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Screening for Hepatocellular Carcinoma in Chronic Liver Disease: A Systematic ReviewScreening for Hepatocellular Carcinoma in Chronic Liver Disease FREE ONLINE FIRST

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; and Janice H. Jou, MD, MHS
[+] Article and Author Information

This article was published online first at www.annals.org on 17 June 2014.


From Veterans Affairs Medical Center and Oregon Health & Science University, Portland, Oregon.

Editor's Note: This online-first version will be replaced with a final version when it is included in the issue. The final version may differ in small ways.

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, kansagar@ohsu.edu.

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. Quinones, M. Motu'apuaka, J.H. Jou.

Final approval of the article: D. Kansagara, M. O'Neil, A. Quinones, 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. Quinones, M. Motu'apuaka.

Collection and assembly of data: D. Kansagara, J. Papak, A.S. Pasha, M. Freeman, R. Relevo, A. Quinones, M. Motu'apuaka, J.H. Jou.


Ann Intern Med. Published online 17 June 2014 doi:10.7326/M14-0558
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Background: Guidelines recommend routine screening for hepatocellular carcinoma (HCC) in high-risk patients, but the strength of evidence supporting these recommendations is unclear.

Purpose: To review the benefits and harms of HCC screening in patients with chronic liver disease.

Data Sources: MEDLINE, PsycINFO, and ClinicalTrials.gov from inception to April 2014; Cochrane databases to June 2013; reference lists; and technical advisors.

Study Selection: English-language trials and observational studies comparing screening versus no screening, studies of harms, and trials comparing different screening intervals.

Data Extraction: Mortality and adverse events were the outcomes of interest. Individual-study quality and the overall strength of evidence were dual-reviewed using published criteria.

Data Synthesis: 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 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 bias 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.

Limitations: Only English-language studies were included. The evidence base is limited by methodological issues and a paucity of trials.

Conclusion: 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.

Primary Funding Source: U.S. Department of Veterans Affairs Quality Enhancement Research Initiative.


Hepatocellular carcinoma (HCC) incidence and mortality have increased internationally over the past 4 decades (12), with localized tumors accounting for most of the increase (3). The rationale for screening is that imaging tests, such as ultrasonography, may identify patients with early-stage HCC (4) and several potential options exist for treating patients with early-stage HCC, including liver transplantation, radiofrequency ablation, and liver resection (5). Several professional societies currently recommend HCC screening using imaging studies and tumor markers, primarily in patients at higher risk for HCC due to chronic hepatitis B or cirrhosis (57). However, recommendations for HCC screening remain controversial, in part because of concerns over the quality and paucity of existing evidence and because concerns about overdiagnosis and patient harms have been raised in other cancer screening programs (812).

We conducted a systematic review of the published literature to better understand the incremental benefits and harms of routine HCC screening compared with clinical diagnosis.

This manuscript is part of a larger report commissioned by the Veterans Health Administration (13). A protocol describing the review plan was posted to a public Web site before the study was initiated (14). The analytic framework that guided this review was developed in collaboration with a panel of technical experts and is provided in Figure 1 of Supplement 1.

Data Sources and Searches

We searched MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from database inception to June 2013. We updated the MEDLINE, PsycINFO, and ClinicalTrials.gov searches in April 2014. The detailed search strategy is provided in Supplement 2. We obtained additional articles from systematic reviews, reference lists of pertinent studies, reviews, and editorials and by consulting technical advisors.

Study Selection

Detailed inclusion and exclusion criteria are provided in Supplement 3. We included English-language controlled clinical trials and observational studies that assessed the effects of screening on HCC-specific and all-cause mortality in adult populations. We used the term “screening” to include any surveillance or screening program in which specific tests (ultrasonography, computed tomography, magnetic resonance imaging, or α-fetoprotein measurement) were performed explicitly to detect HCC in asymptomatic patients. Studies had to include a comparison group of patients who did not have routine screening. We excluded observational studies that did not consider important confounding factors, such as age, sex, and liver disease severity. Because we anticipated few clinical trials comparing screening versus no screening, we also included trials comparing different frequencies of screening. We included studies of any population with chronic liver disease with or without cirrhosis but excluded studies of patients with prior HCC. We also searched for systematic reviews and primary studies that focused on potential harms of HCC screening.

Seven investigators reviewed the titles and abstracts of citations identified from literature searches. If at least 1 reviewer indicated that a citation may be relevant, a second reviewer screened the citation for concordance. Two reviewers independently assessed the full-text articles for inclusion using the eligibility criteria shown in Supplement 3. Disagreements were resolved through consensus.

Data Extraction and Quality Assessment

From each study, we abstracted study design, objectives, setting, population characteristics (including sex, age, race or ethnicity, and liver disease cause and severity), patient eligibility and exclusion criteria, number of patients, years of enrollment, method and frequency of screening, adjusted and unadjusted mortality, and adverse events. A second author checked each entry for accuracy.

Two reviewers independently assessed the quality of each trial by using a tool developed by the Cochrane Collaboration (15). We resolved disagreements through discussion. Each trial was given an overall summary assessment of low, high, or unclear risk of bias. Two reviewers graded the strength of evidence for outcomes by using published criteria that consider the consistency, coherence, directness, and applicability of a body of evidence as well as the internal validity of individual studies (16).

We adapted existing tools to assess the quality of observational studies (1719). We do not report an overall summary assessment for observational studies because there are no validated criteria for doing so.

Data Synthesis and Analysis

We qualitatively synthesized the evidence on the benefits and harms of HCC screening. Clinical heterogeneity and the small number of trials precluded the possibility of combining the findings in a meta-analysis.

Role of the Funding Source

The U.S. Department of Veterans Affairs Quality Enhancement Research Initiative supported this review but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

The electronic and manual searches yielded 13 801 total citations, from which we identified 286 potentially relevant full-text articles. Twenty-two primary studies contained primary data relevant to the efficacy of HCC screening and met our inclusion criteria (Figure).

Grahic Jump Location
Figure.

Summary of evidence search and selection.

RCT = randomized, controlled trial.

Grahic Jump Location
Effects of Screening on Mortality

Two trials and 18 observational studies provided very-low-strength evidence from which to draw conclusions about the mortality effects of HCC screening compared with no screening. The trials had substantial methodological flaws that threatened their internal validity, and their findings have limited applicability beyond the hepatitis B patient population. The observational studies, most of which included patients with cirrhosis and hepatitis B, hepatitis C, or alcoholic liver disease, showed that screening detects patients with earlier-stage disease, who more frequently receive curative therapy. However, it is impossible to say whether the longer survival in patients with screen-detected disease was a true effect of screening or reflects lead- and length-time biases inherent to all observational studies, as well as selection biases that were common in many of the studies.

Randomized, Controlled Trials

Two community-based trials compared the effects on mortality of screening versus no screening (2021). Both were conducted in China in areas with high HCC prevalence, and most participants had hepatitis B with or without cirrhosis (Table 1 of Supplement 4). One cluster randomized trial recruited screening group participants (n = 9757) from 1993 to 1995 and offered them serum α-fetoprotein testing and ultrasonography every 6 months. Participants in the control group (n = 9443) were not made aware of the study or actively followed. Death from HCC occurred less frequently in the screening group (83.2 vs. 131.5 per 100 000 person-years; rate ratio, 0.63 [95% CI, 0.41 to 0.98]).

However, the trial had several serious methodological limitations that gave it a high risk of bias (Table 2 of Supplement 4). One major concern is whether patients in both groups had the same risk for HCC. There is no information about randomization technique or allocation concealment and very little information about the baseline characteristics of the 2 groups, which is especially important in cluster randomized trials. Another concern is that weak methods used to ascertain the outcome measure—death from HCC—could have introduced bias. If deaths were underreported in the control group, results could have been biased toward the null. On the other hand, if outcome adjudicators were not blinded, more deaths in the control group could have been misclassified as HCC-related, especially because the symptoms that define stage III HCC (cachexia, jaundice, and ascites) overlap substantially with symptoms of end-stage liver disease and no data were provided about liver disease severity in either group. Selective reporting and analysis of favorable outcomes was another concern. Although the authors reported that vital status was available for all patients, overall mortality was not reported and there was no statistical adjustment for the effects of clustering. Finally, the study is less applicable to patients in the United States, in whom cirrhosis and thus HCC are usually secondary to hepatitis C, and the results probably have limited applicability to contemporary practice, in which the threshold for imaging for symptoms may be lower and the number of patients with incidentally discovered HCC on imaging is higher.

The second trial used patient-level randomization stratified by township to assign patients with hepatitis B from 1989 to 1992 to the screening intervention (n = 3712), which consisted of serial α-fetoprotein tests followed by ultrasonography for high α-fetoprotein values, or the usual care group (n = 1869) (21). The population-based cancer registry used active case-finding techniques, and mortality was ascertained through the cancer registry and a population-based vital status registry. Cancer staging and cause of death were assessed by personnel blinded to intervention status. Only 28.8% of screening group participants completed all scheduled testing, but all participants completed at least 1 screening test. Fewer patients had stage III HCC in the screening group (19.8% vs. 41.0%; P not reported). Hepatocellular carcinoma mortality was similar in both groups (1138 vs. 1114 per 100 000 person-years; P = 0.86), as was all-cause mortality (1843 vs. 1788 per 100 000 person-years; P not significant). This trial had an unclear risk of bias because of poor reporting of randomization and allocation concealment techniques.

Two additional trials compared different ultrasonography screening intervals (2223). One recent community-based cluster randomized trial in Taiwan compared 4- versus 12-month ultrasonography screening intervals in patients with serologic evidence of hepatitis B or C (22). Although more patients with HCC in the 4-month interval group had very-early-stage disease (37.5% vs. 6.7%; P = 0.017), the 1-, 2-, and 4-year survival rates among patients with HCC were similar (95% vs. 80%, 78.8% vs. 64%, and 57.4% vs. 56%, respectively; P = 0.40). The study had an unclear risk of bias because of poor reporting of outcome assessment and statistical analyses.

A trial with low risk of bias compared 3- versus 6-month ultrasonography screening intervals in 1278 patients with cirrhosis from alcohol use or viral hepatitis and found similar all-cause mortality rates in both groups (11.3% vs. 12.1%; P = 0.38) (23). A similar number of patients were diagnosed with HCC in both groups (8.3% vs. 11.0%; P = 0.13), and most met Milan criteria (79.2% vs. 71.4%; P = 0.40).

Observational Studies

Eighteen observational studies compared survival in patients with screen-detected HCC versus those with HCC diagnosed incidentally as part of another work-up or because of symptoms (Table 3 of Supplement 4) (2441). The studies represented a range of geographic settings, including Asia (6 studies), Europe (6 studies), Australia (1 study), and the United States (5 studies). Most patients included in these studies had hepatitis B or C with Child–Pugh class A or B cirrhosis, although patients in the nonscreening groups had more severe liver disease in many of the studies. Ultrasonography with or without α-fetoprotein measurement was the screening method used in nearly all studies, except for 2 U.S. studies in which a small number of patients had computed tomography (26, 31).

In general, patients who had undergone screening had earlier-stage HCC than those who had HCC diagnosed incidentally or due to symptoms; in 12 studies, 60.0% to 100% of screened patients versus 19.6% to 56.5% of nonscreened patients met the equivalent of Milan criteria. More screened patients received potentially curative treatment, although only a small proportion had hepatic resection (range, 2.8% to 23.9% in 14 studies [24, 26, 2831, 3338, 4041]; 53.5% in 1 outlier study [39]) or liver transplantation (range, 1% to 15% in 5 studies [28, 3132, 36, 38, 41]; 23% and 30.1% in 2 other studies [24, 35, 40]).

Survival from the time of HCC diagnosis was generally higher among screened than nonscreened patients (Figure 2 of Supplement 1). However, several methodological considerations temper the confidence with which one can draw conclusions from this body of observational literature (Table 4 of Supplement 4). Most of the studies were single-center retrospective cohort studies in which all patients with diagnosed HCC were first identified and screening status was subsequently determined. Few studies reported data on loss to follow-up, and many did not report using a comprehensive method to assess mortality outcomes equally in screening and nonscreening groups. Only 4 of the studies reported objective and replicable methods for distinguishing screened from nonscreened patients (2627, 31, 41). Furthermore, selection bias is a concern for all but 3 of the studies (2627, 31). In most studies, the comparison group was drawn from a referral population and unmeasured patient, treatment, health care access, and other factors probably differed between groups.

In addition to the methodological issues specific to individual studies, the potential for length- and lead-time bias is inherent in any observational study of screening effects (42). Although there is no infallible way to circumvent the threat of lead-time bias other than to conduct a well-designed randomized, controlled trial, 5 studies used statistical techniques to adjust for lead-time bias (27, 33, 35, 38, 41). These studies used various assumptions about tumor doubling time to estimate the lead time of screening diagnosis. Three of the studies adjusted for lead time and found that the survival advantage for screened patients disappeared when the tumor doubling time was assumed to be 90 to 120 days or longer (Table 3 of Supplement 4) (27, 33, 38). A fourth study used serial ultrasonographic data from 13 patients to estimate a tumor doubling time of 216 days, although survival among screened patients remained higher even after adjustment for lead time (35). Finally, in a large multisite Italian cohort comparing patients with screen-detected versus symptomatically detected HCC (patients with incidental diagnoses were excluded), adjustment for lead time based on probabilistic estimates of tumor doubling time attenuated survival effects seen over 3 years but not over longer follow-up (41).

Harms of Screening

None of the included studies reported direct harms of screening, and no studies examined the psychological effects of screening.

Patients with positive screening results from ultrasonography or α-fetoprotein testing usually have further confirmatory testing. In most of the studies, confirmatory testing was done with computed tomography and, less commonly, with magnetic resonance imaging or liver biopsy, although few studies reported rates of actual testing used for diagnosis. One meta-analysis of 8 studies found the risk for needle-track seeding from liver biopsy for suspected HCC to be 2.7% (43). One recent systematic review of the diagnostic accuracy of imaging for HCC screening and diagnosis found few studies reporting harms data: 1 study found that contrast-enhanced computed tomography was associated with adverse events in 13% to 15% of patients, and another found mild to moderate adverse events in 25% of patients receiving gadoxetic acid–enhanced magnetic resonance imaging (44).

We systematically reviewed and critically appraised trials and observational studies examining the risks and benefits of HCC screening in patients with chronic liver disease. Periodic ultrasonography and α-fetoprotein testing have been the most commonly evaluated screening methods, and patients with viral hepatitis have been the most frequently studied population. Although screening identifies patients with early-stage HCC and some of these patients do well with curative therapy, there is very-low-strength evidence from which to draw conclusions about the balance of benefits and harms of screening for HCC (Table 1).

Table Jump PlaceholderTable 1. Summary of the Evidence on Screening for HCC in Patients With Chronic Liver Disease and Treatment in Patients With Early-Stage HCC 

The body of evidence on which current recommendations for screening are based has substantial shortcomings. The large-scale trial conducted among hepatitis B–infected patients in China has serious methodological limitations that undermine the validity of its findings (57). The only other trial found that serial α-fetoprotein screening offered no survival advantage. The applicability of these studies, moreover, is limited because of more widespread imaging use, higher rates of incidental diagnosis, and a smaller proportion of patients whose primary risk is hepatitis B.

Although numerous, observational studies do not contribute substantially to the strength of evidence. Most studies included patients with viral hepatitis and cirrhosis and found that patients with screen-detected HCC were more likely to have earlier-stage disease and survived longer from the time of diagnosis. However, most were single-center studies that retrospectively evaluated patients with HCC and had lead- and length-time biases in addition to other design limitations.

Screening programs have the intended effect of identifying patients with early-stage disease, more of whom undergo such potentially curative therapies as liver transplant or partial hepatic resection. Some cohort studies suggest that long-term survival of patients who have liver resection or transplantation for HCC can be high (40% to 70% for resection and 52% to 81% for transplant patients after 5 years [45]), although perioperative morbidity and mortality may be substantial (46). In contrast, a large prospective screening study in patients with viral hepatitis found that 5- and 10-year survival was low (28% and 4%, respectively) among those who developed HCC and received curative treatment (47).

The natural history of early-stage or screen-detected HCC has not been well-characterized, and tumor growth patterns can differ markedly among patients, with some showing steady growth, others showing no growth followed by a period of rapid growth, and others with little or no long-term growth (4851). The net balance of benefits and harms might favor widespread screening if much of the HCC found as a result of routine screening were to progress and cause morbidity before patients' underlying illness did. On the other hand, if screen-detected HCC were more indolent, the risks of treating disease that would not have otherwise been clinically relevant (that is, overdiagnosed HCC) might tip the balance away from routine screening. Unfortunately, we found no evidence examining rates of overdiagnosis.

Several studies suggest that HCC may have variable rates of progression. In 1 trial comparing screening intervals, long-term survival was similar even though more patients undergoing frequent screening had small, early-stage HCC and received potentially curative therapy compared with patients assigned to a less intensive screening program (22). A recent study found that the length of the waiting period for transplantation results in selection of patients with more indolent HCC because those with more aggressive disease lose candidacy while awaiting a transplant (52). Another study of a mixed sample of patients with early- and late-stage disease who were randomly assigned to no treatment in 2 trials found 2 different survival patterns depending on the presence of an invasive tumor pattern and poor performance status (3-year survival of 8% vs. 50%; P = 0.0001) (53).

We searched for systematic reviews through April 2014 and found several that examined HCC screening studies. A recent review of observational studies found that HCC screening was associated with detection of earlier-stage HCC and improved survival (54). A Cochrane review found insufficient evidence for screening but focused only on studies of patients with hepatitis B and did not examine observational studies (11). Several widely disseminated guidelines recommend HCC screening in high-risk patients with liver disease (57), but none used a systematic review that critically appraised included studies as a basis for the recommendations. Finally, a systematic review of cost-effectiveness modeling studies, most of which were based on assumptions from the literature, concluded that periodic surveillance with ultrasonography was probably cost-effective when the annual incidence of HCC was higher than 1.5%, although annual surveillance may be more cost-effective than semiannual surveillance in populations with annual HCC risk of 1.5% to 3.5% (55). The only modeling study using data from a prospective cohort found that surveillance was probably not cost-effective (24).

Our findings neither support nor refute current clinical policy recommendations for HCC screening. Transparency about the strength of the evidence on which these recommendations are based is important, but policy recommendations also take into account other factors, such as clinical experience, patient values and preferences, and cost considerations, especially when empirical evidence with which to judge the balance of benefits and harms is limited (56). If screening is pursued, it will be important to implement programs in ways that minimize potential harms, especially given the limited empirical evidence of benefit. For example, targeting screening to higher-risk individuals with less severe underlying liver disease and developing a better understanding of how to target invasive treatment to those with more aggressive screen-detected tumors might help to increase the detectable benefits of screening while limiting the population exposed to potential harms.

Although a large, well-conducted, randomized, controlled trial would be the most definitive way of establishing the effectiveness of HCC screening, many experts have invoked several potential barriers, including provider and patient willingness to participate, contamination, cost, and the possibility that a screening trial currently enrolling patients will be rendered obsolete in 10 to 20 years by the rapidly evolving viral hepatitis treatment armamentarium (12). Regardless of the feasibility of a randomized, controlled trial of screening, there are many opportunities for further study and it is likely, given the current insufficient body of evidence, that future studies will help clarify the balance of benefits and harms of screening. The key evidence gaps and suggestions for corresponding future research opportunities are summarized in Table 2.

Table Jump PlaceholderTable 2. Evidence Gaps and Recommendations for Future Research 

One limitation of our review was the exclusion of non–English-language articles. However, we mitigated the risk of missing relevant studies by searching multiple databases, bibliographies, and trial registries and by consulting experts. Moreover, evidence suggests that language restrictions do not bias results of reviews of conventional therapies (57).

In conclusion, there is very-low-strength evidence from which to draw conclusions about the effects of HCC screening on mortality in high-risk patients with chronic liver disease. Screening can identify more patients with earlier-stage disease who are candidates for potentially curative treatments, but there is limited evidence from which to draw firm conclusions about the balance of health outcome benefits and harms of using routine screening to identify HCC.

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Leykum LK, El-Serag HB, Cornell J, Papadopoulos KP.  Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival. Clin Gastroenterol Hepatol. 2007;5:508-12. [PMID: 17382601]
 
Pascual S, Irurzun J, Zapater P, Such J, Sempere L, Carnicer F, et al.  Usefulness of surveillance programmes for early diagnosis of hepatocellular carcinoma in clinical practice. Liver Int. 2008;28:682-9. [PMID: 18433394]
 
Tanaka H, Nouso K, Kobashi H, Kobayashi Y, Nakamura S, Miyake Y, et al.  Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival. Liver Int. 2006;26:543-51. [PMID: 16761998]
 
Taura N, Hamasaki K, Nakao K, Ichikawa T, Nishimura D, Goto T, et al.  Clinical benefits of hepatocellular carcinoma surveillance: a single-center, hospital-based study. Oncol Rep. 2005;14:999-1003. [PMID: 16142364]
 
Tong MJ, Sun HE, Hsien C, Lu DS.  Surveillance for hepatocellular carcinoma improves survival in Asian-American patients with hepatitis B: results from a community-based clinic. Dig Dis Sci. 2010;55:826-35. [PMID: 19960258]
 
Trevisani F, De Notariis S, Rapaccini G, Farinati F, Benvegnù L, Zoli M, et al; Italian Liver Cancer Group.  Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience). Am J Gastroenterol. 2002;97:734-44. [PMID: 11922571]
 
Trevisani F, Cantarini MC, Labate AM, De Notariis S, Rapaccini G, Farinati F, et al; Italian Liver Cancer (ITALICA) group.  Surveillance for hepatocellular carcinoma in elderly Italian patients with cirrhosis: effects on cancer staging and patient survival. Am J Gastroenterol. 2004;99:1470-6. [PMID: 15307862]
 
Wong GL, Wong VW, Tan GM, Ip KI, Lai WK, Li YW, et al.  Surveillance programme for hepatocellular carcinoma improves the survival of patients with chronic viral hepatitis. Liver Int. 2008;28:79-87. [PMID: 17900247]
 
Yu EW, Chie WC, Chen TH.  Does screening or surveillance for primary hepatocellular carcinoma with ultrasonography improve the prognosis of patients? Cancer J. 2004;10:317-25. [PMID: 15530261]
 
Gaba RC, Kallwitz ER, Parvinian A, Bui JT, Von Roenn NM, Berkes JL, et al.  Imaging surveillance and multidisciplinary review improves curative therapy access and survival in HCC patients. Ann Hepatol. 2013;12:766-73. [PMID: 24018494]
 
Cucchetti A, Trevisani F, Pecorelli A, Erroi V, Farinati F, Ciccarese F, et al; for the 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. [PMID: 24717522]
 
Fletcher RH, Fletcher SW, Wagner EH.  Clinical Epidemiology. The Essentials. 2nd ed. Baltimore: Williams & Wilkins; 1988.
 
Silva MA, Hegab B, Hyde C, Guo B, Buckels JA, Mirza DF.  Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2008;57:1592-6. [PMID: 18669577]
 
Chou R.  Imaging Techniques for the Surveillance, Diagnosis, and Staging of Hepatocellular Carcinoma. Evidence-based Practice Center Systematic Review Protocol. Rockville, MD: Agency for Healthcare Research and Quality; 2013. Accessed at http://effectivehealthcare.ahrq.gov/ehc/products/479/1600/Liver-cancer-protocol-130724.pdf on 28 May 2014.
 
Rahman A, Assifi MM, Pedroso FE, Maley WR, Sola JE, Lavu H, et al.  Is resection equivalent to transplantation for early cirrhotic patients with hepatocellular carcinoma? A meta-analysis. J Gastrointest Surg. 2012;16:1897-909. [PMID: 22836922]
 
Asiyanbola B, Chang D, Gleisner AL, Nathan H, Choti MA, Schulick RD, et al.  Operative mortality after hepatic resection: are literature-based rates broadly applicable? J Gastrointest Surg. 2008;12:842-51. [PMID: 18266046]
 
Izzo F, Piccirillo M, Albino V, Palaia R, Belli A, Granata V, et al.  Prospective screening increases the detection of potentially curable hepatocellular carcinoma: results in 8,900 high-risk patients. HPB (Oxford). 2013;15:985-90. [PMID: 23607636]
 
Cottone M, Virdone R, Fusco G, Orlando A, Turri M, Caltagirone M, et al.  Asymptomatic hepatocellular carcinoma in Child's A cirrhosis. A comparison of natural history and surgical treatment. Gastroenterology. 1989;96:1566-71. [PMID: 2469617]
 
Ebara M, Ohto M, Shinagawa T, Sugiura N, Kimura K, Matsutani S, et al.  Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology. 1986;90:289-98. [PMID: 2416627]
 
Sheu JC, Sung JL, Chen DS, Yang PM, Lai MY, Lee CS, et al.  Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology. 1985;89:259-66. [PMID: 2408960]
 
Barbara L, Benzi G, Gaiani S, Fusconi F, Zironi G, Siringo S, et al.  Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology. 1992;16:132-7. [PMID: 1352268]
 
Schlansky B, Chen Y, Austin D, Naugler WE.  Wait list time predicts survival after liver transplantation for hepatocellular carcinoma: a cohort study in the UNOS registry. Hepatology. 2013;58:208A.
 
Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M, et al.  Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology. 1999;29:62-7. [PMID: 9862851]
 
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]
 
Cucchetti A, Cescon M, Erroi V, Pinna AD.  Cost-effectiveness of liver cancer screening. Best Pract Res Clin Gastroenterol. 2013;27:961-72. [PMID: 24182614]
 
Guyatt GH, Norris SL, Schulman S, Hirsh J, Eckman MH, Akl EA, et al; American College of Chest Physicians.  Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:53S-70S. [PMID: 22315256]
 
Moher D, Pham B, Lawson ML, Klassen TP.  The inclusion of reports of randomised trials published in languages other than English in systematic reviews. Health Technol Assess. 2003;7:1-90. [PMID: 14670218]
 

Figures

Grahic Jump Location
Figure.

Summary of evidence search and selection.

RCT = randomized, controlled trial.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1. Summary of the Evidence on Screening for HCC in Patients With Chronic Liver Disease and Treatment in Patients With Early-Stage HCC 
Table Jump PlaceholderTable 2. Evidence Gaps and Recommendations for Future Research 

References

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Kansagara D, Papak J, Pasha AS, O'Neil M, Freeman M, Relevo R, et al.  Screening for hepatocellular cancer in chronic liver disease: a systematic review. VA-ESP project no. 05-225. Washington, DC: U.S. Department of Veterans Affairs; 2013.
 
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Viswanathan M, Ansari MT, Berkman ND, Chang S, Hartling L, McPheeters M, et al.  Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; 2012. [PMID: 22479713]
 
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Patient-Centered Outcomes Research Institute.  PCORI Methodology Standards. Washington, DC: Patient-Centered Outcomes Research Institute; 2012.
 
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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. [PMID: 23318478]
 
Trinchet JC, Chaffaut C, Bourcier V, Degos F, Henrion J, Fontaine H, et al; Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire (GRETCH).  Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology. 2011;54:1987-97. [PMID: 22144108]
 
Bolondi L, Sofia S, Siringo S, Gaiani S, Casali A, Zironi G, et al.  Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut. 2001;48:251-9. [PMID: 11156649]
 
Chen TH, Chen CJ, Yen MF, Lu SN, Sun CA, Huang GT, et al.  Ultrasound screening and risk factors for death from hepatocellular carcinoma in a high risk group in Taiwan. Int J Cancer. 2002;98:257-61. [PMID: 11857416]
 
Davila JA, Weston A, Smalley W, El-Serag HB.  Utilization of screening for hepatocellular carcinoma in the United States. J Clin Gastroenterol. 2007;41:777-82. [PMID: 17700427]
 
El-Serag HB, Kramer JR, Chen GJ, Duan Z, Richardson PA, Davila JA.  Effectiveness of AFP and ultrasound tests on hepatocellular carcinoma mortality in HCV-infected patients in the USA. Gut. 2011;60:992-7. [PMID: 21257990]
 
Giannini E, Arzani L, Borro P, Botta F, Fasoli A, Risso D, et al.  Does surveillance for hepatocellular carcinoma in HCV cirrhotic patients improve treatment outcome mainly due to better clinical status at diagnosis? Hepatogastroenterology. 2000;47:1395-8. [PMID: 11100360]
 
Kemp W, Pianko S, Nguyen S, Bailey MJ, Roberts SK.  Survival in hepatocellular carcinoma: impact of screening and etiology of liver disease. J Gastroenterol Hepatol. 2005;20:873-81. [PMID: 15946134]
 
Kuo YH, Lu SN, Chen CL, Cheng YF, Lin CY, Hung CH, et al.  Hepatocellular carcinoma surveillance and appropriate treatment options improve survival for patients with liver cirrhosis. Eur J Cancer. 2010;46:744-51. [PMID: 20060710]
 
Leykum LK, El-Serag HB, Cornell J, Papadopoulos KP.  Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival. Clin Gastroenterol Hepatol. 2007;5:508-12. [PMID: 17382601]
 
Pascual S, Irurzun J, Zapater P, Such J, Sempere L, Carnicer F, et al.  Usefulness of surveillance programmes for early diagnosis of hepatocellular carcinoma in clinical practice. Liver Int. 2008;28:682-9. [PMID: 18433394]
 
Tanaka H, Nouso K, Kobashi H, Kobayashi Y, Nakamura S, Miyake Y, et al.  Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival. Liver Int. 2006;26:543-51. [PMID: 16761998]
 
Taura N, Hamasaki K, Nakao K, Ichikawa T, Nishimura D, Goto T, et al.  Clinical benefits of hepatocellular carcinoma surveillance: a single-center, hospital-based study. Oncol Rep. 2005;14:999-1003. [PMID: 16142364]
 
Tong MJ, Sun HE, Hsien C, Lu DS.  Surveillance for hepatocellular carcinoma improves survival in Asian-American patients with hepatitis B: results from a community-based clinic. Dig Dis Sci. 2010;55:826-35. [PMID: 19960258]
 
Trevisani F, De Notariis S, Rapaccini G, Farinati F, Benvegnù L, Zoli M, et al; Italian Liver Cancer Group.  Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience). Am J Gastroenterol. 2002;97:734-44. [PMID: 11922571]
 
Trevisani F, Cantarini MC, Labate AM, De Notariis S, Rapaccini G, Farinati F, et al; Italian Liver Cancer (ITALICA) group.  Surveillance for hepatocellular carcinoma in elderly Italian patients with cirrhosis: effects on cancer staging and patient survival. Am J Gastroenterol. 2004;99:1470-6. [PMID: 15307862]
 
Wong GL, Wong VW, Tan GM, Ip KI, Lai WK, Li YW, et al.  Surveillance programme for hepatocellular carcinoma improves the survival of patients with chronic viral hepatitis. Liver Int. 2008;28:79-87. [PMID: 17900247]
 
Yu EW, Chie WC, Chen TH.  Does screening or surveillance for primary hepatocellular carcinoma with ultrasonography improve the prognosis of patients? Cancer J. 2004;10:317-25. [PMID: 15530261]
 
Gaba RC, Kallwitz ER, Parvinian A, Bui JT, Von Roenn NM, Berkes JL, et al.  Imaging surveillance and multidisciplinary review improves curative therapy access and survival in HCC patients. Ann Hepatol. 2013;12:766-73. [PMID: 24018494]
 
Cucchetti A, Trevisani F, Pecorelli A, Erroi V, Farinati F, Ciccarese F, et al; for the 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. [PMID: 24717522]
 
Fletcher RH, Fletcher SW, Wagner EH.  Clinical Epidemiology. The Essentials. 2nd ed. Baltimore: Williams & Wilkins; 1988.
 
Silva MA, Hegab B, Hyde C, Guo B, Buckels JA, Mirza DF.  Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2008;57:1592-6. [PMID: 18669577]
 
Chou R.  Imaging Techniques for the Surveillance, Diagnosis, and Staging of Hepatocellular Carcinoma. Evidence-based Practice Center Systematic Review Protocol. Rockville, MD: Agency for Healthcare Research and Quality; 2013. Accessed at http://effectivehealthcare.ahrq.gov/ehc/products/479/1600/Liver-cancer-protocol-130724.pdf on 28 May 2014.
 
Rahman A, Assifi MM, Pedroso FE, Maley WR, Sola JE, Lavu H, et al.  Is resection equivalent to transplantation for early cirrhotic patients with hepatocellular carcinoma? A meta-analysis. J Gastrointest Surg. 2012;16:1897-909. [PMID: 22836922]
 
Asiyanbola B, Chang D, Gleisner AL, Nathan H, Choti MA, Schulick RD, et al.  Operative mortality after hepatic resection: are literature-based rates broadly applicable? J Gastrointest Surg. 2008;12:842-51. [PMID: 18266046]
 
Izzo F, Piccirillo M, Albino V, Palaia R, Belli A, Granata V, et al.  Prospective screening increases the detection of potentially curable hepatocellular carcinoma: results in 8,900 high-risk patients. HPB (Oxford). 2013;15:985-90. [PMID: 23607636]
 
Cottone M, Virdone R, Fusco G, Orlando A, Turri M, Caltagirone M, et al.  Asymptomatic hepatocellular carcinoma in Child's A cirrhosis. A comparison of natural history and surgical treatment. Gastroenterology. 1989;96:1566-71. [PMID: 2469617]
 
Ebara M, Ohto M, Shinagawa T, Sugiura N, Kimura K, Matsutani S, et al.  Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology. 1986;90:289-98. [PMID: 2416627]
 
Sheu JC, Sung JL, Chen DS, Yang PM, Lai MY, Lee CS, et al.  Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology. 1985;89:259-66. [PMID: 2408960]
 
Barbara L, Benzi G, Gaiani S, Fusconi F, Zironi G, Siringo S, et al.  Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology. 1992;16:132-7. [PMID: 1352268]
 
Schlansky B, Chen Y, Austin D, Naugler WE.  Wait list time predicts survival after liver transplantation for hepatocellular carcinoma: a cohort study in the UNOS registry. Hepatology. 2013;58:208A.
 
Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M, et al.  Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology. 1999;29:62-7. [PMID: 9862851]
 
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]
 
Cucchetti A, Cescon M, Erroi V, Pinna AD.  Cost-effectiveness of liver cancer screening. Best Pract Res Clin Gastroenterol. 2013;27:961-72. [PMID: 24182614]
 
Guyatt GH, Norris SL, Schulman S, Hirsh J, Eckman MH, Akl EA, et al; American College of Chest Physicians.  Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:53S-70S. [PMID: 22315256]
 
Moher D, Pham B, Lawson ML, Klassen TP.  The inclusion of reports of randomised trials published in languages other than English in systematic reviews. Health Technol Assess. 2003;7:1-90. [PMID: 14670218]
 

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

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Hepatocellular carcinoma screening: Exceptions deserve patients.
Posted on June 20, 2014
Alain Braillon
Northern Hospital, France
Conflict of Interest: None Declared
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.
The Role of Simulation in Clinical Trials
Posted on July 14, 2014
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
Conflict of Interest: None Declared
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.


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