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
Screening for Hepatocellular Cancer in 

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

9 i CONTENTS 34

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.
Screening for Hepatocellular Cancer in 

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

9 i CONTENTS 1 34

EXECUTIVE SUMMARY

BACKGROUND 

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 

hepatocellular cancer (HCC) diagnoses. From 1996 to 2006, the prevalence of cirrhosis among 

Veterans with chronic hepatitis C infection rose from 9 to 18.5%, and the prevalence of HCC 

rose from 0.07 to 1.3%. 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. 

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

disease has risen. 

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

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

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

Several professional society guidelines currently recommend HCC screening using imaging 

studies and tumor markers mainly in patients with chronic hepatitis B or liver cirrhosis. 

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.

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. 

METHODS 

Data sources: Medline, PsycInfo, Cochrane Central Register of Controlled Trials, and Cochrane 

Database of Systematic Reviews to March 2013; clinical trial registries; reference lists; and 

technical advisors.

Study Selection: We examined controlled clinical trials and observational studies comparing 

screening to no screening, and controlled clinical trials comparing different screening intervals. 

We also examined controlled clinical trials and observational studies comparing one of the 

following active treatments to conservative treatment in patients with early-stage HCC: 

transarterial chemoembolization (TACE), partial hepatic resection, orthotopic liver transplant 

(OLT), radiofrequency ablation (RFA), and sorafenib. Because of the dearth of studies for 

all treatments other than TACE comparing active to conservative treatments, we evaluated 

noncomparative observational studies for evidence on harms and long-term survival. The 

population of interest was patients with chronic liver disease with or without cirrhosis. 
Screening for Hepatocellular Cancer in 

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

9 i CONTENTS 2 34

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. Studies were dual-reviewed for quality 

using standard criteria. 

Data Synthesis: 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. 

RESULTS 

Of 11,321 citations, 264 were reviewed at the full-text level. Thirty-five studies contained 

primary data relevant to the efficacy of HCC screening or treatment of early-stage HCC and met 

our inclusion criteria. We also examined 2 systematic reviews of treatment modalities. 

Overall, we found very low strength evidence examining the effects of screening for HCC on 

mortality among patients with chronic liver disease. Two trials and 16 observational studies 

compared the effects of screening to no screening. Three trials comparing HCC treatment to no 

treatment included patients with early-stage HCC, and 12 observational studies provided data 

about the effects of treatment of early-stage HCC. 

Effects of screening on mortality: RCTs

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

mortality among participants mainly with hepatitis B. 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 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). However, this trial, carried a high-risk of bias because of several serious methodological 

limitations that threaten the validity of the results. 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). 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. One unclear risk of bias 

trial found no survival advantage comparing 4-month to 12-month ultrasound screening intervals 

in patients with serologic evidence of hepatitis B or C. 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. 
Screening for Hepatocellular Cancer in 

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

9 i CONTENTS 3 34

Effects of screening on mortality: observational studies

Sixteen 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. Median survival ranged among studies from 12-56 months 

in the screening group, and from 3-37 months in the non-screening group. Three-year survival 

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

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. 

Harms of screening

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. 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%. 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 that contrast-enhanced CT was associated with 

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

25% of patients receiving gadoxetic acid-enhanced MRI. We found no studies evaluating the 

psychologic harms of screening. 

Effects of treating screen-detected HCC

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 from which to draw conclusions about the net benefits of actively treating earlystage HCC compared to conservative treatment. Low-strength evidence from one trial found 

TACE decreased mortality in patients with hepatitis B, while low-strength evidence from 2 trials 

found TACE increased mortality in patients with alcoholic cirrhosis. Observational studies show 

that patients selected for treatment with OLT, resection, or RFA had good long-term survival 

(27-75%), which was substantially higher than patients not selected for such therapy (0-30%), 

but it is unclear whether such effects reflect a true effect of treatment or reflect confounding by 

indication. Serious harms occurred in 1.8-20% of patients, depending on the intervention.

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 harms. Trials 

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

disease should be considered. The table below summarizes the findings and strength of evidence.
4

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

9CONTENTS 34

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

a

ome

For each study design:

N studies: N studies by liver 

disease etiology;

N=combined number of 

participants

Findings Strength of Evidence* Comments

ality 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. 

needle 

eeding

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 to 5.8%, most recent study not in 

meta-analysis found risk of .12%. Applicability to current practice may be limited as liver biopsy not often used in diagnosis of HCC. 

 other No studies -- No evidence

ality 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. 

ms NA NA
5

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

9CONTENTS 34

ome

For each study design:

N studies: N studies by liver 

disease etiology;

N=combined number of 

participants

Findings Strength of Evidence* Comments

ed or early-stage HCC compared to no treatment

ality 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. 

ms 3 RCT: 1 HBV; 2 EtOH;

N=217

Serious complications in 8 to 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. 

ality 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

ms 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. 

ality 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 

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

ality 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.

ms: 

rative 

ality

1 systematic review of 23 studies 

N=3366

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

unclear.

ality 0 -- No evidence No studies in patients with early-stage disease.

ms 0 --

epatitis B virus; HCV = hepatitis C virus; NCS = non-comparative study; NR = not reported; NRCS = non-randomized comparative study; NS = not specified; RCT = 

e 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.