Devan Kansagara, MD, MCR; Joel Papak, MD; Amirala S. Pasha, DO, MS; Maya O’Neil, PhD; Michele Freeman, MPH; Rose Relevo, MLIS, MS; Ana Quiñones, PhD; Makalapua Motu’apuaka, BS; Janice H. Jou, MD, MHS
Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs or the U.S. government.
Acknowledgment: The authors thank Dr. Mark Helfand for providing comments on an earlier draft of this manuscript.
Financial Support: By the U.S. Department of Veterans Affairs, Veterans Health Administration (VHA) Project ESP 05-225.
Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0558.
Requests for Single Reprints: Devan Kansagara, MD, MCR, Portland Veterans Affairs Medical Center, Mailcode RD71, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Kansagara, Ms. Freeman, and Ms. Relevo: Portland Veterans Affairs Medical Center, Mailcode RD71, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239.
Dr. Papak: Department of Medicine, Portland Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239.
Dr. Pasha: Department of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, PV350, Portland, OR 97239.
Dr. O’Neil: Portland Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Road (R&D 66), Portland, OR 97239.
Dr. Quiñones: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mailcode CB669, Portland, OR 97239.
Ms. Motu’apuaka: Oregon Evidence-based Practice Center, 325 SE 162nd Avenue, Portland, OR 97233.
Dr. Jou: Department of Medicine, Portland Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Road, P3-GI, Portland, OR 97239.
Author Contributions: Conception and design: D. Kansagara, J. Papak, M. O’Neil, J.H. Jou.
Analysis and interpretation of the data: D. Kansagara, J. Papak, A.S. Pasha, M. O’Neil, M. Freeman, R. Relevo, J.H. Jou.
Drafting of the article: D. Kansagara, A.S. Pasha, M. O’Neil, M. Freeman, J.H. Jou.
Critical revision of the article for important intellectual content: D. Kansagara, J. Papak, M. O’Neil, M. Freeman, A. Quiñones, M. Motu’apuaka, J.H. Jou.
Final approval of the article: D. Kansagara, M. O’Neil, A. Quiñones, M. Motu’apuaka, J.H. Jou.
Provision of study materials or patients: M. Freeman.
Obtaining of funding: D. Kansagara.
Administrative, technical, or logistic support: J. Papak, M. Freeman, R. Relevo, A. Quiñones, M. Motu’apuaka.
Collection and assembly of data: D. Kansagara, J. Papak, A.S. Pasha, M. Freeman, R. Relevo, A. Quiñones, M. Motu’apuaka, J.H. Jou.
Guidelines recommend routine screening for hepatocellular carcinoma (HCC) in high-risk patients, but the strength of evidence supporting these recommendations is unclear.
To review the benefits and harms of HCC screening in patients with chronic liver disease.
MEDLINE, PsycINFO, and ClinicalTrials.gov from inception to April 2014; Cochrane databases to June 2013; reference lists; and technical advisors.
English-language trials and observational studies comparing screening versus no screening, studies of harms, and trials comparing different screening intervals.
Mortality and adverse events were the outcomes of interest. Individual-study quality and the overall strength of evidence were dual-reviewed using published criteria.
Of 13 801 citations, 22 studies met inclusion criteria. The overall strength of evidence on the effects of screening was very low. One large trial of patients with hepatitis B found decreased HCC mortality with periodic ultrasonographic screening (rate ratio, 0.63 [95% CI, 0.41 to 0.98]), but the study was limited by methodological flaws. Another trial in patients with hepatitis B found no survival benefit with periodic α-fetoprotein screening. In 18 observational studies, screened patients had earlier-stage HCC than clinically diagnosed patients, but lead- and length-time biases confounded the effects on mortality. Two trials found no survival differences between shorter (3- to 4-month) and longer (6- to 12-month) screening intervals. Harms of screening were not well-studied.
Only English-language studies were included. The evidence base is limited by methodological issues and a paucity of trials.
There is very-low-strength evidence about the effects of HCC screening on mortality in patients with chronic liver disease. Screening tests can identify early-stage HCC, but whether systematic screening leads to a survival advantage over clinical diagnosis is uncertain.
U.S. Department of Veterans Affairs Quality Enhancement Research Initiative.
Summary of evidence search and selection.
RCT = randomized, controlled trial.
Table 1. Summary of the Evidence on Screening for HCC in Patients With Chronic Liver Disease and Treatment in Patients With Early-Stage HCC
Table 2. Evidence Gaps and Recommendations for Future Research
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Northern Hospital, France
June 20, 2014
Hepatocellular carcinoma screening: Exceptions deserve patients.
Congratulations to the Journal for opening a scientific debate on hepatocellular carcinoma (HCC) screening.(1,2) This contrasts with the national associations of hepatologists which enduringly issue grade I (highest level) recommendation for screening despite “there is very-low-strength evidence about the effects of HCC screening on mortality in patients with chronic liver disease”.(2)
“Enduringly”, because since long a ago, raw data allowed to easily calculate that screened patients are dying 2 or 1,5 years younger than non screened patients, despite hepatologists only limited their conclusions to an improved survival, ignoring lead-time bias.(3,4)
Why hepatologists in developed countries have failed to perform randomized control trials for cancer screening as others specialists and now claims, with a growing denial, that trials are not feasible? Are there undisclosed potential conflicts of interest?(5)
Hepatologists must also acknowledge, as others specialists do, that screening is more than a periodic testing, it must be a national program to ensure a minimal participation, quality controls, and evaluation of the results. These are basic pre-requisites for any efficacy, if it could exist.
Can hepatology remain an exception, out of Evidence Based Medicine and Public Health?
1 Kansagara D, Papak J, Pasha AS et al. Screening for hepatocellular carcinoma in chronic liver disease: A systematic review Ann Intern Med 2014. On line Jun 17. doi: 10.7326/M14-0558.
2 Atkins D, Ross D, Kelley M, Acting in the face of uncertainty. Ann Intern Med 2014. On line Jun 17. doi:10.7326/M14-1344
3 Braillon A. Screening for hepatocellular carcinoma: still in search for evidence based medicine? J Gastroenterol Hepatol 2006;21:1355-6.
4 Braillon A. Hepatocellular carcinoma. Lancet 2012;380:469.
5 Braillon A. Is the American Association for the Study of Liver Diseases recommendation for hepatocellular carcinoma screening a cul-de-sac? World J Gastroenterol. 2013;19:3369-70.
Keywords: hepatocellular carcinoma, screening, EBM, Public Health.
Diana Chirovsky MS, PhD, Kristen Hassmiller Lich, MHA, PhD, A. Sidney Barritt IV, MD, MSCR
University of North Carolina Schools of Medicine and Gillings School of Global Public Health
July 14, 2014
The Role of Simulation in Clinical Trials
To the Editor:
We read with interest, Screening for Hepatocellular Carcinoma in Chronic Liver Disease: A Systematic Review, by Kansagara et al.(1) As the authors suggest, a clinical trial would be the most definitive way to establish the effectiveness of hepatocellular carcinoma (HCC) screening, but there are multiple barriers, including cost, ethical concerns, and the enduring impact of such a trial in the face of new therapies for viral hepatitis. The use of simulation models to predict risk, cost effectiveness, and outcomes have become increasingly common in the medical literature.(2, 3) Modeling techniques, like discrete event and individual-based simulation, can incorporate individual patient-level heterogeneity for underlying risk-factors and tumor characteristics. Simulation models can account for changing technologies and innovations that occur in real time, making simulations far more flexible than a clinical trial.(2) Different assumptions can also be used to reflect distinct contexts (e.g., in terms of the prevalence of risk factors or changes in practice patterns), so that the effect of alternative screening programs can be readily understood without undertaking multiple trials.
Many of the evidence gaps highlighted by Kansagara et al in table 2 are amenable for simulation study design. Issues surrounding selection bias, commonly seen in observation studies, may be addressed by random allocation of clinical characteristics across screening groups. Lead time bias can be diminished by redefining survival from the time of HCC development, as opposed to time of diagnosis, and by assessing tumor growth across a range of tumor volume doubling times. Screening intervals and modalities can be compared through probabilistic sensitivity analyses to estimate a range in survival benefit, based on current evidence. Lastly, potential risks and resource use implications of procedures may be predicted across a range of possibilities without ever exposing a single patient to harm.
Any simulation is only as valuable as the data on which the model is based. Natural history data for HCC are abundant. Through model-based calibration, complex components of HCC disease progression can be estimated based on tumor characteristics that are observable in clinical practice.(4) In addition to simulating trial results, these models can be used to estimate outcomes that cannot readily be measured directly in trials. Further work should explore the use of simulation to address gaps noted by Kansagara et al. to guide clinical trials(5) or replace trial data when such information is impractical or unethical to obtain.
Diana Chirovsky MS, PhD
Kristen Hassmiller Lich, MHA, PhD
A. Sidney Barritt IV, MD, MSCR
1. Kansagara D, Papak J, Pasha AS, O'Neil M, Freeman M, Relevo R, Quinones A, et al. Screening for Hepatocellular Carcinoma in Chronic Liver Disease: A Systematic Review. Ann Intern Med 2014.
2. Brennan A, Chick SE, Davies R. A taxonomy of model structures for economic evaluation of health technologies. Health Econ 2006;15:1295-1310.
3. Morrissey JP, Lich KH, Price RA, Mandelblatt J. Computational modeling and multilevel cancer control interventions. J Natl Cancer Inst Monogr 2012;2012:56-66.
4. Vanni T, Karnon J, Madan J, White RG, Edmunds WJ, Foss AM, Legood R. Calibrating models in economic evaluation: a seven-step approach. Pharmacoeconomics 2011;29:35-49.
5. Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P. The role of modelling in prioritising and planning clinical trials. Health Technol Assess 2003;7:iii, 1-125.
Edoardo G. Giannini, MD, PhD, FACG,1 Franco Trevisani, MD2
1Unità di Gastroenterologia, Dipartimento di Medicina Interna, IRCCS-Azienda Ospedaliera Universitaria San Martino-IST, Università di Genova, Genova, Italia. 2Unità di Semeiotica Medica
August 26, 2014
Evidence supporting surveillance for hepatocellular carcinoma: more than enough?
TO THE EDITOR: Kansagara and colleagues (1) reviewed the literature regarding hepatocellular carcinoma (HCC) surveillance, and come to the conclusion that the evidence supporting surveillance benefit is flawed by the retrospective nature of most studies, and by the confounding effect of lead-time bias. Moreover, they surmise that the possible harms of surveillance have not been adequately assessed and, taking into account the frequent coexistence of liver cirrhosis, the risk of overdiagnosis may be substantial. They conclude that the benefit of surveillance is supported by a very-low-strength evidence as compared to clinical diagnosis of HCC.In most patients HCC ensues in the setting of well-compensated cirrhosis (2) and their prognosis mainly depends upon receipt of curative treatments, which are only feasible in early stage cancer. Indeed, a host of studies and a recent meta-analysis have shown that surveillance allows diagnosis of HCC at earlier stages and increases application of curative treatments as compared to symptomatic HCC diagnosis, thus improving patients survival (3). In this regard, it has been demonstrated that the survival advantage obtained with surveillance cannot be attributed to lead-time bias alone, particularly in a 3- and 5-year time-horizon for patients with fast- and slow-growing HCCs, respectively (4). A fundamental prerequisite is, however, that surveillance must be targeted to the adequate population in terms of both HCC risk and potential candidacy to curative treatment so as to obtain the highest survival benefit. Moreover, the risk of overdiagnosis can be minimised by implementing surveillance only in patients with well-preserved liver function and general conditions, ensuring their amenability to curative treatments for HCC (5).All in all, we may agree with Kansagara and colleagues that the level of evidence supporting the routine use of HCC surveillance is not very high, but this is likely the highest level we can afford, and has been considered sufficient to recommend this practice by all professional societies.Regarding the surveillance harms, the authors point out that no studies assessed the potential (negative) psychological effects of surveillance Although this assumption is formally correct, there is strong evidence that almost all patients, if adequately informed on the potential harms and benefits of surveillance, prefer to undergo surveillance rather than care on demand (6).Noteworthy, the authors themselves correctly conclude that their findings neither support nor refute current clinical recommendations, which are dictated by a number of measurable and immeasurable clinical factors. Therefore, we feel that rather than to insist on debating the strength of evidence supporting the efficacy of HCC surveillance, we should strive to do it at best. How? By selecting appropriate patients, promoting their compliance, using a proper interval, relying on expert liver sonographers, implementing timely recall policies, and choosing treatment in a multidisciplinary way (7). Altogether, these actions will succeed in greatly improving the clinical effectiveness of this practice. References1. Kansagara D, Papak J, Pasha AS, O'Neil M, Freeman M, Relevo R, Quiñones A, Motu'apuaka M, Jou JH. Screening for hepatocellular carcinoma in chronic liver disease: a systematic review. Ann Intern Med 2014; 161: 261-9. [PMID: 24934699] doi: 10.7326/M14-0558.2. Santi V, Buccione D, Di Micoli A, Fatti G, Frigerio M, Farinati F, Del Poggio P, Rapaccini G, Di Nolfo MA, Benvegnù L, Zoli M, Borzio F, Giannini EG, Caturelli E, Chiaramonte M, Bernardi M, Trevisani F. The changing scenario of hepatocellular carcinoma over the last two decades in Italy. J Hepatol 2012; 56: 397-405. [PMID: 21756850] doi: 10.1016/j.jhep.2011.05.026.3. Singal AG, 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: e1001624. [PMID: 24691105] doi: 10.1371/journal.pmed.1001624.4. Cucchetti A, Trevisani F, Pecorelli A, Erroi V, Farinati F, Ciccarese F, Rapaccini GL, Di Marco M, Caturelli E, Giannini EG, Zoli M, Borzio F, Cabibbo G, Felder M, Gasbarrini A, Sacco R, Foschi FG, Missale G, Morisco F, Baroni GS, Virdone R, Bernardi M, Pinna AD; Italian Liver Cancer (ITA.LI.CA) group. Estimation of lead-time bias and its impact on the outcome of surveillance for the early diagnosis of hepatocellular carcinoma. J Hepatol 2014; 61: 333-41. [PMID: 24717522] doi: 10.1016/j.jhep.2014.03.037.5. Trevisani F, Santi V, Gramenzi A, Di Nolfo MA, Del Poggio P, Benvegnù L, Rapaccini G, Farinati F, Zoli M, Borzio F, Giannini EG, Caturelli E, Bernardi M; Italian Liver Cancer Group. Surveillance for early diagnosis of hepatocellular carcinoma: is it effective in intermediate/advanced cirrhosis? Am J Gastroenterol 2007; 102: 2448-57. [PMID: 17617210]6. Poustchi H, Farrell GC, Strasser SI, Lee AU, McCaughan GW, George J. 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. [PMID: 21800340] doi: 10.1002/hep.24581.7. Giannini EG, Cucchetti A, Erroi V, Garuti F, Odaldi F, Trevisani F. Surveillance for early diagnosis of hepatocellular carcinoma: how best to do it? World J Gastroenterol 2013; 19: 8808-21. [PMID: 24379604] doi: 10.3748/wjg.v19.i47.8808.
Devan Kansagara MD MCR, Joel Papak MD, Janice Jou MD MHS
Portland VA Medical Center
October 20, 2014
HCC screening: more work to be done
We agree with Chirovsky et al that modeling and simulation data have potential utility, but we did not find ample natural history data that could be used as a foundation for such models. We found little data about the natural history of screen-detected cancer which can be quite different from the natural history of clinically-detected cancer. As we note, there are several older studies which suggest a broad range of natural history for HCC.1 We found several observational studies which attempted to adjust for lead-time and found that when longer tumor doubling time estimates were used, observed differences in survival could be attributed to lead-time bias. This is not a surprising finding and still leaves unresolved the assumptions that should be used for modeling studies. Furthermore, models would need to consider treatment effects, but there are few data on effects of treating screen-detected cancer.2 We agree with Giannini et al that, if screening is done, patient selection and program implementation are important considerations. We also agree that any potential benefits of screening are likely to be seen in higher risk patients who are healthy enough both to undergo treatment if necessary and to reduce the chance of overdiagnosis. However, we disagree with their assertion that the current body of evidence is as strong as it can feasibly be, and that it should continue to be seen as sufficient to support existing guideline recommendations for screening. The lack of good-quality evidence demonstrating benefits of screening is important because it underscores the need to consider issues such as overdiagnosis, the harms of screening, and the harms of treating screen-detected cancer. As we note, there was a suggestion of overdiagnosis in one trial comparing screening intervals: intensive screening detected more small tumors and more patients underwent treatment with curative intent but there was no difference in survival between groups.3 A shared understanding of the current state of evidence is also important in developing a research agenda. A screening trial is the most definitive way of clarifying the balance of benefits and harms, though others have raised concerns about the feasibility of conducting a screening trial. Regardless, further work in clarifying the natural history of very small screen-detected HCC, comparing invasive and watchful waiting approaches to treating small screen-detected tumors, and further trials comparing screening intervals would at least provide valuable indirect evidence and should be feasible to conduct. 1. Kansagara D, Papak J, Pasha AS, O'Neil M, Freeman M, Relevo R, Quiñones A, Motu'apuaka M, Jou JH. Screening for hepatocellular carcinoma in chronic liver disease: a systematic review. Ann Intern Med 2014; 161: 261-92. Kansagara D, Papak J, Pasha AS, O’Neil M, Freeman M, Relevo R, Quinones A, Motu’apuaka M, Jou JH. Screening for hepatocellular cancer in chronic liver disease: a systematic review. VA-ESP Project #05-225; 20133. Wang JH, Chang KC, Kee KM, Chen PF, Yen YH, Tseng PL, et al. Hepatocellular carcinoma surveillance at 4- vs. 12-month intervals for patients with chronic viral hepatitis: a randomized study in community. Am J Gastroenterol. 2013;108:416-24.
Devan Kansagara, Joel Papak, Amirala S. Pasha, Maya O’Neil, Michele Freeman, Rose Relevo, et al. Screening for Hepatocellular Carcinoma in Chronic Liver Disease: A Systematic Review. Ann Intern Med. 2014;161:261–269. doi: 10.7326/M14-0558
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Published: Ann Intern Med. 2014;161(4):261-269.
Cancer Screening/Prevention, Gastroenterology/Hepatology, Hematology/Oncology, Infectious Disease, Liver Disease.
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