EDITORIAL Surveillance for Hepatocellular Carcinoma: Can We Focus on the Mission? epatocellular carcinoma (HCC) is the fastest increasing cause of cancer-related deaths in the United States.1 Major risk factors for HCC in the United States include hepatitis C virus (HCV), heavy alcohol drinking, and hepatitis B virus (HBV) infection. Most of these HCC risk factors lead to the formation and progression of cirrhosis, which is present in approximately 90% of HCC patients.2,3 The overall prognosis of patients with HCC remains dismal (5-year survival rate, 12%),4 except for a small subset of patients in whom HCC is detected at an early stage and who receive potentially curative therapies including liver transplant, surgical resection, and possibly local ablation. Efforts focused on the primary prevention of HCC (eg, HBV vaccination and reduced HCV transmission) have met with success.5,6 However, despite the sharp decreases in the incidence of these infections in several regions of the world, the prevalence of individuals who already have acquired chronic HBV or HCV—and thus remain at risk for HCC—is quite high. For example, in the United States, approximately 2.3 million individuals have chronic HCV; of these, more than 35% are expected at this time to have advanced fibrosis and/or cirrhosis.7,8 Treatment of HBV and HCV can reduce HCC risk in patients who achieve viral suppression (secondary prevention)9–12; however, the availability of these expensive treatments to all at-risk patients remains limited. Even if universal antiviral treatment were to become a reality, viral suppression does not eliminate the risk of HCC in patients with established cirrhosis, which continues to develop at an annual rate of more than 1.0%.12 Therefore, for patients at increased risk of HCC (ie, primarily those with cirrhosis), clinical practice guidelines recommend regular surveillance using liver ultrasound and/or a-fetoprotein measurements to increase the likelihood of detecting early stage treatable cancer (tertiary prevention).13 This recommendation is based on modest evidence from randomized controlled trials (RCTs). However, considerable evidence from observational studies has shown that patients who undergo screening have earlier-stage HCC, are more likely to receive potentially curative treatment, and live longer than those who had HCC diagnosed incidentally or because of symptoms.14 Despite the wide dissemination of HCC surveillance recommendations, fewer than 20% of patients with cirrhosis in the United States undergo surveillance.15 The low utilization of HCC surveillance may be owing to cognitive factors (eg, insufficient knowledge of guidelines
H
or of high-risk groups) or logistical factors (eg, need for repeated testing), or it may primarily reflect a lack of high-quality evidence supporting the benefits of surveillance. In this issue of Clinical Gastroenterology and Hepatology, there are 2 articles that examined HCC surveillance patterns as well as barriers and facilitators to surveillance in 2 disparate health care settings, and the investigators arrived at similar findings.16,17 Both studies reported results of surveys conducted among primary care physicians (PCPs) about their selfreported knowledge of HCC surveillance including methods, frequency, and perceived barriers to surveillance. In the study by Dalton-Fitzgerald et al,16 a Webbased survey was sent to 131 PCPs in a single center in Dallas, Texas. There was a provider-level response rate of 59% (77 of 131 providers). More than 90% of PCPs believed that HCC surveillance was their responsibility. However, only 65% of respondents reported annual surveillance and only 15% reported biannual surveillance of patients for HCC. Barriers to HCC surveillance included not being up-to-date with HCC guidelines (68% of PCPs), difficulties in communicating effectively with patients about HCC surveillance (56%), and the presence of more important and competing issues to manage in the clinic (52%). Approximately half of the PCPs (52%) reported using ultrasound or measurements of a-fetoprotein in surveillance; 96% said that this combination was effective in reducing HCC-related mortality. However, many providers incorrectly believed that clinical examination (45%), levels of liver enzymes (59%), or a-fetoprotein level alone (89%), were effective surveillance tools. In the study by McGowan et al17 a mailed survey was sent to a random sample of 1000 community-based PCPs in North Carolina, of whom 391 (39%) completed the survey. Most (89%) PCPs saw patients with cirrhosis in their practice, but only 45% screened for HCC. Among PCPs who conducted surveillance, the most common tests were ultrasound and a-fetoprotein measurements (66%). Reasons for surveillance included supportive published evidence (72%), recommendations by hepatology societies (42%), and concerns regarding malpractice liability for not performing surveillance (26%). Barriers to surveillance included poor patient adherence (54%), patient financial constraints (53%), lack of insurance (49%), or insurance constraints on coverage (32%). Of the PCPs who did not screen, 84% reported that they referred patients to gastroenterologists for surveillance. In general, PCP knowledge of effective HCC therapy options was suboptimal. Hepatic resection and liver transplantation were identified as effective therapies by 67% and 56%, respectively, but all other effective therapies were identified by less than half of the PCPs. Clinical Gastroenterology and Hepatology 2015;13:805–807
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Kanwal et al
Provider recommendation is likely to be the strongest predictor for receipt of HCC surveillance. Currently, PCPs follow up most patients with cirrhosis in the United States, with only 20% to 40% being followed up by gastroenterologists and hepatologists.18 Thus, by recommending or referring their patients for HCC surveillance, PCPs play a central role in implementing HCC surveillance. The findings reported in the 2 studies provide data highlighting the need for PCP-targeted provider education to optimize HCC surveillance effectiveness in clinical practice. For example, the survey by McGowan et al17 suggests that PCP knowledge of more recently established treatments is low. This is highly relevant because early detection is beneficial only if effective therapies are applied in a timely matter, and therefore knowledge of therapy is arguably the most compelling justification for surveillance. Furthermore, HCC treatment options have evolved greatly in the past decade; for example, survival of HCC patients within the Milan criteria treated with liver transplantation is approximately 70% at 5 years.13 Studies also have shown high and equivalent survival rates for patients with early HCC treated with ablation or surgical resection.19 A meta-analysis of RCTs of transarterial chemoembolization (TACE) vs placebo concluded a small significant benefit of TACE in selected patients.20 Finally, large well-designed RCTs showed a small but significant prolongation of survival in patients treated with sorafenib than for patients given placebo.21 Filling this knowledge gap regarding RCT data for TACE, radiofrequency ablation, and sorafenib could increase surveillance rates by PCPs. Of note, the ability to identify at least one effective therapy was associated independently with twice the odds of recommending surveillance in the article by McGowan et al.17 Integration of decision support tools such as clinical reminders with electronic health records may help mitigate gaps in provider knowledge about HCC surveillance. In a recent study of electronic clinical reminders at Veterans Health Administration facilities, use of such reminders increased HCC surveillance rates by 51%, with an increase in HCC diagnoses.22 Given initiatives to promote meaningful use of electronic health records in routine clinical practice,23 such tools have significant potential for improving HCC surveillance. The study by Dalton-Fitzgerald et al16 also underscores the importance of provider-patient communication about HCC risk and surveillance options. Surveillance for HCC demands adherence to the recommended bi-annual imaging recommendation. Moreover, not all patients may benefit from (or need) surveillance. Thus, HCC surveillance decisions need to be informed not only by the scientific knowledge base of the treating clinician, but also by patients’ perceptions of outcome expectancies, risks, and benefits associated with the available treatment options, and subsequent preferences for surveillance. Despite the complexity of HCC surveillance decisions, little work has been performed to
Clinical Gastroenterology and Hepatology Vol. 13, No. 4
examine and improve this decision-making process. The little available data suggest that both patients and their providers prefer surveillance compared with no surveillance despite the controversy in the literature regarding the evidence base for HCC surveillance.24 These data call for shared decision-making aids that prepare patients to participate in the shared decisionmaking process, present evidence-based information about the treatment options (associated benefits, harms, probabilities, and scientific uncertainties), as well as provide structured guidance in communication of informed values. In summary, the studies by Dalton-Fitzgerald16 and McGowan17 address existing knowledge gaps by providing descriptive data on PCP-reported barriers and potential facilitators of improving surveillance in patients at risk for HCC. However, how can we put these data within a context given the ongoing controversy regarding the effectiveness of HCC surveillance? A recent systematic review concluded that there is very-lowstrength evidence about the effects of HCC screening on mortality rate in patients with chronic liver disease.25 Although the review found that screening tests identify early stage HCC, there were insufficient data to determine whether systematic screening led to a survival advantage compared with clinical diagnosis. We believe that the conclusions of this review reflect a lack of highquality evidence from RCTs and cannot be construed as a lack of a surveillance effect. High-quality data strengthening the evidence linking HCC surveillance and improved outcomes are needed urgently to provide guidance to clinicians and patients alike. We recognize that an RCT that includes sufficient numbers of patients who are assigned randomly to surveillance vs no surveillance is not forthcoming, particularly given evidence that patients strongly prefer surveillance to no surveillance.24 Properly designed retrospective cohort studies that analyze all patients eligible for screening can begin to fill this gap. Although these studies have their own set of limitations (with selection and lead time biases being the biggest threat to internal validity), consistent results across multiple studies (and multiple settings) may provide the best, albeit not the highest, level evidence. Without these data, we may continue in this current status quo of irregular and highly variable surveillance or worse, no surveillance at all. It is time to focus on the mission of improving what we have, but also getting the best of what we have. We need to develop the needed evidence base documenting the effectiveness of HCC surveillance, and improving surveillance methods (biomarkers and imaging). In parallel, efforts targeted at examining patients and providers’ perceptions of decision-making approaches regarding HCC surveillance, enhancing providers’ knowledge of existing treatment options, and improving coordination of care across different disciplines may provide a platform to successfully implement HCC surveillance.
April 2015
Editorial
FASIHA KANWAL, MD, MSHS HASHEM B. EL-SERAG, MD, MPH Michael E. DeBakey VA and Baylor College of Medicine Houston, Texas DAVID ROSS, MD Veterans Health Administration Office of Public Health Washington DC VA Medical Center, and George Washington University School of Medicine and Health Sciences Washington, DC
References 1. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365:1118–1127. 2. Lok AS, Seeff LB, Morgan TR, et al. , HALT-C Trial Group. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 2009;136:138–148. 3. Yang JD, Kim WR, Coelho R, et al. Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9:64–70. 4. Artinyan A, Mailey B, Sanchez-Luege N, et al. Race, ethnicity, and socioeconomic status influence the survival of patients with hepatocellular carcinoma in the United States. Cancer 2010; 116:1367–1377. 5. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997;336:1855–1859. 6. Wasley A, Grytdal S, Gallagher K, Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis–United States, 2006. MMWR Surveill Summ 2008;57:1–24. 7. Bichoupan K, Martel-Laferriere V, Sachs D, et al. Costs of telaprevir-based triple therapy for hepatitis C: $189,000 per sustained virological response. Hepatology 2014;60:1187–1195. 8. Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010;138:513–521. 9. Papatheodoridis GV, Lampertico P, Manolakopoulos S, et al. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol 2010;53:348–356. 10. Gordon SC, Lamerato LE, Rupp LB, et al. , CHeCS Investigators. Antiviral therapy for chronic HBV infection and development of hepatocellular carcinoma in a U.S. population. Clin Gastroenterol Hepatol 2014;12:885–893. 11. Zoutendijk R, Reijnders JG, Zoulim F, et al. , VIRGIL Surveillance Study Group. Virological response to entecavir is associated
807
with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut 2013;62:760–765. 12. Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013;158:329–337. 13. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236. 14. Sherman M, Bruix J, Porayko M, et al. , AASLD Practice Guidelines Committee. Screening for hepatocellular carcinoma: the rationale for the American Association for the Study of Liver Diseases Recommendations. Hepatology 2012;56:793–796. 15. Singal AG, Li X, Tiro J, et al. Racial, social, and clinical determinants of hepatocellular carcinoma surveillance. Am J Med 2015;128:90.e1–7. 16. Dalton-Fitzgerald E, Tiro J, Kandunoori P, et al. Practice patterns and attitudes of primary care providers and barriers to surveillance of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2015;13:791–798. 17. McGowan CE, Edwards TP, Luong MU, et al. Suboptimal surveillance for and knowledge of hepatocellular carcinoma among primary care providers. Clin Gastroenterol Hepatol 2015;13:799–804. 18. Kanwal F, Volk M, Singal A, et al. Improving quality of healthcare for patients with cirrhosis. Gastroenterology 2014;147:1204–1207. 19. Wang Y, Luo Q, Li Y, Deng S, Wei S, Li X. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinomas: a meta-analysis of randomized and nonrandomized controlled trials. PLoS One 2014;9:e84484. 20. Cammà C, Schepis F, Orlando A, et al. Transarterial hemoembolization for unresectable hepatocellular carcinoma: metaanalysis of randomized controlled trials. Radiology 2002;224: 47–54. 21. Llovet JM, Ricci S, Mazzaferro V, et al. , SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390. 22. Beste LA, Ioannou GN, Yang Y, et al. Improved surveillance for hepatocellular carcinoma with a primary care-oriented clinical reminder. Clin Gastroenterol Hepatol 2015;13:172–179. 23. Blumenthal D, Tavenner M. The “meaningful use” regulation for electronic health records. N Engl J Med 2010;363:501–504. 24. Poustchi H, Farrell GC, Strasser SI, et al. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology 2011;54:1998–2004. 25. Kansagara D, Papak J, Pasha AS, et al. Screening for hepatocellular carcinoma in chronic liver disease: a systematic review. Ann Intern Med 2014;161:261–269.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.12.016
H
or of high-risk groups) or logistical factors (eg, need for repeated testing), or it may primarily reflect a lack of high-quality evidence supporting the benefits of surveillance. In this issue of Clinical Gastroenterology and Hepatology, there are 2 articles that examined HCC surveillance patterns as well as barriers and facilitators to surveillance in 2 disparate health care settings, and the investigators arrived at similar findings.16,17 Both studies reported results of surveys conducted among primary care physicians (PCPs) about their selfreported knowledge of HCC surveillance including methods, frequency, and perceived barriers to surveillance. In the study by Dalton-Fitzgerald et al,16 a Webbased survey was sent to 131 PCPs in a single center in Dallas, Texas. There was a provider-level response rate of 59% (77 of 131 providers). More than 90% of PCPs believed that HCC surveillance was their responsibility. However, only 65% of respondents reported annual surveillance and only 15% reported biannual surveillance of patients for HCC. Barriers to HCC surveillance included not being up-to-date with HCC guidelines (68% of PCPs), difficulties in communicating effectively with patients about HCC surveillance (56%), and the presence of more important and competing issues to manage in the clinic (52%). Approximately half of the PCPs (52%) reported using ultrasound or measurements of a-fetoprotein in surveillance; 96% said that this combination was effective in reducing HCC-related mortality. However, many providers incorrectly believed that clinical examination (45%), levels of liver enzymes (59%), or a-fetoprotein level alone (89%), were effective surveillance tools. In the study by McGowan et al17 a mailed survey was sent to a random sample of 1000 community-based PCPs in North Carolina, of whom 391 (39%) completed the survey. Most (89%) PCPs saw patients with cirrhosis in their practice, but only 45% screened for HCC. Among PCPs who conducted surveillance, the most common tests were ultrasound and a-fetoprotein measurements (66%). Reasons for surveillance included supportive published evidence (72%), recommendations by hepatology societies (42%), and concerns regarding malpractice liability for not performing surveillance (26%). Barriers to surveillance included poor patient adherence (54%), patient financial constraints (53%), lack of insurance (49%), or insurance constraints on coverage (32%). Of the PCPs who did not screen, 84% reported that they referred patients to gastroenterologists for surveillance. In general, PCP knowledge of effective HCC therapy options was suboptimal. Hepatic resection and liver transplantation were identified as effective therapies by 67% and 56%, respectively, but all other effective therapies were identified by less than half of the PCPs. Clinical Gastroenterology and Hepatology 2015;13:805–807
806
Kanwal et al
Provider recommendation is likely to be the strongest predictor for receipt of HCC surveillance. Currently, PCPs follow up most patients with cirrhosis in the United States, with only 20% to 40% being followed up by gastroenterologists and hepatologists.18 Thus, by recommending or referring their patients for HCC surveillance, PCPs play a central role in implementing HCC surveillance. The findings reported in the 2 studies provide data highlighting the need for PCP-targeted provider education to optimize HCC surveillance effectiveness in clinical practice. For example, the survey by McGowan et al17 suggests that PCP knowledge of more recently established treatments is low. This is highly relevant because early detection is beneficial only if effective therapies are applied in a timely matter, and therefore knowledge of therapy is arguably the most compelling justification for surveillance. Furthermore, HCC treatment options have evolved greatly in the past decade; for example, survival of HCC patients within the Milan criteria treated with liver transplantation is approximately 70% at 5 years.13 Studies also have shown high and equivalent survival rates for patients with early HCC treated with ablation or surgical resection.19 A meta-analysis of RCTs of transarterial chemoembolization (TACE) vs placebo concluded a small significant benefit of TACE in selected patients.20 Finally, large well-designed RCTs showed a small but significant prolongation of survival in patients treated with sorafenib than for patients given placebo.21 Filling this knowledge gap regarding RCT data for TACE, radiofrequency ablation, and sorafenib could increase surveillance rates by PCPs. Of note, the ability to identify at least one effective therapy was associated independently with twice the odds of recommending surveillance in the article by McGowan et al.17 Integration of decision support tools such as clinical reminders with electronic health records may help mitigate gaps in provider knowledge about HCC surveillance. In a recent study of electronic clinical reminders at Veterans Health Administration facilities, use of such reminders increased HCC surveillance rates by 51%, with an increase in HCC diagnoses.22 Given initiatives to promote meaningful use of electronic health records in routine clinical practice,23 such tools have significant potential for improving HCC surveillance. The study by Dalton-Fitzgerald et al16 also underscores the importance of provider-patient communication about HCC risk and surveillance options. Surveillance for HCC demands adherence to the recommended bi-annual imaging recommendation. Moreover, not all patients may benefit from (or need) surveillance. Thus, HCC surveillance decisions need to be informed not only by the scientific knowledge base of the treating clinician, but also by patients’ perceptions of outcome expectancies, risks, and benefits associated with the available treatment options, and subsequent preferences for surveillance. Despite the complexity of HCC surveillance decisions, little work has been performed to
Clinical Gastroenterology and Hepatology Vol. 13, No. 4
examine and improve this decision-making process. The little available data suggest that both patients and their providers prefer surveillance compared with no surveillance despite the controversy in the literature regarding the evidence base for HCC surveillance.24 These data call for shared decision-making aids that prepare patients to participate in the shared decisionmaking process, present evidence-based information about the treatment options (associated benefits, harms, probabilities, and scientific uncertainties), as well as provide structured guidance in communication of informed values. In summary, the studies by Dalton-Fitzgerald16 and McGowan17 address existing knowledge gaps by providing descriptive data on PCP-reported barriers and potential facilitators of improving surveillance in patients at risk for HCC. However, how can we put these data within a context given the ongoing controversy regarding the effectiveness of HCC surveillance? A recent systematic review concluded that there is very-lowstrength evidence about the effects of HCC screening on mortality rate in patients with chronic liver disease.25 Although the review found that screening tests identify early stage HCC, there were insufficient data to determine whether systematic screening led to a survival advantage compared with clinical diagnosis. We believe that the conclusions of this review reflect a lack of highquality evidence from RCTs and cannot be construed as a lack of a surveillance effect. High-quality data strengthening the evidence linking HCC surveillance and improved outcomes are needed urgently to provide guidance to clinicians and patients alike. We recognize that an RCT that includes sufficient numbers of patients who are assigned randomly to surveillance vs no surveillance is not forthcoming, particularly given evidence that patients strongly prefer surveillance to no surveillance.24 Properly designed retrospective cohort studies that analyze all patients eligible for screening can begin to fill this gap. Although these studies have their own set of limitations (with selection and lead time biases being the biggest threat to internal validity), consistent results across multiple studies (and multiple settings) may provide the best, albeit not the highest, level evidence. Without these data, we may continue in this current status quo of irregular and highly variable surveillance or worse, no surveillance at all. It is time to focus on the mission of improving what we have, but also getting the best of what we have. We need to develop the needed evidence base documenting the effectiveness of HCC surveillance, and improving surveillance methods (biomarkers and imaging). In parallel, efforts targeted at examining patients and providers’ perceptions of decision-making approaches regarding HCC surveillance, enhancing providers’ knowledge of existing treatment options, and improving coordination of care across different disciplines may provide a platform to successfully implement HCC surveillance.
April 2015
Editorial
FASIHA KANWAL, MD, MSHS HASHEM B. EL-SERAG, MD, MPH Michael E. DeBakey VA and Baylor College of Medicine Houston, Texas DAVID ROSS, MD Veterans Health Administration Office of Public Health Washington DC VA Medical Center, and George Washington University School of Medicine and Health Sciences Washington, DC
References 1. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365:1118–1127. 2. Lok AS, Seeff LB, Morgan TR, et al. , HALT-C Trial Group. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 2009;136:138–148. 3. Yang JD, Kim WR, Coelho R, et al. Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9:64–70. 4. Artinyan A, Mailey B, Sanchez-Luege N, et al. Race, ethnicity, and socioeconomic status influence the survival of patients with hepatocellular carcinoma in the United States. Cancer 2010; 116:1367–1377. 5. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997;336:1855–1859. 6. Wasley A, Grytdal S, Gallagher K, Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis–United States, 2006. MMWR Surveill Summ 2008;57:1–24. 7. Bichoupan K, Martel-Laferriere V, Sachs D, et al. Costs of telaprevir-based triple therapy for hepatitis C: $189,000 per sustained virological response. Hepatology 2014;60:1187–1195. 8. Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010;138:513–521. 9. Papatheodoridis GV, Lampertico P, Manolakopoulos S, et al. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol 2010;53:348–356. 10. Gordon SC, Lamerato LE, Rupp LB, et al. , CHeCS Investigators. Antiviral therapy for chronic HBV infection and development of hepatocellular carcinoma in a U.S. population. Clin Gastroenterol Hepatol 2014;12:885–893. 11. Zoutendijk R, Reijnders JG, Zoulim F, et al. , VIRGIL Surveillance Study Group. Virological response to entecavir is associated
807
with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut 2013;62:760–765. 12. Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013;158:329–337. 13. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236. 14. Sherman M, Bruix J, Porayko M, et al. , AASLD Practice Guidelines Committee. Screening for hepatocellular carcinoma: the rationale for the American Association for the Study of Liver Diseases Recommendations. Hepatology 2012;56:793–796. 15. Singal AG, Li X, Tiro J, et al. Racial, social, and clinical determinants of hepatocellular carcinoma surveillance. Am J Med 2015;128:90.e1–7. 16. Dalton-Fitzgerald E, Tiro J, Kandunoori P, et al. Practice patterns and attitudes of primary care providers and barriers to surveillance of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2015;13:791–798. 17. McGowan CE, Edwards TP, Luong MU, et al. Suboptimal surveillance for and knowledge of hepatocellular carcinoma among primary care providers. Clin Gastroenterol Hepatol 2015;13:799–804. 18. Kanwal F, Volk M, Singal A, et al. Improving quality of healthcare for patients with cirrhosis. Gastroenterology 2014;147:1204–1207. 19. Wang Y, Luo Q, Li Y, Deng S, Wei S, Li X. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinomas: a meta-analysis of randomized and nonrandomized controlled trials. PLoS One 2014;9:e84484. 20. Cammà C, Schepis F, Orlando A, et al. Transarterial hemoembolization for unresectable hepatocellular carcinoma: metaanalysis of randomized controlled trials. Radiology 2002;224: 47–54. 21. Llovet JM, Ricci S, Mazzaferro V, et al. , SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390. 22. Beste LA, Ioannou GN, Yang Y, et al. Improved surveillance for hepatocellular carcinoma with a primary care-oriented clinical reminder. Clin Gastroenterol Hepatol 2015;13:172–179. 23. Blumenthal D, Tavenner M. The “meaningful use” regulation for electronic health records. N Engl J Med 2010;363:501–504. 24. Poustchi H, Farrell GC, Strasser SI, et al. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology 2011;54:1998–2004. 25. Kansagara D, Papak J, Pasha AS, et al. Screening for hepatocellular carcinoma in chronic liver disease: a systematic review. Ann Intern Med 2014;161:261–269.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.12.016
