Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program 

January 2014

Screening for Hepatocellular Cancer

in Chronic Liver Disease:

A Systematic Review

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Portland VA Medical Center

Portland, OR

Devan Kansagara, M.D., M.C.R., Director

Investigators:

Principal Investigators:

Devan Kansagara, M.D., M.C.R.

Janice H. Jou, M.D., M.H.S.

Co-Investigators

Joel Papak, M.D.

Amirala S. Pasha, D.O., M.S.

Maya O’Neil, Ph.D.

Michele Freeman, M.P.H.

Rose Relevo, MLIS, M.S.

Ana Quinones, Ph.D.

Makalapua Motu’apuaka, B.S.

4
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PREFACE

Quality Enhancement Research Initiative’s (QUERI) Evidence-based Synthesis Program 

(ESP) was established to provide timely and accurate syntheses of targeted healthcare topics 

of particular importance to Veterans Affairs (VA) managers and policymakers, as they work to 

improve the health and healthcare of Veterans. The ESP disseminates these reports throughout 

VA.

QUERI provides funding for four ESP Centers and each Center has an active VA affiliation. The 

ESP Centers generate evidence syntheses on important clinical practice topics, and these reports 

help:

• develop clinical policies informed by evidence,

• guide the implementation of effective services to improve patient 

outcomes and to support VA clinical practice guidelines and performance 

measures; and 

• set the direction for future research to address gaps in clinical knowledge.

In 2009, the ESP Coordinating Center was created to expand the capacity of QUERI Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of QUERI field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov.

Recommended citation: 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; 2013.

This report is based on research conducted by the Evidence-based Synthesis Program 

(ESP) Center located at the Portland VA Medical Center, funded by the Department of 

Veterans Affairs, Veterans Health Administration, Office of Research and Development, 

Quality Enhancement Research Initiative. The findings and conclusions in this document 

are those of the author(s) who are responsible for its contents; the findings and conclusions 

do not necessarily represent the views of the Department of Veterans Affairs or the United 

States government. Therefore, no statement in this article should be construed as an 

official position of the Department of Veterans Affairs. No investigators have any affiliations 

or financial involvement (e.g., employment, consultancies, honoraria, stock ownership or 

options, expert testimony, grants or patents received or pending, or royalties) that conflict 

with material presented in the report.
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TABLE OF CONTENTS 

EXECUTIVE SUMMARY .............................................................................................................................. 1

Table. Summary of the evidence on screening for hepatocellular carcinoma in patients with chronic liver 

disease, and treatment in patients with early-stage hepatocellular carcinoma .............................................. 4

BACKGROUND .................................................................................................................................................. 6

METHODS

Data sources and searches............................................................................................................................. 7

Study selection............................................................................................................................................... 7

Data extraction and quality assessment......................................................................................................... 8

Data synthesis and analysis........................................................................................................................... 8

RESULTS

Effects of screening on mortality................................................................................................................... 9

Effects of screening on mortality: RCTs.............................................................................................. 9

Effects of screening on mortality: observational studies................................................................... 11

Harms of screening...................................................................................................................................... 12

HCC screening in VHA............................................................................................................................... 12

Effects of treating HCC detected as a result of screening ........................................................................... 13

Harms associated with treatment of early-stage HCC................................................................................. 14

Current HCC screening guidelines.............................................................................................................. 14

DISCUSSION...................................................................................................................................................... 15

Limitations................................................................................................................................................... 16

Future Studies.............................................................................................................................................. 17

Table 1. Gaps in evidence and recommendations for future research................................................... 18

CONCLUSIONS ................................................................................................................................................ 20

Table 2. Summary of the evidence on screening for hepatocellular carcinoma in patients with 

chronic liver disease, and treatment in patients with early-stage hepatocellular carcinoma ... 21

REFERENCES ................................................................................................................................................... 23

APPENDIX A. Search Strategy .............................................................................................................. 30

APPENDIX B. Figures

Figure 1. Analytic framework................................................................................................................. 32

Figure 2. Literature flow diagram........................................................................................................... 33

Figure 3. Median survival in cohort studies of HCC patients diagnosed through screening 

programs compared with non-screening ................................................................................. 34

APPENDIX C. Inclusion/Exclusion Criteria .................................................................................... 35
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APPENDIX D. Tables

Table 1. Randomized trials of hepatocellular carcinoma screening in patients with chronic 

liver disease ............................................................................................................................. 37

Table 2. Assessment of study methods for potential sources of bias in randomized trials of 

hepatocellular carcinoma screening......................................................................................... 38

Table 3. Cohort studies of screening for hepatocellular carcinoma in patients with chronic 

liver disease ............................................................................................................................. 39

Table 4. Assessment of study methods for potential sources of bias in cohort studies of screening 

for hepatocellular carcinoma in patients with chronic liver disease........................................ 43

Table 5. Randomized controlled trials comparing TACE to supportive care in patients with 

hepatocellular carcinoma......................................................................................................... 45

Table 6. Assessment of study methods for potential sources of bias in randomized trials of 

TACE in patients with early stage hepatocellular carcinoma.................................................. 46

Table 7. Cohort studies comparing resection, RFA, TACE, and OLT to supportive care in 

patients with hepatocellular carcinoma ................................................................................... 47

Table 8. Assessment of study methods for potential sources of bias in cohort studies of 

resection, OLT, RFA, and TACE in patients with hepatocellular carcinoma .......................... 49

Table 9. Non-comparative observational studies of OLT, RFA, and TACE in patients with 

hepatocellular carcinoma......................................................................................................... 50

Table 10. Summary of AASLD, APASL, and EASL-EORTC guidelines for screening for 

hepatocellular carcinoma......................................................................................................... 51

Table 11. AGREE II quality assessment of guidelines for screening for hepatocellular 

carcinoma ................................................................................................................................ 52

APPENDIX E. Peer Review Comments and Responses .................................................................. 53
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EVIDENCE REPORT

BACKGROUND

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer related death among men 

and ninth leading cause of cancer related death among women in the United States.1,2 Chronic 

hepatitis B, common in Asia, is associated with HCC even in the absence of cirrhosis because of 

direct oncogenic properties of the virus. In Western countries, on the other hand, cirrhosis, most 

commonly from chronic hepatitis C infection and alcoholic liver disease, is the predominant risk 

factor for the development of HCC.3 In the Veterans Health Administration (VHA), there has 

been a marked increase in the prevalence of cirrhosis from chronic hepatitis C infection with a 

corresponding increase in the number of HCC diagnoses. From 1996 to 2006, the prevalence 

of cirrhosis among Veterans with chronic hepatitis C infection rose from 9-18.5%, and the 

prevalence of HCC rose from 0.07-1.3%.4

 In the general population, the incidence of HCC rose 

between 1992 and 2005 from 3.1/100,000 to 5.1/100,000, with localized tumors accounting for 

most of the increase.5

 While on average the 5-year survival of HCC is low (13-16.5%),5,6 the 

survival of early-stage disease has risen.5

The rationale for screening is that imaging tests such as ultrasound can identify patients with 

early stage HCC7 and there are several potentially curative treatment options for patients with 

early stage HCC including liver transplantation, radiofrequency ablation, and liver resection.8

Several professional society guidelines currently recommend HCC screening using imaging 

studies and tumor markers, mainly in patients with chronic hepatitis B or liver cirrhosis.8-10

However, recommendations for HCC screening remain controversial in part because of concerns 

over the quality and paucity of existing evidence, and because there have been concerns raised 

about overdiagnosis and patient harms in other cancer screening programs.11-15

We conducted a systematic review of the published literature to better understand the incremental 

benefits and harms of routine HCC screening in patients with chronic liver disease compared to 

clinical or incidental diagnosis. We looked for direct evidence of the health outcome effects of 

screening. We also looked for indirect evidence of the effects of screening by evaluating studies 

examining the health outcome benefits and harms of treating early-stage HCC which, because 

the intent and result of routine screening is detection of early-stage disease, is a proxy for screendetected disease. 
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METHODS

DATA SOURCES AND SEARCHES 

We conducted a search for literature published in Medline, PsycInfo, the Cochrane Central 

Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from database 

inception to March 2013. The search strategy included terms for HCC, screening/screening, 

treatment modalities, and adverse effects including psychological harms of screening/screening. 

The detailed search strategy is provided in Appendix A. We obtained additional articles from 

systematic reviews, reference lists of pertinent studies, reviews, editorials, and by consulting 

experts. We also searched for ongoing and recently completed studies on ClinicalTrials.gov. 

STUDY SELECTION

This review was commissioned by the VHA Oncology Program Office and the VHA HIV, 

Hepatitis and Public Health Pathogen Program. A protocol describing the review plan was 

posted to a publicly accessible website before the study was initiated.16 The analytic framework 

and key questions which guided this review were developed in conjunction with a panel of VA 

and non-VA technical experts and are provided in Appendix B, Figure 1. Detailed inclusion and 

exclusion criteria are provided in Appendix C. We used a “best-evidence” approach to guide 

study design criteria depending on the question under consideration and the literature available.17

We prioritized controlled clinical trials, then comparative observational studies, then large cohort 

studies. To assess the effects of screening on HCC-specific and all-cause mortality, we included 

clinical trials and observational studies providing primary data in adult populations. We use the 

term “screening” to refer to any program in which tests – including ultrasonography, computed 

tomography, magnetic resonance imaging, and/or alpha-fetoprotein levels – were done explicitly 

to look for HCC in asymptomatic patients. Studies had to include a contemporary comparison 

group of patients who did not undergo screening and had testing done only to evaluate 

symptoms. We excluded observational studies that did not account for basic confounding factors 

such as age, sex, and liver disease severity. Because we anticipated few clinical trials comparing 

screening to 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. To assess the harms of screening, we abstracted any 

reported adverse effects data from studies included from the above search. We also additionally 

searched for trials or observational studies focused on potential harms of HCC screening.

To assess the benefits and harms of treating HCC found as a result of screening, we included 

trials or large prospective cohort studies examining the effects of liver resection, transplant, 

radiofrequency ablation, transarterial chemoembolization, or sorafenib, compared to no treatment 

in patients with early stage HCC (defined as the equivalent of Barcelona Clinic Liver Cancer 

(BCLC) Stage A, or early-stage HCC by the Milan criteria).18,19 We included studies with 

mixed populations of patients with early and advanced disease, but not studies including only 

patients with advanced disease. Because comparative effectiveness studies would not directly 

address the incremental effects of screening or treating screen-detected disease, we excluded 

studies comparing 2 or more active treatments without an untreated control group. We found 
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no trials and only a small number of comparative observational studies of liver resection, 

transplantation, and radiofrequency ablation, so we included non-comparative cohort studies of 

these interventions if they included consecutive patients with adequate long-term follow-up and, 

in the case of OLT for which several large cohorts were available, large sample size (n > 500). 

We prioritized systematic reviews of such studies if available. 

In order to better understand the quality and content of existing recommendations guiding the 

practice of HCC screening, we systematically searched for HCC screening guidelines. Among 

published guidelines, we identified the 3 most widely disseminated guidelines representing 

distinct geographic areas including North America,8

 Europe,9 and Asia.10

Seven investigators reviewed the titles and abstracts of citations identified from literature 

searches, and 2 reviewers independently assessed the selected full-text articles for inclusion 

based on the eligibility criteria shown in Appendix C. 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/ethnicity, liver disease etiology and severity), subject eligibility and 

exclusion criteria, number of subjects, years of enrollment, mode 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 using a tool developed by the 

Cochrane Collaboration.20 Disagreements were resolved through discussion. Each study was 

given an overall summary assessment of low, high, or unclear risk of bias. We graded the 

strength of evidence for outcomes using published criteria which consider the consistency, 

coherence, and applicability of a body of evidence, as well as the internal validity of individual 

studies.21

Though there is no widely accepted standard for quality assessment of observational studies, we 

adapted existing assessment tools.22,23 For the observational screening studies, we additionally 

adapted causal inference criteria24 relevant to this review and specifically assessed: 1) methods 

for ascertaining screening status, and 2) use of an inception cohort. We do not report an overall 

summary assessment for observational studies because there are no validated criteria for doing 

so.

We assessed the quality of published guidelines using the AGREE framework.25

DATA SYNTHESIS AND ANALYSIS 

We did not perform meta-analyses of screening or treatment interventions because of the 

dearth of trial data and the clinical heterogeneity among the small number of trials. Rather, we 

qualitatively synthesized the results of trials and observational studies. 
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RESULTS

We reviewed 11,321 titles and abstracts, including 10,996 from the electronic search and an 

additional 325 from reviewing reference lists and performing manual searches for recently 

published and unpublished or ongoing studies (Appendix B, Figure 2). After applying inclusion/

exclusion criteria at the abstract level, 264 full-text articles were reviewed. Thirty-five primary 

studies contained primary data relevant to the efficacy of HCC screening or treatment of earlystage HCC and met our inclusion criteria. We also included 2 systematic reviews of providing 

evidence on harms of treatment modalities.26,27

EFFECTS OF SCREENING ON MORTALITY

Two trials and 16 observational studies provided very low strength evidence from which to draw 

conclusions about the mortality effects of HCC screening compared to no screening. The trials 

had substantial methodologic flaws that threaten their internal validity, and their applicability 

was limited to the hepatitis B population. The observational studies, which mainly included 

patients with HBV, HCV, and/or alcoholic liver disease, showed that screening detects patients 

with earlier stage disease, more of whom undergo potentially curative therapy. However, it 

is impossible to say whether the longer survival in screen-detected patients is a true effect of 

screening or, rather, reflects lead- and length-time biases inherent to all observational studies, and 

selection biases which were common in many of the studies. 

Effects of screening on mortality: Randomized controlled trials

Two trials, both conducted in China, compared the effects of screening to no screening on 

mortality among participants mainly with hepatitis B (Appendix D, Table 1).28,29 One trial 

used a cluster-randomized design to assign factories, business, and schools to screening or no 

screening groups. Screening group participants (n = 9,757) were offered serum AFP testing and 

ultrasonography every 6 months. The control group (n = 9,443) was not made aware of the study 

or actively followed. Information on HCC development and mortality was based on physician 

reporting and a cancer registry, though there were no details reported about registry development. 

The primary outcome of HCC mortality occurred less frequently in the screening group 

(83.2/100,000 person-years vs 131.5/100,000 person-years; rate ratio 0.63, 95% CI 0.41-0.98). 

The trial, however, carries a high risk of bias because of several serious methodological 

limitations (Appendix D, Table 2). One major concern is whether the baseline groups had 

the same risk of HCC. There is no information about randomization technique or allocation 

concealment, and very little information about the baseline characteristics of the 2 groups. In 

cluster-randomized trials, in which patients are assigned to treatments based on where they live 

or work, it is important to know whether the underlying populations are similar in socioeconomic 

status, the incidence of other diseases, and overall mortality. Another concern is that weak 

methods used to ascertain the outcome measure – death from HCC – could have introduced 

bias. Outcome ascertainment depended on physician report, but there was no systematic effort 

described to ensure complete and equal outcome reporting nor was there any information about 

the cancer registry or about the proportion of patients for whom survival data was available. 

If deaths were under-reported in the control group, results could have been biased towards the 
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null. On the other hand, if outcome adjudicators were not blinded, more control group deaths 

could have been misclassified as HCC-related, especially because the symptoms that define stage 

III HCC (cachexia, jaundice, ascites) overlap substantially with symptoms of end-stage liver 

disease and there was no data provided about liver disease severity in either group. Selective 

reporting and analysis of favorable outcomes was another concern. Though the authors report 

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 the 

US wherein cirrhosis, most often from hepatitis C, is the most common risk factor for HCC, and 

there is probably limited applicability for these results to contemporary practice, in which the 

threshold for imaging for symptoms may be lower and the number of patients with incidentallydiscovered HCC on imaging is higher.

The second trial used patient-level randomization stratified by township to assign hepatitis B 

patients to the screening intervention (n = 3,712), which consisted of serial AFP tests followed 

by ultrasound for high AFP values, or the usual care group (n = 1,869).29

 Cancer diagnoses 

were available in a population-based cancer registry which used active case finding techniques, 

and mortality was ascertained through the cancer registry and a population-based vital status 

registry. Cancer staging using the same Chinese staging system was done by personnel blinded 

to intervention status. Only 28.8% of screening-group participants completed all scheduled 

testing, but all participants completed at least one screening test. There were fewer Stage III 

HCC in the screening group (19.8 vs 41.0%, p = NR). HCC mortality was similar in both 

groups (1,138/100,000 person-years vs 1114/100,000 person-years, p = 0.86), as was all-cause 

mortality (1,843/100,000 person-years vs 1,788/100,000 person-years, p = NS). This trial carried 

an unclear risk of bias because of poor reporting of randomization and allocation concealment 

techniques. 

Two additional trials compared different ultrasound screening intervals.30,31 One found no 

survival advantage comparing 4-month to 12-month ultrasound screening intervals in patients 

with serologic evidence of hepatitis B or C.30 About one-third of patients in both groups had liver 

cirrhosis. Systematic ultrasound exams were performed by trained hepatologists and all patients 

with new nodules ≥ 1 cm were referred for further follow-up. More patients in the 4-month 

interval group had new liver nodules (11.9 vs 7.8%, p = 0.049), but the 3-year cumulative 

incidence of HCC was similar in both groups (11.7 vs 9.7%, p = 0.198). Although screening 

every 4 months identified more patients with ≤ 2 cm HCC (70.8 vs 20.0%, p = 0.006) and 

more patients with HCC in the 4-month interval group underwent resection or radiofrequency 

ablation treatment (54.2 vs 20%, p = 0.049), the 1-, 2-, and 4-year survival rates among patients 

with HCC were similar (95.8/78.8/57.4% vs 80/64/56%, p = 0.399). The trial used clustered 

randomization and carried an unclear risk of bias because of poor reporting of outcome 

assessment and statistical analyses. 

A trial with low risk-of-bias compared 3-month to 6-month ultrasound screening intervals in 

1,278 patients with cirrhosis from alcohol use and/or viral hepatitis and found similar all-cause 

mortality rates in both groups (11.3 vs 12.1%, p = 0.38).31

 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). 
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Effects of screening on mortality: Observational studies 

We included 16 observational studies which compared survival in patients with HCC diagnosed 

with screening to HCC diagnosed incidentally as part of another work-up or because of 

symptoms (Appendix D, Table 3).32-47

Studies represented a range of geographic settings including Asia (6 studies), Europe (5 studies), 

Australia (1 study), and the US (4 studies, of which 3 were conducted in the VA). The vast majority 

of patients included in these studies had hepatitis B or C with Child-Pugh class A or B cirrhosis, 

though in many studies, liver disease severity was significantly higher in the non-screening groups. 

Ultrasound with or without AFP measurement was the screening method used in nearly all studies, 

except for 2 US studies in which a small number of patients underwent CT.34,39 

In general, patients who had undergone screening had earlier stage HCC than those who had HCC 

diagnosed incidentally or due to symptoms (% range meeting equivalent of Milan criteria: 60.0-100 

vs 19.6-56.5 in 10 studies). More screen-detected patients received potentially curative treatment, 

though only a small proportion of screening group patients underwent hepatic resection (range 2.8-

23.9% in 12 studies,32,34,36-39,41-46 and 53.5% in one outlier study47

) or liver transplantation (1-15% in 

5 studies,36,39,40,44,46 and 26-30.1% in 2 other studies).32,43 Survival from the time of HCC diagnosis 

was generally higher among screening group patients than non-screening group patients (Appendix 

D, Table 3). Median survival ranged among studies from 12-56 months in the screening group, 

and from 3-37 months in the non-screening group (Appendix B, Figure 3). Three-year survival 

ranged from 22-67% in the screening group, and from 15-51 percent in the non-screening group. 

Unadjusted mortality risk was significantly lower in the screening group in some studies35,38,39,47

although this survival advantage was not statistically significant in one study.33

 

Three of the observational studies reported objective and replicable methods for distinguishing 

screening from non-screening patients, and had comparatively fewer issues with selection bias 

by drawing patients from the VA – a single, large integrated health system.34,35,39 The largest of 

these used the national VA HCV clinical case registry to identify 1,480 HCC patients, and was 

the only study to assess survival from the time at-risk for HCC (in this case, the HCV diagnosis 

date), rather than from the date of HCC diagnosis.35 Patients who had had screening done 

both 0-6 months and 7-24 months prior to HCC diagnosis had modestly longer survival than 

those with no screening (median survival from HCV diagnosis 1,951 vs 1,782 days; HR=0.82; 

95% CI: 0.72-0.95). Those with screening in either, but not both, time periods had similar 

survival as those with no screening. In models adjusted for lead-time, the survival advantage 

of recurrent screening was attenuated with longer lead-time assumptions. The other 2 studies 

were also conducted in VA and included patients with HCV and HCC. One of the studies found 

that screening was not associated with improved survival, but rates of screening were low and 

cited as a possible reason for the lack of observed survival effect.34

 The other study found HCC 

screening was not associated with improved survival, though receipt of potentially curative 

therapy was associated with improved survival.39

Overall, there are several methodologic considerations which temper the confidence with which 

one can draw conclusions from the body of observational literature (Appendix D, Table 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 
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reported data about loss to follow-up, and many studies did not report using a comprehensive 

method to assess mortality outcomes equally in screening and non-screening groups. In most 

studies, the comparison group was drawn from a referral population and there are likely 

unmeasured patient, treatment, health care access and other factors that are different between 

groups. Even in the VHA studies in which all patients are part of the same health system, most 

screen-detected patients were followed by hepatologists and it is possible that co-interventions 

unrelated to HCC treatment differed between groups.

In addition to the methodologic issues specific to individual studies detailed in Appendix 

D, Tables 2 and 4, the potential for lead-time bias, in which the “lead-time” between cancer 

diagnosis in screened and unscreened groups adds to the apparent survival advantage, is inherent 

in any observational study of screening effects.48 Though there is no infallible way to circumvent 

the threat of lead-time bias other than the conduct of a well-designed RCT, 4 studies used 

statistical techniques to adjust for lead-time bias.35,41,43,46 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 the survival advantage for screening patients disappeared when 

the tumor doubling time was assumed to be 90-120 days or longer.35,41,46 A fourth study used 

serial ultrasound data from 13 patients to estimate a tumor doubling time of 216 days, though 

survival among screening patients remained higher even after adjusting for lead-time.43

Of note, length-time bias, in which screening identifies patients with slower growing tumors, 

may complicate lead-time estimates. 

HARMS OF SCREENING

Potential harms of screening can relate to the physical effects of the screening tests themselves, 

to testing triggered by a positive screening test, or to the psychologic effects of having a positive 

screening test. None of the included studies reported harms of screening, but the direct physical 

harms of HCC screening using ultrasound and/or AFP – which were the most commonly studied 

screening modalities - are likely to be minimal. However, most patients with positive screening 

ultrasound and/or AFP undergo further confirmatory testing. In most of the studies, confirmatory 

testing was done with CT and, less commonly, with MRI or liver biopsy, though very few studies 

reported rates of actual testing used for diagnosis. In 2 studies, HCC diagnosis was based on 

biopsy in 33-80.3% of cases.32,39 One meta-analysis of 8 studies found the risk of needle track 

seeding from liver biopsy done for work-up of HCC to be 2.7%.26

 One single-center study 

published after this meta-analysis found 0.12% of patients experienced needle track seeding.49

One recent systematic review of the diagnostic accuracy of imaging for HCC screening and 

diagnosis found very few studies reporting harms data: one study found contrast-enhanced CT 

was associated with adverse events in 13-15% of patients, while another found mild-moderate 

adverse events in 25% patients receiving gadoxetic acid-enhanced MRI.50 We found no studies 

evaluating the psychologic harms of screening.

HCC SCREENING IN VHA

Three observational studies, all comparing outcomes in patients with screen-detected HCC 

to those incidentally diagnosed, were conducted in the VHA; the results are summarized 
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above.34,35,39 The bulk of the remaining screening literature is less directly applicable to VA, 

where HCV cirrhosis is the major risk factor for HCC. The screening trials included only patients 

with HBV. While many of the remaining observational studies included subgroups with HCV, 

subgroup-specific data were not available (Appendix D, Table 3).

Studies suggest the practice of HCC screening in VA is inconsistent. The VA HCV Clinical 

Case Registry study of 1480 HCV-infected patients with HCC found that, though the vast 

majority had received one AFP test (89%) or ultrasound exam (78%) between HCV and HCC 

diagnoses, only 21.2% of the ultrasounds were classified as screening tests and about one-third 

of patients (34.4%) had received annual testing in the 2 years prior to HCC diagnosis.35

 The 

other 2 VA studies examined patients at 1-3 VA centers and similarly found low rates of routine 

screening.34,39

Another VHA HCV Clinical Case Registry study examining screening practices found that, of 

the 10.1% of HCV-infected Veterans with cirrhosis, 42% received at least one screening US 

or AFP test in the first year after diagnosis of cirrhosis.51 However, an additional 30% of these 

patients had had one of these tests done for reasons other than screening in the same time frame. 

Rates of screening declined in each year after cirrhosis diagnosis, and several clinical factors 

such as higher comorbidity burden, more advanced liver disease, and higher rates of alcohol use 

were associated with lower use of screening. On the other hand, nearly 30% of HCV patients 

without cirrhosis received a screening test the year following HCV diagnosis. 

In contrast to the inconsistent observed use of screening in VHA, a majority (71%) of VHA 

providers reported recommending HCC screening in a recent survey.52 Providers specializing in 

the care of patients with liver disease, and those practicing at centers where HCC treatment was 

readily available were more likely to report recommending HCC screening.

EFFECTS OF TREATING HCC DETECTED AS A RESULT OF 

SCREENING

No studies specifically enrolled patients with screen-detected HCC, so we examined studies of 

patients with early-stage HCC as a way of approximating screen-detected disease. Overall, there 

is little evidence with which to draw conclusions about the net benefits of actively treating earlystage HCC compared to conservative treatment. The few trials comparing active to conservative 

treatment of early stage HCC examined TACE. Observational studies do show that patients 

selected for treatment with OLT, resection, or RFA had good long-term survival, which was 

substantially higher than patients not selected for such therapy, but it is unclear whether such 

effects reflect a true effect of treatment or reflect confounding by indication. 

Three clinical trials that included patients with early-stage HCC compared TACE to conservative 

treatment, but these studies were limited by small sample size and lack of subgroup information 

specific to patients with early-stage disease (Appendix D, Tables 5-6). Low strength evidence 

from 2 trials found no survival benefit from TACE in patients with alcoholic liver disease. One 

of these was a multicenter trial with low risk of bias which was stopped early for futility after 

enrolling 96 patients,53

 and the other was a smaller study with unclear risk of bias of 42 patients 

in France.54 Low strength evidence from one trial with unclear risk of bias, about half of whom 
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had early-stage HCC, found TACE was associated with improved survival in HBV patients (RR 

0.49; 95% CI 0.29-0.81).55

 We excluded a fourth trial because it included only patients with 

advanced HCC.56

Low strength evidence from one large cohort study of patients with early-stage HCC found lower 

mortality among those that had undergone resection compared to those treated conservatively, 

after adjusting for tumor size and basic demographic characteristics (adjusted HR 0.45; 95% CI 

0.34-0.59, p < 0.01).57 The 4 other comparative observational studies were difficult to interpret 

because they compared more than one treatment across heterogeneous groups of patients 

with early- and late-stage disease (Appendix D, Tables 7-8). However, many patients selected 

for treatment had good long-term (4- or 5-year) survival: 53-73% for OLT,58-61 33-75% for 

resection,57,62 and 27-77% for RFA.58,62-64

HARMS ASSOCIATED WITH TREATMENT OF EARLY-STAGE HCC

Serious harms occurred in 1.8-20% of patients, depending on the intervention (Appendix 

D, Tables 5, 7, and 9). Across the 3 trials examining the effects of TACE, 8-20% of patients 

experienced serious treatment related complications though it is unclear what proportion of 

these patients had early- versus late-stage disease. A systematic review of 23 studies found an 

aggregate perioperative mortality rate among 3,366 patients undergoing resection of 4%.27

One single-center cohort study of 1,031 consecutive patients found 3.2% of patients developed 

needle-track seeding after undergoing RFA for HCC.65 Two single-center cohort studies found 

serious complications in 1.8-9.9% of patients including peritoneal bleeding, hemothorax, and 

portal vein thrombosis.63,66 Harms of OLT were not well-reported. 

CURRENT HCC SCREENING GUIDELINES

We found 26 guidelines addressing HCC screening. We focused on the 3 most widely 

disseminated guidelines representing North America, Europe, and Asia (see Appendix D, 

Table 10 for a summary of the screening recommendations from the 3 guidelines). All 3 

recommend that those at high risk for HCC should be routinely screened every 6 months by 

US (AASLD & EASL)8,9 or by US and AFP (APASL).10 The 3 guidelines provide different 

specific recommendations about high risk groups and screening schedules based on initially 

positive screening results. We critically appraised the guidelines using the AGREE II framework 

and identified several methodological flaws (Appendix D, Table 11 describes the AGREE II 

ratings for each guideline). None of the guidelines reported a systematic review of the literature 

and none reported critically appraising included studies to assess their internal validity. The 

guidelines lacked a description of the strengths and weaknesses of the overall body of evidence 

and, rather, cited levels of evidence based simply on study design (Level I evidence based on 

RCT in the case AASLD, level 2a evidence based on consistent evidence from cohort studies in 

the case of APASL) or did not define the level of evidence (EASL). Each of the guidelines cited 

the Zhang 2004 trial as the major source of evidence supporting recommendations, though, as we 

describe above, the methodologic flaws of this trial and many of the observational studies limit 

their internal validity which, in turn, weakens the strength of evidence. 
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DISCUSSION

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 

ultrasound and/or alpha-fetoprotein testing have been the most commonly evaluated screening 

modalities. Patients with viral hepatitis have been the most frequently studied populations. 

Although screening identifies patients with early-stage HCC and some patients with early-stage 

HCC selected for curative therapy do well, there is very low strength evidence from which to 

draw conclusions about the balance of benefits and harms of screening for HCC and treating 

HCC found as a result of screening across a population of patients. 

The body of evidence was limited in part by the paucity and substantial methodologic 

shortcomings of screening trials. Indeed, the one large-scale trial conducted among hepatitis B 

infected patients in China that serves as the primary evidence base for these recommendations 

has serious methodologic limitations which undermine the validity of its findings.28

 The other 

trial found serial AFP screening offered no survival advantage.29

 Limited applicability, because 

of more widespread imaging use, higher rates of incidental diagnosis, and a smaller proportion of 

patients whose main risk is hepatitis B, further diminish the strength of evidence.

Though we found a large body of observational studies, they did not substantively add to the 

strength of evidence. Most were single center studies retrospectively evaluating patients with 

HCC and had several methodologic flaws, in addition to lead- and length-time biases. Four 

studies attempted to account for lead-time bias and 3 of them found, in doing so, that the 

survival advantage of screening was greatly attenuated. However, estimates of lead-time bias are 

uncertain at best in part because there are few data available about the natural history of earlystage or screen-detected HCC from which to estimate tumor doubling times. The small amount 

of information that does exist comes from older studies that suggest tumor growth patterns can 

differ markedly among patients, with some patients exhibiting steady growth, others no growth 

followed by a period of rapid growth, and others still with little to no long-term growth.67-70

Another study of a mixed population of patients with early- and late-stage disease randomized 

to no treatment in 2 trials found 2 very different survival patterns depending on the presence or 

absence of an invasive tumor pattern and poor performance status (8 vs 50% 3-year survival, 

p=0.00010).71

Potentially curative treatments for HCC such as liver transplant and resection exist, but have 

the potential for substantial perioperative morbidity and mortality. Trials comparing screening 

intervals show that most of the HCC identified as a result of periodic screening were small, 

early-stage HCC.30,31 If many of the HCC found as a result of routine screening would progress 

and cause morbidity before patients’ underlying illness did, then the net balance of benefits and 

harms might favor widespread screening. If, on the other hand, HCC identified as a result of 

screening were more indolent, then the risks of treating disease that would not have otherwise 

been clinically relevant (ie, overdiagnosed HCC) might tip the balance away from routine 

screening. Unfortunately, we found no evidence examining rates of overdiagnosis. Many HCC 

are diagnosed with imaging alone, in part because of concerns over the risks of liver biopsy. 

The accuracy of such diagnoses – and the corresponding risk of overtreatment – may also 

be important considerations in evaluating the balance of benefits and harms of screening. A 
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forthcoming systematic review examining the diagnostic accuracy of imaging tests for HCC 

should help address this knowledge gap.72

Most patients with HCC diagnosed with screening had smaller tumors that would be potentially 

amenable to curative therapies such as resection or liver transplantation. Cohort studies suggest 

that long-term survival of patients undergoing liver resection or transplantation for HCC is 

quite high, but such treatments may be associated with substantial perioperative morbidity and 

mortality.27,73 Whether there is a net benefit from aggressive treatment of all early stage HCC is 

unclear from current data. We found little trial data focused on early-stage HCC treatment, and 

reporting of harms was inconsistent. The reasons why patients were not selected for surgical 

therapy are not clear. If there were random variations in patient selection practices, then the 

observational studies showing that surgically treated patients had markedly increased survival 

compared to nonsurgically treated patients would be quite compelling. If, on the other hand, 

patient factors such as comorbidity burden, performance status, and social determinants of health 

were the main considerations in influencing the decision to undergo treatment then the potential 

for confounding may be considerable. A recent US study found that tumor stage and performance 

status were the factors associated with receipt of curative therapy.74

 There is also emerging 

evidence that the waiting period for OLT selects patients with more indolent HCC, since patients 

with more aggressive disease lose candidacy while awaiting transplant.75

We found few other systematic reviews examining HCC screening studies. A recent Cochrane 

review similarly found insufficient evidence for screening, but focused only on studies of HBV

patients and did not examine observational studies.14

 Several widely disseminated guidelines 

recommend HCC screening in high-risk patients with liver disease,8-10 but none used a systematic 

review which critically appraised included studies as a basis for the recommendations. Other 

systematic reviews have evaluated HCC treatment trials but, apart from the TACE trials 

discussed above, they included trials of patients with late-stage HCC.76,77

Our finding that the strength of published evidence examining HCC screening is very low 

neither supports nor refutes current clinical policy recommendations for HCC screening. 

Transparency about the strength of evidence on which these recommendations are based is 

important, but policy recommendations also take into account other factors such as patient values 

and preferences, expert opinion, and cost considerations.78 It is likely to be the case that there is 

variation in the natural history of screen-detected HCC. Additional information clarifying natural 

history patterns and ways of distinguishing patients with more aggressive tumors from those with 

more indolent tumors might facilitate patient selection practices that would optimize the benefits 

of screening while minimizing the risks of overdiagnosis. 

LIMITATIONS

One limitation of our review was the exclusion of articles whose full-text was not in English. 

However, we mitigated the risk of missing relevant studies by searching multiple databases, 

bibliographies, speaking with experts, and searching trial registries. Moreover, there is evidence 

to suggest that language restrictions do not bias results of reviews of conventional therapies.79

Our focus on studies comparing active treatment to conservative management admittedly may 

have missed important effects of current treatments for HCC, since many have been evaluated in 
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the context of comparative effectiveness studies. However, a comparative effectiveness review 

of current treatments for HCC was beyond the scope of our review and would not have provided 

direct evidence about the utility of treating screen-detected HCC. Also, we did include systematic 

reviews of current treatments as a way to broaden our understanding of the benefits and harms 

of current therapies. We excluded studies of patients with advanced stage HCC so our findings 

apply only to patients with early stage disease. While it is possible that screening would identify 

some patients with advanced stage disease, the incremental effects of routine screening compared 

to clinical or incidental diagnosis would mainly be to increase the number of early stage HCC 

detected. 

FUTURE STUDIES

Overall, we found little high-quality direct evidence from which to draw conclusions about the 

balance of benefits and harms of routine HCC screening. There are a number of opportunities 

for further study and it is likely, given the current insufficient body of evidence, that future 

studies will have a substantial impact on the strength of evidence. The key evidence gaps and 

suggestions for corresponding future research opportunities are summarized in Table 1. 

The current body of published evidence does not, in and of itself, appear to constitute a threat 

to clinical equipoise over the health outcome effects of HCC screening. Experts have, however, 

raised other concerns about the ethics and feasibility of conducting such a study. The research 

and health care community should continue discussions about the feasibility and equipoise of an 

HCC screening trial. 

Research to more definitively evaluate the balance of benefits and harms of treating early 

stage HCC is imperative. Even in the absence of randomized controlled trials of screening, 

observational studies using well-designed registries of HCC patients, their treatments, 

complication rates, and long-term outcomes could prove useful. These registries should include 

consecutive patients and prospectively collect clinical information about potential adverse effects 

over time. Studies examining the psychologic impact of screening are also needed. 

Imaging tests can clearly identify small, early-stage HCCs. Future studies should evaluate the 

contemporary natural history of such lesions and consideration should be given to treatment trials 

that include a watchful waiting arm for very early HCC. 
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Table 1. Gaps in evidence and recommendations for future research

Topic Evidence gap Potential future research

Screening

No methodologically sound trials 

have examined the effects of 

screening on health outcomes in 

patients with chronic liver disease.

Trials examining the health outcome 

effects of screening should be considered, 

including patients with hepatitis B, hepatitis 

C, and other forms of chronic liver disease. 

The feasibility of conducting 

randomized trials of screening in 

patients with chronic liver disease 

has been questioned. 

Future studies should evaluate public 

willingness to participate in screening 

studies based on available evidence in the 

US and including patients with hepatitis C. 

Observational studies are 

limited by selection bias, limited 

generalizability (mostly singlecenter), retrospective design, and 

inability to identify time at risk for 

HCC.

Large registries of patients with chronic liver 

disease, with prospective recording of date 

of diagnosis of chronic liver disease, date 

of cirrhosis diagnosis, screening practice, 

imaging findings, HCC diagnosis, and 

treatment received. 

The contemporary natural history 

of early-stage HCC detected 

by imaging tests is not well 

understood. 

Prospective cohort studies examining the 

growth patterns of small (< 2 cm) liver 

lesions suspicious for HCC should be 

considered. Studies would ideally examine 

and compare independent interpretations of 

serial imaging studies. 

The harms of screening have not 

been well-explored. 

Studies examining the psychologic effects 

of screening (anxiety, depression) should 

be considered. Registry studies should 

include information about the cost of initial 

screening as well as the rates of repeat 

imaging required for initial positive results 

and associated resource use and harms. 

Current guidelines recommend 

6 month screening intervals. 

Two trials demonstrate that 3- or 

4-month screening intervals are not 

associated with benefit compared 

to 12-month intervals. However, no 

trials have compared 6 to 12 month 

screening intervals.

Trials comparing 6 to 12 month screening 

intervals should be considered. 

Treatment

Overall The benefits and harms of treating 

very early stage HCC compared 

to a watchful waiting strategy are 

unknown. 

Trials comparing various treatment 

strategies to watchful waiting for very early 

stage HCC should be considered. 

TACE Trials of TACE have included 

mixed populations with early and 

late stage disease. Trials have 

been small and have not included 

patients with hepatitis C. 

Trials examining the effects of TACE on 

health outcomes in patients with early-stage 

HCC should be considered. Trials should 

include patients with hepatitis C. 
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Topic Evidence gap Potential future research

RFA No trials have examined the 

health outcome effects of RFA. 

Observational studies are limited 

by biases such as confounding by 

indication. 

Trials comparing RFA to conservative 

treatment in patients with early stage 

disease may be considered. In the 

absence of such trials, prospective cohort 

studies using well-designed registries 

of patients with chronic liver disease 

should be conducted, using techniques 

such as propensity scoring to control for 

confounding factors related to patient 

selection. Rates of needle-track seeding 

and other complications should be 

examined in these prospective studies. 

OLT No trials have examined the 

benefits and harms of OLT for 

patients with HCC compared to 

conservative treatment. Harms 

associated with OLT for HCC 

have not been well reported in 

observational studies. 

Prospective cohort studies using welldesigned registries of patients with chronic 

liver disease should be conducted, using 

techniques such as propensity scoring to 

control for confounding factors related to 

patient selection. Rates of perioperative 

morbidity and mortality, as well as 

longer-term harms such as infectious 

complications should be examined in 

prospective studies. 

Resection No trials have examined the 

benefits and harms of resection 

for patients with HCC compared 

to conservative treatment. One 

observational study did attempt 

to control for patient selection 

factors and found resection was 

associated with lower mortality, 

but did not explicitly account for 

some important confounding 

factors such as patient comorbidity 

and performance status. While 

perioperative mortality had been 

well-examined, most of the data are 

over a decade old and applicability 

to current practice is unclear. 

Prospective cohort studies using welldesigned registries of patients with chronic 

liver disease should be conducted, using 

techniques such as propensity scoring to 

control for confounding factors related to 

patient selection. Rates of perioperative 

morbidity and mortality, as well as longerterm harms should be examined in 

contemporary prospective studies.

Sorafenib No trials have examined the 

benefits and harms of sorafenib in 

patients with early stage HCC. 

Trials and prospective cohort studies of 

sorafenib in patients with early-stage HCC 

should be considered. 
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CONCLUSIONS

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 tests 

can identify early stage HCC and patients who are selected for surgical treatment often have 

good long-term survival, but some treatments may be associated with substantial harm. Trials 

examining the balance of benefits and harms of HCC screening in patients with chronic liver 

disease should be considered. 
21

ancer in Chronic Liver Disease: A Systematic Review Evidence-based Synthesis Program

9CONTENTS 34

nce on screening for hepatocellular carcinoma in patients with chronic liver disease, and treatment in patients with early

a

Outcome

For each study design:

N studies: N studies by liver 

disease etiology;

N=combined number of 

participants

Findings Strength of Evidence* Comments

Mortality 2 RCT: 2 HBV; N=19200

16 NRCS: 1 HBV; 3 HCV; 7 HBV/

HCV; 5 HBV/HCV/EtOH;

 N =11340

One high risk of bias trial of US, RR 

of death due to HCC, 0.63 (95% CI, 

0.41-0.98)

One unclear risk of bias trial of 

AFP, Incidence rate all-cause 

mortality/100 person-years: 1.83 vs 

1.79, P = NS

Very low Numerous methodologic issues in the trials 

including allocation concealment, outcome assessment, analytic problems, and selective outcome reporting limit conclusions. Methodologic issues in the observational studies including selection bias, as well as lead- and length-time bias similarly limit conclusions. Studies consistently found HCC diagnosed with screening was earlier stage, but impact on overall mortality unclear. Applicability to hepatitis C and alcoholic liver disease populations limited. 

rms: needle 

ck seeding

1 Meta-analysis of 8 NCS; N=1340

1 NCS; N=3391

Overall risk of seeding: 2.7%

(95% CI, 1.8-4.0%)

Low Range of seeding 0-5.8%, most recent study not in 

meta-analysis found risk of 0.12%. Applicability to current practice may be limited as liver biopsy not often used in diagnosis of HCC. 

arms: other No studies -- No evidence

Mortality 2 RCT: 1 HCV/EtOH, 1 HBV/HCV; 

N=2022

Shorter screening intervals (3-4 

months) offered no advantage over 

longer intervals (6-12 months)

Moderate One trial had unclear risk of bias. No evidence 

comparing 6- to 12-month intervals. 

Harms NA NA

ed or early-stage HCC compared to no treatment
22

ancer in Chronic Liver Disease: A Systematic Review Evidence-based Synthesis Program

9CONTENTS 34

Outcome

For each study design:

N studies: N studies by liver 

disease etiology;

N=combined number of 

participants

Findings Strength of Evidence* Comments

Mortality 3 RCT: 1 HBV, 2 EtOH; N=217

3 NRCS: 1 HBV, HCV; 1 HBV, 

EtOH; 1 HBV, HCV, EtOH;

N=795

No difference in 2 trials of EtOH 

patients.

RR of death, 0.49 (95% CI, 0.29-

0.81) in one trial of HBV patients.

Low (EtOH)

Low (HBV)

Evidence base is limited by poor methods reporting in 2 trials and small sample size. Directness of evidence to screen-detected disease also limited. 

Harms 3 RCT: 1 HBV; 2 EtOH;

N=217

Serious complications in 8-20% 

patients

Low Serious complications included GI hemorrhage, 

treatment-related death, renal failure, and thrombosis. Studies included patients with both early and late-stage disease and applicability to those with early-stage disease is unclear. 

Mortality 4 NRCS: 1 HBV, HCV; 1 HBV, 

EtOH; 2 HBV, HCV, EtOH; N=965

2 NCS: 2 HBV/HCV; N=339

5-year survival 27-55%

vs 0-30% 

Very low All non-randomized studies in which confounding 

by indication limits conclusions about impact on mortality

Harms 1 NRCS: 1 HBV, HCV, EtOH; 

N=170

2 NCS: 2 HBV/HCV; N=1249

Serious complications in 1.8-9.9%; 

needle-track seeding in 3.2%

Low Complications included peritoneal bleeding, 

hemothorax, and portal vein thrombosis. Information comes from one large cohort study focused only on needle-track seeding, and 2 small cohort studies. 

Mortality 1 NRCS: 1 HBV, HCV; N=278

3 NCS: 2 HBV/HCV, 1 NR; 

N=12,304

4-5 year survival, 53-73%

vs 0-30%

Very low All non-randomized studies in which confounding 

by indication limits conclusions about impact on mortality 

Harms 0 -- No evidence Poor reporting of harms in studies. 

Mortality 3 NRCS: 1 HBV, HCV; 1 HBV, 

EtOH; 1 NR; N=952

5-year survival, 33-75% 

vs 0-8.3% 

HR for death, 0.45 

(95% CI,0.34-0.59)

Low No direct evidence examining mortality. Data from 

one large, well-conducted observational study which did account for some important confounding factors, but was not able to control for patient comorbidities.

Harms: 

rioperative 

mortality

1 systematic review of 23 studies 

N=3366

Perioperative mortality 4% Low Data up through 2004; applicability to current 

practice unclear.

Mortality 0 -- No evidence No studies in patients with early-stage disease

Harms 0 --

epatitis B virus; HCV = hepatitis C virus; KQ = key question; NCS = non-comparative study; NR = not reported; NRCS = non-randomized comparative study; NS = 

ed trial; RR = relative risk

search is very unlikely to change our confidence on the estimate of effect; moderate = further research is likely to have an important impact on our confidence in 

e estimate; low = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very 

rtain.
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