Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis

Amit G Singal, Anjana Pillai, Jasmin Tiro, Amit G Singal, Anjana Pillai, Jasmin Tiro

Abstract

Background: Surveillance for hepatocellular carcinoma (HCC) has level I evidence among patients with hepatitis B but only level II evidence in patients with cirrhosis. This lack of randomized data has spurred questions regarding the utility of HCC surveillance in this patient population; however, lack of randomized data does not equate to a lack of data supporting the efficacy of surveillance. The aim of our study was to determine the effect of HCC surveillance on early stage tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis.

Methods and findings: We performed a systematic literature review using Medline from January 1990 through January 2014 and a search of national meeting abstracts from 2009-2012. Two investigators identified studies that reported rates of early stage tumor detection, curative treatment receipt, or survival, stratified by HCC surveillance status, among patients with cirrhosis. Both investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for a random effects model. We identified 47 studies with 15,158 patients, of whom 6,284 (41.4%) had HCC detected by surveillance. HCC surveillance was associated with improved early stage detection (odds ratio [OR] 2.08, 95% CI 1.80-2.37) and curative treatment rates (OR 2.24, 95% CI 1.99-2.52). HCC surveillance was associated with significantly prolonged survival (OR 1.90, 95% CI 1.67-2.17), which remained significant in the subset of studies adjusting for lead-time bias. Limitations of current data included many studies having insufficient duration of follow-up to assess survival and the majority not adjusting for liver function or lead-time bias.

Conclusions: HCC surveillance is associated with significant improvements in early tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis. Please see later in the article for the Editors' Summary.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1. Map of literature search and…
Figure 1. Map of literature search and selection process.
Figure 2. Association between HCC surveillance and…
Figure 2. Association between HCC surveillance and early tumor detection rates.
Figure 3. Association between HCC surveillance and…
Figure 3. Association between HCC surveillance and curative treatment rates.
Figure 4. Association between HCC surveillance and…
Figure 4. Association between HCC surveillance and survival.

References

    1. El-Serag HB (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142: 1264–1273.
    1. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA (2003) The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139: 817–823.
    1. Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, et al. (1999) Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 29: 62–67.
    1. Padhya KT, Marrero JA, Singal AG (2013) Recent advances in the treatment of hepatocellular carcinoma. Curr Opin Gastroenterol 29: 285–292.
    1. Bruix J, Sherman M (2010) Management of hepatocellular carcinoma: an update. Hepatology 53: 1–35.
    1. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, et al. (2001) Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35: 421–430.
    1. Zhang BH, Yang BH, Tang ZY (2004) Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 130: 417–422.
    1. Singal AG, Conjeevaram HS, Volk ML, Fu S, Fontana RJ, et al. (2012) Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis. Cancer Epidemiol Biomarkers Prev 21: 793–799.
    1. Lederle FA, Pocha C (2012) Screening for liver cancer: the rush to judgment. Ann Intern Med 156: 387–389.
    1. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151: 264–269, W264.
    1. Wells GA, Shea B, O'Connell D, Peterson J (2000) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 3rd Symposium on Systematic Reviews: Beyond the Basics. Available: .
    1. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, et al. (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334: 693–699.
    1. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21: 1539–1558.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560.
    1. Copas JB, Shi JQ (2001) A sensitivity analysis for publication bias in systematic reviews. Stat Methods Med Res 10: 251–265.
    1. Singal A, Volk ML, Waljee A, Salgia R, Higgins P, et al. (2009) Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 30: 37–47.
    1. Ando E, Kuromatsu R, Tanaka M, Takada A, Fukushima N, et al. (2006) Surveillance program for early detection of hepatocellular carcinoma in Japan: results of specialized department of liver disease. J Clin Gastroenterol 40: 942–948.
    1. Ayala G, Dickson R, Toor A (2012) Does surveillance affect the outcome of patients with HCC? Hepatology 56: 486A.
    1. Bolondi L, Sofia S, Siringo S, Gaiani S, Casali A, et al. (2001) Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut 48: 251–259.
    1. Bouali R, Bizid S, Jeddi H (2012) Screening for hepatocellular carcinoma in cirrhotics: 20 years' experience. Berlin: International Liver Cancer Association.
    1. Caumes JL, Nousbaum JB, Bessaguet C, Faycal J, Robaszkiewicz M, et al. (2007) Epidemiology of hepatocellular carcinoma in Finistere. Prospective study from June 2002 to May 2003. Gastroenterol Clin Biol 31: 259–264.
    1. Chan AC, Poon RT, Ng KK, Lo CM, Fan ST, et al. (2008) Changing paradigm in the management of hepatocellular carcinoma improves the survival benefit of early detection by screening. Ann Surg 247: 666–673.
    1. Cheung TK, Lai CL, Wong BC, Fung J, Yuen MF (2006) Clinical features, biochemical parameters, and virological profiles of patients with hepatocellular carcinoma in Hong Kong. Aliment Pharmacol Ther 24: 573–583.
    1. Cho SJ, Yoon JH, Hwang SS, Lee HS (2007) Do young hepatocellular carcinoma patients with relatively good liver function have poorer outcomes than elderly patients? J Gastroenterol Hepatol 22: 1226–1231.
    1. Davila JA, Weston A, Smalley W, El-Serag HB (2007) Utilization of screening for hepatocellular carcinoma in the United States. J Clin Gastroenterol 41: 777–782.
    1. Durand F, Buffet C, Pelletier G, Hagege H, Ink O, et al. (1995) Screening of hepatocellular carcinoma in French patients. Dig Dis Sci 40: 706–707.
    1. El-Serag HB, Kramer JR, Chen GJ, Duan Z, Richardson PA, et al. (2011) Effectiveness of AFP and ultrasound tests on hepatocellular carcinoma mortality in HCV-infected patients in the USA. Gut 60: 992–997.
    1. Garcia Gullon C, Rendon Unceta P, Martin Herrera L, Soria de la Cruz M, Macias M, et al. (1995) Utilidad de la ecografia en el diagnostico precoz del hepatocarcinoma en pacientes con cirrosis hepatica. Restiva espanola de enfermedades digestivas 87: 798–801.
    1. Gellert L, Jalaludin B, Levy M (2007) Hepatocellular carcinoma in Sydney South West: late symptomatic presentation and poor outcome for most. Intern Med J 37: 516–522.
    1. Giannini E, Arzani L, Borro P, Botta F, Fasoli A, et al. (2000) Does surveillance for hepatocellular carcinoma in HCV cirrhotic patients improve treatment outcome mainly due to better clinical status at diagnosis? Hepatogastroenterology 47: 1395–1398.
    1. Goh B, Chang J, Ong W (2010) Surveillance for hepatocellular carcinoma in chronic liver disease is associated with increased diagnosis of early HCC and a genuine improvement in survival - a study of 1,113 cases. Hepatology 52: 1136A.
    1. Jou JH, Chen PH, Jazwinski A, Bouneva I, Smith AD, et al. (2010) Rates of surveillance and management of hepatocellular carcinoma in patients evaluated at a liver transplant center. Dig Dis Sci 55: 3591–3596.
    1. Kallwitz E, Gaba RC, Huang Y (2011) Survival with hepatocellular carcinoma is associated with surveillance, lesion size, ablation and transplant in an area with limited organ availability. Hepatology 54: 1381A.
    1. Kuo YH, Lu SN, Chen CL, Cheng YF, Lin CY, et al. (2010) Hepatocellular carcinoma surveillance and appropriate treatment options improve survival for patients with liver cirrhosis. Eur J Cancer 46: 744–751.
    1. Leykum LK, El-Serag HB, Cornell J, Papadopoulos KP (2007) Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival. Clin Gastroenterol Hepatol 5: 508–512.
    1. Martinez Cerezo F, Puig M, Martinez Nogueras A, Tomas A, Pamplona J, et al. (1993) Valor de la ecografia en el diagnostico precoz del carcinoma hepatocelular. Revista espanola de enfermedades digestivas 84: 311–314.
    1. Miguel M, Sopena J, Vergara M, Gil M (2012) Factors related to survival in hepatocellular carcinoma in the geographic area of Sabadell (Catalonia, Spain). Rev Esp Enferm Dig 104: 242–247.
    1. Noda I, Kitamoto M, Nakahara H, Hayashi R, Okimoto T, et al. (2010) Regular surveillance by imaging for early detection and better prognosis of hepatocellular carcinoma in patients infected with hepatitis C virus. J Gastroenterol 45: 105–112.
    1. Onodera H, Ukai K, Nakano N, Takeda T, Suzuki H, et al. (1994) Outcomes of 116 patients with hepatocellular carcinoma. Cancer Chemother Pharmacol 33 (Suppl) S103–108.
    1. Pascual S, Irurzun J, Zapater P, Such J, Sempere L, et al. (2008) Usefulness of surveillance programmes for early diagnosis of hepatocellular carcinoma in clinical practice. Liver Int 28: 682–689.
    1. Reau N, Aronsohn A, Te HS (2011) Managing physician, not patient factors, predict hepatocellular carcinoma (HCC) screening outcomes. Hepatology 54: 1410A.
    1. Rodriguez R, Gutierrez M, Gonzalez de Frutos C, de Artaza Varasa T, de la Cruz Perez G, et al. (2011) Caracteristicas clinicas, estadiicacion y tratamiento de los pacientes con carcinoma hepatocelular en la practica clinica. Estudio propsectivo de una serie de 136 pacientes. Gastroenterologia y Hepatologia 34: 524–531.
    1. Sarkar M, Stewart S, Yu A, Chen MS, Nguyen TT, et al. (2012) Hepatocellular carcinoma screening practices and impact on survival among hepatitis B-infected Asian Americans. J Viral Hepat 19: 594–600.
    1. Silveira MG, Suzuki A, Lindor KD (2008) Surveillance for hepatocellular carcinoma in patients with primary biliary cirrhosis. Hepatology 48: 1149–1156.
    1. Singal AG, Nehra M, Adams-Huet B, Yopp AC, Tiro JA, et al. (2013) Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: where did surveillance fail? Am J Gastroenterol 108: 425–432.
    1. Smirniotopoulos J, Wright H, Nusbaum J (2011) Surveillance for hepatocelluar carcinoma (HCC) and impact on management at a liver transplant center. Hepatology 54: 1414A.
    1. Stravitz RT, Heuman DM, Chand N, Sterling RK, Shiffman ML, et al. (2008) Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome. Am J Med 121: 119–126.
    1. Stroffolini T, Trevisani F, Pinzello G, Brunello F, Tommasini MA, et al. (2011) Changing aetiological factors of hepatocellular carcinoma and their potential impact on the effectiveness of surveillance. Dig Liver Dis 43: 875–880.
    1. Tanaka H, Nouso K, Kobashi H, Kobayashi Y, Nakamura S, et al. (2006) Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival. Liver Int 26: 543–551.
    1. Tanaka S, Kitamura T, Nakanishi K, Okuda S, Yamazaki H, et al. (1990) Effectiveness of periodic checkup by ultrasonography for the early diagnosis of hepatocellular carcinoma. Cancer 66: 2210–2214.
    1. Taura N, Hamasaki K, Nakao K, Ichikawa T, Nishimura D, et al. (2005) Clinical benefits of hepatocellular carcinoma surveillance: a single-center, hospital-based study. Oncol Rep 14: 999–1003.
    1. Tong MJ, Chavalitdhamrong D, Lu DS, Raman SS, Gomes A, et al. (2010) Survival in Asian Americans after treatments for hepatocellular carcinoma: a seven-year experience at UCLA. J Clin Gastroenterol 44: e63–70.
    1. Tong MJ, Sun HE, Hsien C, Lu DS (2010) Surveillance for hepatocellular carcinoma improves survival in Asian-American patients with hepatitis B: results from a community-based clinic. Dig Dis Sci 55: 826–835.
    1. Toyoda H, Kumada T, Kiriyama S, Sone Y, Tanikawa M, et al. (2006) Impact of surveillance on survival of patients with initial hepatocellular carcinoma: a study from Japan. Clin Gastroenterol Hepatol 4: 1170–1176.
    1. Trevisani F, De NS, Rapaccini G, Farinati F, Benvegnu L, et al. (2002) Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience). Am J Gastroenterol 97: 734–744.
    1. Unoura M, Kaneko S, Matsushita E, Shimoda A, Takeuchi M, et al. (1993) High-risk groups and screening strategies for early detection of hepatocellular carcinoma in patients with chronic liver disease. Hepatogastroenterology 40: 305–310.
    1. Van Vlierberghe H, Colle I, Henrion J, Michielsen P, Delwaide J, et al. (2005) The HepCar registry: report on a one-year registration program of hepatocellular carcinoma (HCC) in Belgium. What is daily practice in HCC? Acta Gastroenterol Belg 68: 403–411.
    1. Wong GL, Wong VW, Tan GM, Ip KI, Lai WK, et al. (2008) Surveillance programme for hepatocellular carcinoma improves the survival of patients with chronic viral hepatitis. Liver Int 28: 79–87.
    1. Wong LL, Limm WM, Severino R, Wong LM (2000) Improved survival with screening for hepatocellular carcinoma. Liver Transpl 6: 320–325.
    1. Wong N, Haydon A, Kemp W, Wijeratne P, Roberts S (2013) Improved survival trend of patients with hepatocellular carcinoma at an Australian tertiary hospital between 1995–2009. Intern Med J 43: 197–203.
    1. Yang JD, Harmsen WS, Slettedahl SW, Chaiteerakij R, Enders FT, et al. (2011) Factors that affect risk for hepatocellular carcinoma and effects of surveillance. Clin Gastroenterol Hepatol 9: 617–623 e611.
    1. Yu EW, Chie WC, Chen TH (2004) Does screening or surveillance for primary hepatocellular carcinoma with ultrasonography improve the prognosis of patients? Cancer J 10: 317–325.
    1. Zapata E, Zubiaurre L, Castiella A, Salvador P, Garcia-Bengoechea M, et al. (2010) Are hepatocellular carcinoma surveillance programs effective at improving the therapeutic options. Rev Esp Enferm Dig 102: 484–488.
    1. Davila JA, Morgan RO, Richardson PA, Du XL, McGlynn KA, et al. (2010) Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology 52: 132–141.
    1. Singal A, Volk M, Rakoski M, Fu S, Su G, et al. (2011) Patient Involvement is Correlated with Higher HCC Surveillance in Patients with Cirrhosis. J Clin Gastroenterol 45: 727–732.
    1. Singal AG, Tiro JA, Gupta S (2013) Improving hepatocellular carcinoma screening: applying lessons from colorectal cancer screening. Clin Gastroenterol Hepatol 11: 472–477.
    1. Singal AG, Yopp A, C SS, Packer M, Lee WM, et al. (2012) Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review. J Gen Intern Med 27: 861–867.
    1. Singal AG, Yopp AC, Gupta S, Skinner CS, Halm EA, et al. (2012) Failure Rates in the Hepatocellular Carcinoma Surveillance Process. Cancer Prev Res (Phila) 5: 1124–1130.
    1. Lieberman DA (2009) Clinical practice. Screening for colorectal cancer. N Engl J Med 361: 1179–1187.
    1. Rex DK, Johnson DA, Lieberman DA, Burt RW, Sonnenberg A (2000) Colorectal cancer prevention 2000: screening recommendations of the American College of Gastroenterology. American College of Gastroenterology. Am J Gastroenterol 95: 868–877.
    1. Vijan S, Hwang EW, Hofer TP, Hayward RA (2001) Which colon cancer screening test? A comparison of costs, effectiveness, and compliance. Am J Med 111: 593–601.
    1. Singal A, Marrero J (2008) Screening for hepatocellular carcinoma. Gastroenterology and Hepatology 4: 1–8.
    1. Poustchi H, Farrell GC, Strasser SI, Lee AU, McCaughan GW, et al. (2011) 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 54: 1998–2004.
    1. Fattovich G, Stroffolini T, Zagni I, Donato F (2004) Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127: S35–50.
    1. Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H (2012) Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a danish nationwide cohort study. Ann Intern Med 156: 841–847.
    1. White DL, Kanwal F, El-Serag HB (2012) Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10: 1342–1359 e1342.
    1. Lee E, Edward S, Singal AG, Lavieri MS, Volk M (2013) Improving screening for hepatocellular carcinoma by incorporating data on levels of alpha-fetoprotein, over time. Clin Gastroenterol Hepatol 11: 437–440.
    1. Singal AG, Mukherjee A, Joseph Elmunzer B, Higgins PD, Lok AS, et al. (2013) Machine learning algorithms outperform conventional regression models in predicting development of hepatocellular carcinoma. Am J Gastroenterol 108: 1723–1730.
    1. Gopal P, Yopp AC, Waljee AK, Chiang J, Nehra M, et al. (2013) Factors that affect accuracy of alpha-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol In press.
    1. Loomba R, Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10: 686–690.
    1. Tan D, Yopp A, Beg MS, Gopal P, Singal AG (2013) Meta-analysis: underutilisation and disparities of treatment among patients with hepatocellular carcinoma in the United States. Aliment Pharmacol Ther 38: 703–712.
    1. Duffy SW, Nagtegaal ID, Wallis M, Cafferty FH, Houssami N, et al. (2008) Correcting for lead time and length bias in estimating the effect of screen detection on cancer survival. Am J Epidemiol 168: 98–104.
    1. Chen JG, Parkin DM, Chen QG, Lu JH, Shen QJ, et al. (2003) Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen 10: 204–209.

Source: PubMed

3
Abonnieren