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Kansagara D, Papak J, Pasha AS, et al. Screening for Hepatocellular Cancer in Chronic Liver Disease: A Systematic Review [Internet]. Washington (DC): Department of Veterans Affairs (US); 2014 Jan.

APPENDIX CINCLUSION/EXCLUSION CRITERIA

CodeDefinitionExclusion criteria/notesScreening studies inclusion criteriaTreatment studies inclusion criteria
I-Screening
I-Treatment		Include – screening
Include – treatment		KQ1 –Benefits of screening:
1a. In which subgroups of patients with chronic liver disease have the effects of HCC screening on patient survival been evaluated?
1b. What are the effects of HCC screening on disease-specific and all-cause mortality in these patient subgroups?
1c. Are there particular HCC screening modalities that are more effective on patient survival than others?

KQ2 –Harms of screening:
2. What are the harms of HCC screening among patients with chronic liver disease?		KQ3 – What are the benefits and harms of treating early stage HCC?
I-SRInclude – systematic reviewSystematic review or meta-analysis that addresses any of the key questions. Code X9-SR for comparative effectiveness reviews of treatment modalities.
X1Non-English languageMost foreign language abstracts have been filtered out, but can be retrieved for further review as needed.
X2Not relevant to HCC
X3Study population is not in scope for either screening or treatment KQs.Exclude: Patients with prior, advanced, or metastatic HCC; in vitro studies.Adults with chronic active viral hepatitis, alcohol-related liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis – all with or without cirrhosis.Patients with early stage HCC, defined as patients with the equivalent of BCLC Stage A (3 or fewer nodules, <3cm, or 1 nodule <5 cm).
Milan criteria = early stage HCC.
Include studies for which at least a portion of the population is Stage A and B (these studies may be useful for addressing harms).
X4No primary data, or study design not in scopeExclude: Non-systematic or narrative reviews, opinions, case studies, case series, quasi-experimental studies, or other excluded study designs.Include studies that compare screened patients with unscreened patients, using any of the following study designs:
  • Observational studies, e.g., cohort or case-control designs
  • Controlled studies, e.g., RCT, controlled clinical trial, controlled before/after designs.
Also include: active-controlled/head-to-head trials and observational studies that compare screening modalities or screening intervals.

For cost studies: include primary data collected in U.S. settings. Exclude modeling and simulation studies, and primary studies in non-U.S. settings.		Included study designs:
  • Randomized, placebo-controlled trials comparing a single treatment or combination of included treatment modalities vs no active treatment/placebo/active screening without treatment (analogous to watchful waiting);
  • Observational studies of a single or combination treatment modality that:
    -

    include a comparison group of untreated HCC patients, and

    -

    have a sample size ≥ 100 patients (treated plus untreated)

    -

    adjust for potential confounders. Studies that do not examine the effects of potential confounders (age, sex, baseline liver disease) are excluded.

Specific exclusions for treatment studies:

Code X9 for head-to-head/active-controlled treatment trials;

X9-SR for comparative effectiveness reviews; add combo (e.g. X9-combo) to indicate multiple treatment modalities.

Use code X10 for observational studies include an untreated comparison group, and contain data on harms of treatment but sample size is <100 treated patients.
X5Modality used for screening or treatment is not in scopeExcluded screening modalities:
Biomarkers, thrombocytopenia, DNA/ RNA analyses.

Excluded treatment modalities:
Exclude percutaneous alcohol injection (no longer in use, and not in 2010 guidelines). Specify excluded treatments as they occur in the screening process.		Ultrasound, CT, MRI, and/or alpha-fetal protein screening for primary HCC.Early stage/curative treatments include resection, transplant, radiofrequency ablation, transarterial chemoembolization, and sorafenib.
X6None of the reported outcomes are in scopeExclude studies that do not report any of the outcomes of interest.
Exclude diagnostic accuracy studies.		Benefits:
  • Mortality due to HCC, liver disease, or all causes
Harms:
  • Psychological effects (eg, anxiety, stress, depression, labeling)
  • Liver biopsy-related complications (eg, bleeding, infection)
  • Renal insufficiency
  • Overdiagnosis (ie, identifying cancers that would not have caused disease undetected)
• Cost – include primary data collected in U.S. settings.		Benefits:
  • Mortality
  • Quality of life
Harms:
  • Hospitalizations
  • Bleeding
  • Pain
  • Acute liver injury
  • Infections
  • Quality of life
  • Reports of any adverse event
X7Other reason: specifyAdd comments or keywords as needed.
X9Exclude head-to-head/active-controlled treatment trials.
Code X9-SR for systematic reviews/ meta-analyses on comparative effectiveness.
X9-combo, where applicable.
X10Exclude relevant observational studies on treatments with sample size <100 treated patients (we may pull these later if low yield of studies with n≥100).
X11Duplicate publicationExclude older publications or conference proceedings that have been subsequently published as full-text articles
Note: Excluded articles should each receive a single X code, according to the order listed. Articles coded for background (‘B’) should also receive an X code.
BBackgroundAdd ‘B’ any of the above X codes (e.g., ‘X6–B’) if the article contains information that may be useful for the introduction, discussion, limitations, future research, or other contextual purposes. Add comments or keywords as needed.