Capitalising on improved rates of diagnosis of early hepatocellular carcinoma

Birth cohort-specific disparities in hepatocellular carcinoma stage at diagnosis, treatment, and long-term survivalJournal of HepatologyVol. 64Issue 2PreviewIndividuals born between 1945 and 1965 account for nearly 75% of hepatitis C virus (HCV) infections in the United States. As this cohort ages, progressive HCV-related liver disease leading to cirrhosis and hepatocellular carcinoma (HCC) will place a significant burden on the healthcare system. We aim to evaluate birth cohort-specific disparities in HCC stage at diagnosis, treatment rates, and overall survival with a focus on the 1945–1965 birth cohort. Full-Text PDF The incidence of hepatocellular carcinoma (HCC) is increasing rapidly [[1]El-Serag H.B. Hepatocellular carcinoma.N Engl J Med. 2011; 365: 1118-1127Crossref PubMed Scopus (3144) Google Scholar]. The majority of HCC diagnosed remains at an incurable stage and mortality remains high [[2]Park J.W. Chen M. Colombo M. Roberts L.R. Schwartz M. Chen P.J. et al.Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study.Liver Int. 2015; 35: 2155-2166Crossref PubMed Scopus (590) Google Scholar]. Curative treatments are available providing HCC is detected early and provided that liver function is preserved, since these are the major determinants of long-term survival after treatment [[3]Forner A. Llovet J.M. Bruix J. Hepatocellular carcinoma.Lancet. 2012; 379: 1245-1255Abstract Full Text Full Text PDF PubMed Scopus (3676) Google Scholar]. Since cirrhosis is associated with a high risk of the development of HCC and outcomes for patients with advanced HCC are poor, surveillance for HCC in at risk individuals is recommended [4EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4551) Google Scholar, 5Sherman M. Bruix J. Porayko M. Tran T. Screening for hepatocellular carcinoma: the rationale for the American Association for the Study of Liver Diseases recommendations.Hepatology. 2012; 56: 793-796Crossref PubMed Scopus (122) Google Scholar]. In this edition of the Journal of Hepatology Yan and colleagues report temporal trends in the incidence of HCC in three birth cohorts: patients born before 1945, patients born between 1945 and 1965, and those born after 1965 [[6]Yan M. Ha J. Aguilar M. Bhuket T. Liu B. Gish R.G. et al.Birth cohort-specific disparities in hepatocellular carcinoma stage at diagnosis, treatment, and long-term survival.J Hepatol. 2016; 64: 326-332Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. The authors used the Surveillance, Epidemiology, and End Results (SEER) registry to describe the rates of HCC diagnosis and outcomes in each of these groups. HCC incidence increased in each of the birth cohorts with the largest increase in the patients born between 1945 and 1965 – the so-called baby-boomer (BB) cohort. Perhaps this is not surprising considering the preponderance of risk factors in that group. It is well documented that this group has a high prevalence of hepatitis C virus (HCV) infection to an extent where birth cohort screening has been recommended to detect and treat patients with HCV infection [7Rein D.B. Smith B.D. Wittenborn J.S. Lesesne S.B. Wagner L.D. Roblin D.W. et al.The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings.Ann Intern Med. 2012; 156: 263-270Crossref PubMed Scopus (260) Google Scholar, 8Smith B.D. Morgan R.L. Beckett G.A. Falck-Ytter Y. Holtzman D. Teo C.G. et al.Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965.MMWR Recomm Rep. 2012; 61: 1-32PubMed Google Scholar]. It is also apparent from epidemiological data that this group also has high rates of obesity and type 2 diabetes mellitus [[9]Menke A. Rust K.F. Fradkin J. Cheng Y.J. Cowie C.C. Associations between trends in race/ethnicity, aging, and body mass index with diabetes prevalence in the United States: a series of cross-sectional studies.Ann Intern Med. 2014; 161: 328-335Crossref PubMed Scopus (85) Google Scholar], both of which are also associated with the development of HCC [[10]Noureddin M. Rinella M.E. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma.Clin Liver Dis. 2015; 19: 361-379Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar]. Although the authors speculate that it is the prevalence of HCV that has contributed to the increased rates of HCC the SEER registry does not contain information regarding the nature of the underlying liver disease to inform the degree to which each of these risk factors contributes to the increased incidence of HCC. The SEER registry does however contain some information regarding the stage of HCC at presentation, subsequent treatment allocation, and outcomes. In the BB cohort the rates of diagnosis of HCC within curative criteria (here defined by the Milan criteria [[11]Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5645) Google Scholar]) were significantly higher than in the cohort of patients born before 1945: 38.5% vs. 24.5%. The authors speculate that this is due to an increased awareness of liver disease in the BB cohort and increased use of surveillance in this group. If this were the case then one would hope that the increase in early detection would translate into a significant survival advantage for the BB group. Unfortunately this was not the case. Whilst there was statistically improved survival in the BB group compared to the pre-1945 group the absolute difference in survival was only small. Here we explore some of the reasons why this was the case. At 5 years after diagnosis survival was 29.5% vs. 23.2% and, though it is not stated, median survival was prolonged by only a small number of months. These differences might be explained by increased use of transplantation in the BB group but there is also likely a contribution by lead-time bias since HCC was less advanced in the BB group. Furthermore since the pre-1945 group were older at diagnosis and likely had more co-morbidity one might expect that the outcomes in that group would be worse even if tumour characteristics were similar, an expectation that would only serve to widen the survival discrepancy if it were confirmed. Therefore the difference in early diagnosis for the BB cohort likely had very little impact on survival outcomes. This raises the question as to why the improvement in survival was not greater and did not more closely resemble the difference in the stage of disease at presentation. The justifications for adoption of surveillance for HCC in individuals with cirrhosis in the acknowledged absence of high quality evidence focus on the ability of surveillance to detect early stage disease. There are several possible explanations that are important when considering the potential effectiveness (how things occur in real-life or uncontrolled settings), rather than efficacy (how things occur under controlled circumstances of clinical trials), of surveillance for HCC. Surveillance in individuals with cirrhosis is a multifaceted intervention. It consists of a three-step process: diagnosis of cirrhosis and identification of suitable patients for surveillance, the surveillance intervention (i.e. 6-monthly ultrasound scans) and appropriate recall policies, and then treatment once HCC is identified. As has been described previously for other interventions deficiencies in any or all of these steps has a negative impact on the effectiveness of surveillance overall [[12]El-Serag H.B. Talwalkar J. Kim W.R. Efficacy, effectiveness, and comparative effectiveness in liver disease.Hepatology. 2010; 52: 403-407Crossref PubMed Scopus (33) Google Scholar]. The stated aim of surveillance for HCC in the EASL-EORTC guidelines is to decrease mortality from liver disease [[4]EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4551) Google Scholar]. Therefore to make an impact in the population there would need to be a coordinated effort to identify patients with cirrhosis. In countries such as Japan where HCV is the major contributor to the development of HCC it seems possible to make a major impact on HCC related mortality [[2]Park J.W. Chen M. Colombo M. Roberts L.R. Schwartz M. Chen P.J. et al.Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study.Liver Int. 2015; 35: 2155-2166Crossref PubMed Scopus (590) Google Scholar]. This impact is achieved through both population screening for HCV and subsequently intensive surveillance for HCC. However whilst birth cohort screening for HCV infection in the US might identify a significant proportion of those individuals with cirrhosis in the population there are other prevalent liver diseases where cirrhosis drives the development of HCC. Most notably the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) has already led to increases in NAFLD associated HCC [13Younossi Z.M. Otgonsuren M. Henry L. Venkatesan C. Mishra A. Erario M. et al.Association of non-alcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004–2009.Hepatology. 2015; ([Epub ahead of print])Google Scholar, 14Beste L.A. Leipertz S.L. Green P.K. Dominitz J.A. Ross D. Ioannou G.N. Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001–2013.Gastroenterology. 2015; 149: 1471-1482Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar] that are likely to continue over the next decade. Having identified individuals at high risk of developing HCC selection of those suitable for surveillance remains a challenge. The ideal candidate for surveillance is young, with early cirrhosis (ideally Child-Pugh A), and without significant medical co-morbidity. These characteristics are loosely defined based on the candidate’s ability to withstand potentially curative treatment and to survive without liver failure or other medical problems. It might be expected that these characteristics would be enriched in the BB cohort however there is no information regarding the stage of liver disease in the SEER registry, nor are any data recorded regarding co-morbidity to further explore this issue. The efficacy of six monthly ultrasound surveillance is frequently discussed and has been the subject of two systematic reviews in the recent past. These reviews have differing conclusions regarding the efficacy of surveillance: the first concludes that surveillance improves survival in patients with cirrhosis based on meta-analysis of non-randomised studies [[15]Singal A.G. Pillai A. Tiro J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.PLoS Med. 2014; 11: e1001624Crossref PubMed Scopus (488) Google Scholar]; the second recognised excessive heterogeneity in those studies and reported a narrative conclusion that there was very low strength evidence to support surveillance [[16]Kansagara D. Papak J. Pasha A.S. O’Neil M. Freeman M. Relevo R. et al.Screening for hepatocellular carcinoma in chronic liver disease: a systematic review.Ann Intern Med. 2014; 161: 261-269Crossref PubMed Scopus (148) Google Scholar]. Therefore there are few data that prove surveillance decreases mortality in cirrhosis. Surveillance is however recognised as a standard of care in many healthcare systems though its application remains poor. Multiple reports, particularly from the US have highlighted major deficiencies in the use of surveillance in individuals with cirrhosis [17Davila J.A. Henderson L. Kramer J.R. Kanwal F. Richardson P.A. Duan Z. et al.Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States.Ann Intern Med. 2011; 154: 85-93Crossref PubMed Scopus (235) Google Scholar, 18Singal A.G. Yopp A. Skinner S.C. Packer M. Lee W.M. Tiro J.A. Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review.J Gen Intern Med. 2012; 27: 861-867Crossref PubMed Scopus (193) Google Scholar]. Regardless of the efficacy of surveillance these deficiencies will inevitably have a major impact on the effectiveness of surveillance since suitable patients are either not exposed to surveillance, or surveillance is done too infrequently, or it is done without sufficient sensitivity to identify early HCC that is suitable for potentially curative treatment. Finally the identification of early HCC is only of benefit at the population level if that HCC is treated. In the data presented only a minority of patients appeared to have any treatment for HCC though deficiencies in the reporting of treatment with transarterial chemoembolization and likely ablative strategies exaggerates this observation. Importantly however, fewer patients were treated with surgical therapies (as a surrogate for curative treatment) than there were patients with disease within the Milan criteria. This suggests either that patients with HCC within Milan criteria were either not suitable for potentially curative treatment due to the presence of liver failure or due to other non-liver co-morbidity, or that those individuals were not offered treatment. Since the outcomes of surveillance are dependent not only on diagnosis but also subsequent treatment it is clear that including patients in surveillance who are not suitable for treatment or not treating those who are when HCC is identified for whatever reason will reduce the effectiveness of surveillance overall. This study from Yan and colleagues highlights the issues that need to be addressed in improving outcomes for individuals with HCC. The SEER registry is not the ideal tool to examine these issues and greater detail is needed to understand the potential deficiencies described above. These areas where studies should be targeted show the size of the task that remains to achieve improvements in mortality from HCC through identification of individuals with cirrhosis, appropriate surveillance, and improved access to care and treatment. The authors declared that they do not have any conflict of interest with respect to this manuscript.