telaprevir) in cirrhotic patients .Table 3Recommendations for HCC surveillance: categories of adult patients in whom surveillance is recommended.∗Evidence 3A; strength B1;∗∗evidence 3D; strength B1;∗∗∗evidence 1B; strength A1 for Asian patients; evidence 3D; strength C1 for Western patients;∗∗∗∗evidence 3D; strength B1 for Asian patients; evidence 3D; strength B2 for Western patients. Open table in a new tab ∗Evidence 3A; strength B1;