Screening for Hepatocellular Cancer in 

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

9 i CONTENTS 30 34

APPENDIX A. SEARCH STRATEGY

Key Question 1 (Screening)

Medline (via PubMed) Searched 1/29/2013. 

HCC “hepatocellular carcinoma”[Title/Abstract] OR “HCC”[Title/Abstract] OR

“Carcinoma, Hepatocellular”[Mesh]

OR

“liver cancer”[Title/Abstract] OR "Liver Neoplasms"[Mesh]

AND

Screening “alpha-Fetoproteins”[Mesh] OR alpha-fetoprotein*[Title/Abstract] OR alfafetoprotein*[Title/Abstract] OR alpha-foetoprotein*[Title/Abstract] OR alfafoetoprotein*[Title/Abstract] OR alpha-fetalprotein*[Title/Abstract] OR

alfa-fetalprotein*[Title/Abstract] OR alpha fetalprotein*[Title/Abstract] OR

alfa fetalprotein*[Title/Abstract] OR alphafetoprotein*[Title/Abstract] OR

alfafetoprotein*[Title/Abstract] OR alphafoetoprotein*[Title/Abstract] OR

alfafoetoprotein*[Title/Abstract] OR alphafetalprotein*[Title/Abstract] OR

alfafetalprotein*[Title/Abstract]

OR

CT[Title/Abstract] OR “Tomography, X-Ray Computed”[Mesh]

OR

mri[Title/Abstract] OR magnetic resonance imaging[Title/Abstract] OR “Magnetic 

Resonance Imaging”[Mesh]

OR

screen-detected[Title/Abstract] OR screening[Title/Abstract] OR “Mass 

Screening”[Mesh] OR “Early Detection of Cancer”[Mesh]

OR

ultrasonography[Title/Abstract] OR “Ultrasonography”[Mesh] OR

"ultrasonography"[Subheading]

Key Question 2 (Harms of Screening)

(Note: medical adverse effects of screening would be included in above search. An additional 

search was designed to capture psychological harms of screening specifically.)

Medline (via PubMed) Searched 3/5/2013. 

HCC “hepatocellular carcinoma”[Title/Abstract] OR “HCC”[Title/Abstract] OR

“Carcinoma, Hepatocellular”[Mesh]

OR

“liver cancer”[Title/Abstract] OR "Liver Neoplasms"[Mesh]

AND

Psych harms “False Positive Reactions”[Mesh] OR “False Negative Reactions”[Mesh] OR

“Anxiety”[Mesh] OR “Depression”[Mesh] OR “Stress, Psychological”[Mesh] OR

“Patient Acceptance of Health Care”[Mesh] OR "psychology"[Subheading]

An additional search for psychological harms of screening was conducted in PsycInfo (via 

OVID) on 6/28/2013:

(((“hepatocellular carcinoma”[Title/Abstract]) OR “HCC”[Title/Abstract])) OR (“Carcinoma, 

Hepatocellular”[Mesh])OR((“liver cancer”[Title/Abstract])) OR (“Liver Neoplasms”[Mesh])

The search of PsycInfo yielded 160 citations; none were found to be relevant.
Screening for Hepatocellular Cancer in 

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

9 i CONTENTS 31 34

Key Question 3 (Treatment)

Medline (via PubMed) Searched 3/5/2013. 

HCC "hepatocellular carcinoma"[Title/Abstract] OR "HCC"[Title/Abstract] OR 

"Carcinoma, Hepatocellular"[Mesh]

OR

"liver cancer"[Title/Abstract] OR "Liver Neoplasms"[Mesh]

AND

Treatment ablation[Title/Abstract] OR “Ablation Techniques”[Mesh]

OR

hepatectomy[Title/Abstract] OR resection[Title/Abstract] OR excision[Title/

Abstract] OR “Hepatectomy”[Mesh]

OR

Sorafenib[Title/Abstract] OR Nexavar[Title/Abstract] OR

“sorafenib”[Supplementary Concept]

OR

transplant[Title/Abstract] OR transplantation[Title/Abstract] OR “Liver 

Transplantation”[Mesh]

OR

treatments[Title/Abstract] OR treatment[Title/Abstract] OR “Therapeutics”[Mesh] 

OR "therapy"[Subheading]

AND

Mortality mortality[Title/Abstract] OR survival[Title/Abstract] OR “Mortality”[Mesh] OR

“mortality”[Subheading] OR "Survival Rate"[Mesh]

Additional searches:

The searches developed for MEDLINE were adapted for the Cochrane Central Register of 

Controlled Trials and searched on 6/28/2013. 

ClinicalTrials.gov was searched on 9/3/2013 with the term “Hepatocellular Carcinoma” and no 

limitations on study type, recruitment status, etc.
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RES
Screening for Hepatocellular Cancer in 

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

9 i CONTENTS 33 34

Figure 2. Literature flow diagram
Screening for Hepatocellular Cancer in 

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

9 i CONTENTS 34 34

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

compared with non-screening 

*P < 0.05

†P-value was not reported.

‡Screening group includes patients screened at both 0-6 and 7-24 month intervals before HCC 

diagnosis. 
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USION/EXCLUSION CRITERIA

Exclusion criteria/notes Screening studies inclusion criteria Treatment studies inclusion criteria

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 diseasespecific 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? 

Systematic review or meta-analysis that addresses any of the key questions.Code X9-SR for comparative effectiveness reviews of treatment modalities. 

ost foreign language abstracts have 

een filtered out, but can be retrieved 

r further review as needed.

xclude: Patients with prior, advanced, 

 metastatic HCC; 

 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). 

xclude: Non-systematic or narrative 

views, opinions, case studies, case 

eries, quasi-experimental studies, or 

her 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.
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Exclusion criteria/notes Screening studies inclusion criteria Treatment studies inclusion criteria

xcluded screening modalities: 

omarkers, thrombocytopenia, DNA/

NA analyses. 

xcluded treatment modalities: xclude percutaneous alcohol 

ection (no longer in use, and not in 

010 guidelines). Specify excluded 

eatments as they occur in the 

creening 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.

xclude studies that do not report any 

 the outcomes of interest.

xclude 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

dd comments or keywords as 

eeded.

xclude head-to-head/active-controlled 

eatment trials. 

ode X9-SR for systematic reviews/

eta-analyses on comparative 

fectiveness. 

9-combo, where applicable.xclude relevant observational studies 

n treatments with sample size <100 

eated patients (we may pull these 

ter if low yield of studies with n≥100).

xclude older publications or 

onference proceedings that have 

een subsequently published as full

xt articles

eive a single X code, according to the order listed. Articles coded for background (‘B’) should also receive an X code. 

dd ‘B’ any of the above X codes 

.g., ‘X6–B’) if the article contains 

formation that may be useful for the troduction, discussion, limitations, 

ture research, or other contextual 

urposes. Add comments or keywords s needed.
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LES

hepatocellular carcinoma screening in patients with chronic liver disease

N, screening vs no 

screening

Demographics: 

mean age; % male; 

race Etiology, %

Liver 

disease 

severity, %

Stage at 

Diagnosis, % Treatment received, %

Mortality, screening vs 

no screening, or interval 

comparison

3712 vs 1869 age: 41.0 vs 41.3 HBV: 100 NR *I: 29.6 vs 6.0 

II: 50.6 vs 53.0

III: 19.8 vs 41.0 

NR All-cause mortality rate 

(per 100,000): 

1.842 person-yr vs 

1.788 person-yr 

HCC mortality rate: 1.138 

person-yr vs 1.113 personyr, p=0.86

9757 vs 9443 age: 42 vs 41

male: 62.6 vs 63.3

HBsAg+: 64.8 vs 63.8

HBsAg+ and history 

of hepatitis: 26.8 vs 

28.0

NR I: 60.5 vs 0

II:13.9 vs 37.3

III: 25.6 vs 62.7

p<0.01

Resection: 46.5 vs 7.5

TACE or PEI: 32.6 vs 

41.8

Conservative treatment: 

20.9 vs 50.7

HCC mortality (per 

100,000): 83.2 vs 131.5, 

RR 0.63 (95% CI 0.41-

0.98), p<0.01; NR; 

NR

640 vs 638 age: 54 vs 55

male: 69.5 vs 68.7

HBV: 12.8 vs 12.2

HCV: 44.7 vs 43.6

EtOH: 39.4 vs 39

; 

hemochromatosis: 0.8 

vs 2.3

other: 2.3 vs 2.6

Child A or B: 

100

Milan: 79.2 vs 71.4 OLT: 18.9 vs 4.3

resection:5.7 vs 9.7

percutaneous ablation:

37.7 vs 44.3

TACE: 17 vs 12.3

**24mo survival: 95.8 vs 

93.5; 

60mo survival: 84.9 vs 

85.8

Total mortality: 11.3 vs 

12.1, p=0.38

387 vs 357 Group A: 4mo Group 

B: 12mo

age: 63.8 vs 66.6, 

p<0.001

male: 47.8 vs 51.8

race: NR

HBV: 30 vs 25.2

HCV: 63 vs 67.2

HBV+HCV:

7 vs 7.6

NR BCLC:

Very-early: 37.5 

vs 6.7

Early: 54.2 vs 66.6

Others: 8.3 vs 26.7

, p=0.02

Curative treatment 

(surgical resection or 

RFA): 

54.2 vs 20, p=0.05

1 vs 2 vs 4yr cumulative 

survival:

Group A: 95.8 vs 78.8 vs 

57.4 

Group B: 80 vs 64 vs 56, 

p=0.399;

 NR

sification. I-subclinical or early stage (no signs/sx, tumor usually <5 cm). II-moderate stage, intermediate between I and III. III-late stage (obvious cachexia, 

s) Confounders adjusted for in analysis: **EtOH, HCV, age, platelet count, bilirubin, AST, ALT, alk phos, GGT, albumin, PT and AFP.
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methods for potential sources of bias in randomized trials of hepatocellular carcinoma screening

ation Allocation concealment Blinding (patients, personnel, outcome assessors) Incomplete outcome data Selective outcome reporting Other sources of bias Overall risk of bias

Unclear: NR Yes - personnel 

staging cancers, Probably no - all others Low for mortality outcome

Mortality data likely available for everyone. Mean duration f/u similar in both groups Low

Low Low: Baseline 

characteristics similar, but only age, ALT and AFP levels reported. 

Unclear

Unclear: NR Unclear: NR High 

Unclear for what proportion survival data were available. 

HighVital status data reportedly available, but allcause mortality not reported. 

HighSparse baseline data available to compare both groups. No statistical analysis done to account for effects of clustering.

High

Low Low (no mention of 

blinding, but low risk of bias for mortality outcomes)

Low Low, intention-toscreen analysis Low - groups similar at baseline Low

Low Unclear, probably 

no blinding. Patient survival followed by public health nurses for all patients, so probably low risk of bias for mortality outcome. 

Unclear: NR Unclear how many patients were lost to follow-up and there was no mention of death registry to ensure complete follow-up of mortality outcomes. 

High: ITT analysis probably done, but not specifically mentioned. Clustered trial and no mention of adjustment for clustering. 

Low Groups comparable at baseline, other than higher age and bilirubin in control group (though similar on other liver disease severity markers). Demographic characteristics among those with HCC similar in both groups. 

Unclear
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ening for hepatocellular carcinoma in patients with chronic liver disease 

mographics

e; % male; 

race)

tiology, %

Etiology, % Liver disease 

severity, %

Stage at 

Diagnosis, %

Treatment received, 

%

Observed mortality,

screening vs no screening

Adjusted mortality, 

screening vs no 

screening

  vs 63.8 

e: 

 vs 67.3

screening group only: HBV: 17.6 HCV: 64.2 Alcohol: 25.2 Primary biliary cirrhosis: 3.2

Child-Pugh: A: 41.0 vs 38.5 B: 47.5 vs 49.0 C: 11.5 vs 12.5

Unifocal HCC: 80 vs 53, p<0.001 Diffuse/infiltrative HCC: 10 vs 29,p<0.01

Resection: 9 vs 8 OLT: 26 vs 13,p<0.01 PEI: 24 vs 23 TACE+PEI: 10 vs 10 TACE: 31 vs 46,p<0.05

Median survival (m)30 vs 15 (p<0.02)Survival (%) at 3yr: 45 vs 31.7 

*

 ≥ 50: 

 vs 43.3 

e: 

 vs 59.8

HBV: 65.9 vs 67.0 HCV: 18.2 vs 14.9

NR, but only 7 had cirrhosis

NR NR Unadjusted HR 

0.76 (95% CI 0.38-1.52)

Adjusteda HR 

0.59 (95% CI 0.29-1.20)

 <65: 

 vs 55.8 

0.01) 

 ≥ 65: 

 vs 44.3 

e: 

 vs 55.8

HBV: 6.8 vs 8.0 HCV: 72.7 vs 47.8 ETOH: 40.9 vs 14.2

Child-Pugh: A: 15.9 vs 26.5 B: 52.3 vs 35.4 C: 31.8 vs 38.1

One mass: 52.3 vs 38.1 2-3 masses: 22.7 vs 27.4 >3 masses: 18.2 vs 22.1

treatment n=54: Resection: 18.5 RFA: 11.1 PEI: 1.9 TACE: 35.2 chemotherapy: 31.5

Survival (%) at1yr: 39 vs 313yr: 30 vs 21 (p=0.07)

*

 58.1 

e: 99.3 

e: 55.6

HCV:100 NR (but 

measured)

NR NR Unadjusted HR (95% CI) from date of 

HCC diagnosis, by timeframe screened during 24m prior to HCC diagnosis:7-24m: 0.84 (0.69-1.01)0-6m: 0.80 (0.68-0.94)Both periods: 0.71 (0.62-0.82)Median survival (days) from date of HCC diagnosis among pts screened in both periods vs neither: 368 vs 130 (p<0.01) Unadjusted HR (95% CI) from date of HCV diagnosis:7-24m: 0.86 (0.72-1.04)0-6m: 0.90 (0.77-1.06)Both periods: 0.82 (0.72-0.95)Median survival (days) from date of HCV diagnosis among pts screened in both periods vs neither: 1951 vs 1782

Adjustedb HR (95% CI) 

by timeframe screened during 24m prior to HCC diagnosis:7-24m: 0.93 (0.77-1.13)0-6m: 0.93 (0.79-1.09)Both periods: 0.84 (0.72-0.98)Adjusted HR corrected for lead time, assuming HCC sojourn time of 140 days:7-24m: 1.04 (0.87-1.26)0-6m: 1.00 (0.85-1.17)Both periods: 0.88 (0.76-1.02)

 67 vs 68 HCV: 100 Mean ChildPugh: 

6 vs 8

One mass: 58.8 vs 51.9 >2 masses: 41.2 vs 48.5

Resection: 11.8 vs 7.4 OLT: 2.9 vs 0 PEI: 52.9 vs 33.3 TACE: 29.4 vs 25.9 None: 2.9 vs 33.3

Median survival (m) 23 vs 15 (p=0.03) 

Adjustedc HR

0.38 (95% CI 0.17-0.87)
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mographics

e; % male; 

race)

tiology, %

Etiology, % Liver disease 

severity, %

Stage at 

Diagnosis, %

Treatment received, 

%

Observed mortality,

screening vs no screening

Adjusted mortality, 

screening vs no 

screening

 65 vs 68 

e: 

 vs 78.2

n: 

 vs 16.7

HBV: 26.8 vs 12.9 HCV: 39.0 vs 29.6 Alcohol use: 43.9 vs 37.0

Child-Pugh: A: 63 vs 42 B: 27 vs 33 C: 10 vs 25

TNM I/II: 61.1 vs 21.7 III/IV: 38.9 vs 78.3, p<0.001

Resection: 11.8 vs 6.8 PEI or RFA: 52.9 vs 6.8 TACE: 33.0 vs 13.0

Median survival (m) 29.0 vs 3.3 (p<0.001) 

Adjustedd HR 

0.24 (p<0.0005)

  vs 59.4 

e: 

 vs 76.4

0.002)

HBV: 48.7 vs 47.1 HCV: 38.1 vs 33.4 HBV + HCV: 9.1 vs 7.8 Other: 4.1 vs 11.7

Child-Pugh: A: 73.3 vs 62.4 B: 23.9 vs 30.4 C: 2.8 vs 7.2 (p<0.001)

BCLC, p<0.001: Very early: 8.2 vs 6.5 Early: 60.4 vs 23.1 Intermediate: 21.7 vs 35.2 Advanced:6.9 vs 30.9 Terminal:2.8 vs 7.1

Resection: 23.9 vs 17.0 RFA: 12.6 vs 3.2 PEI: 9.1 vs 2.5 TACE: 47.2 vs 38.2 chemotherapy or radiation: 1.6 vs 12.3 None: 5.6 vs 26.7(p<0.001)

Unadjusted HR 0.43 (95% CI 0.37-0.52)Median survival (m)

48.1 vs 12.7 Survival (%) at3yr: 59.1 vs 29.3 (p<0.001)

Adjustede HR 

0.83 (95% CI 0.67-1.0)

 59 vs 53.8

e: 64.2 vs 

HBV: 40 vs 40HCV: 100 ETOH: 0.68 vs 13.6

Child-Pugh: 6.3 vs 7.2

BCLC early: 100 vs 22, p<0.001

Resection: 6.3 vs 0 OLT: 6.3 vs 0 RFA: 50 vs 10.7

Unadjusted HR 0.27 (95% CI 0.13-0.60)Mean survival (m) 19.8 vs 8.5

Adjustedf HR 

1.01 (95% CI 0.33-3.07)

  vs 68.2 

e: 

s 81

0.002)

HBV: 3 vs 6HCV: 61 vs 35EtOH: 21 vs 35 EtOH + virus: 5 vs 11(p<0.001)

Child-Pugh: A: 64 vs 33 B: 27 vs 48C: 9 vs 19 (p<0.001)

<5cm: 60 vs 33 >5cm: 9 vs 28 multifocal: 14 vs 32 (p=0.003)

OLT: 15 vs 3 PEI: 19 vs 9 RF: 13 vs 4 TACE: 39 vs 20 none: 14 vs 64 (p<0.001) 

Median survival (m) 27 vs 6 (p=0.001)

Adjusted HRg

0.4 (0.3-0.6), p=0.00003)

e: 60 vs 78 HCV: 100 Child-Pugh: 

A: 64 vs 58 B: 32 vs 39 C: 3 vs 3 

Milan: 86 vs 50

Resection: 16 vs 12 PEI/RFA: 60 vs 34 TACE: 20 vs 42 Chemotherapy:  3 vs 9 (p<0.001) 

Median survival (y) 4.7 vs 3.1 (p<0.001)Survival (%) at3yr: 67 vs 515yr: 46 vs 32

Adjustedh RR 

0.63 (95%CI 0.48–0.82).Corrected for lead time, survival was longer with screening among Child–Pugh class A patients when assumed tumor doubling time was ≤120 days: 60 days (p=0.005) 90 days (p=0.016)120 days (p=0.048)150 days (p=0.129)180 days (p=0.293)
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mographics

e; % male; 

race)

tiology, %

Etiology, % Liver disease 

severity, %

Stage at 

Diagnosis, %

Treatment received, 

%

Observed mortality,

screening vs no screening

Adjusted mortality, 

screening vs no 

screening

 64.9 vs  

e: 71.3 vs 

HBV: 15.8 vs 15.0 HCV: 74.7 vs 69.9 HBV + HCV: 3.9 vs 1.1 Alcohol: 1.7 vs 4.3

Child-Pugh: A: 69.7 vs 74.2 B: 24.2 vs 20.4 C:6.1 vs 5.4

<3 cm: 64.6 vs 22.6<5 cm: 94.4 vs 51.6 >3 tumors: 24.7 vs 45.2

Resection: 2.8 vs 3.2 RFA/PEI: 48.3 vs 17.2, p<0.0001 TACE:41.0 vs 59.2, (p=0.01)

Median survival overall (m): 37.3.Cumulative survival was significantly higher in screening vs no screening, NOS (p=0.01) 

*

 61.5 vs  (p=0.009) 

e: 80.8 vs 

 

HBV: 100 Child-TurcottPugh: 

A: 65 vs 72.1 B: 25 vs 23.3 C: 10 vs 4.70 

Milan: 61.5 vs 19.6, p=0.0004 UCSF: 76.9 vs 27.5, p<0.0001  tumors: Single: 81 vs 52 Multiple/diffuse: 19 vs 48 Metastasis: 7.7 vs 19.2 (p=0.02) 

No screening vs screening: Resection: 19.2 vs 17.3 OLT: 30.1 vs 5.8 RFA and/or TACE: 26.9 vs 23.1 Chemotherapy:0 vs 9.6 Supportive care: 23.1 vs 44.2 (p=0.012)

Survival (%) at1yr: 100 vs 76.93yr: 62.5 vs 36.6 5yr: 35.7 vs 16.3 (p=0.007)

Adjustedi HR was nonsignificant, NOS. 

A lead time bias interval was added to the survival time of patients who presented with HCC, with tumor doubling time assumed to be 216 days. 

e: 70.7 vs 

s 78.7

0.03)

HBV: 13.6 vs 20.4 vs 20.5 HCV: 66.6 vs 62.5 vs 55.9 HBV+HCV: 9.9 vs 9.9 vs 8.4 EtOH:8.5 vs 7.2 vs 13.8

Child-Pugh: A: 63.7 vs 70.9 vs 54 B: 30.7 vs 23.7 vs 33.8 C: 5.6 vs 5.4 vs 12.2 (p=0.001)

Milan: 68.7 vs 60.4 vs 31(p<0.001)

OLT: 3.9 vs 0.2 resection: 11.6 vs 8.2 PEI: 26 vs 18.7 TACE: 33.4 vs 27.3 (p<0.001)

Median survival (m) 36 vs 34 vs 14 (p<0.001)

Adjustedj RR for ChildPugh A subgroup: 

0.59 (95% CI 0.45-0.78).Survival corrected for lead time was NS higher with screening in ChildPugh B (p=0.051) and C subgroups (p=0.49).

 73.9 vs  vs 74.6 

e: 60.8 vs 

 vs 76.1 

0.04) 

HBV: 9.5 vs 6.5 vs 11.9 HCV: 67.1 vs 58.0 vs 53.7 HBV+HCV: 2.5 vs 3.6 vs 7.5 EtOH:5.7 vs 12.3 vs 10.4 EtOH+viral: 10.8 vs 10.9 vs 7.5

Child-Pugh: A: 76.8 vs 68.7 vs 42.4 B: 18.8 vs 29.8 vs 43.9 C: 4.6 vs 1.5 vs 13.6 (p<0.001)

Milan: 70.3 vs 39.1 vs 25.4(p<0.001)

Resection: 8.4 vs 2.9 vs 0 PEI: 35.7 vs 36.8 vs 10.8 TACE: 28.6 vs 17.6 vs 20 Other/palliation: 27.3 vs 42.6 vs 69.2 (p<0.001)

Median survival (m) 30 vs 21(p=0.006) v 7 (p<0.001)

*
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mographics

e; % male; 

race)

tiology, %

Etiology, % Liver disease 

severity, %

Stage at 

Diagnosis, %

Treatment received, 

%

Observed mortality,

screening vs no screening

Adjusted mortality, 

screening vs no 

screening

 59.5 vs  

e: 70 vs 88 

overall HBV: 91 HCV: 10

Mean childPugh: 6.0 vs 6.4 (p=0.02)

Mean tumor, n: 2.6 vs 3.8 (p=0.03) Median tumor diameter (cm): 4.2 vs 7.7 (p<0.001) Extrahepatic metastasis: 8 vs 23 (p=0.002) Portal vein thrombosis: 11 vs 30 (p=0.001) Bilobal involvement: 14 vs 31 (p=0.01) 

Resection: 20 vs 10, p=0.01 Transplant: 1 vs 1 Chemotx:13 vs 15 Local ablative tx: 46 vs 19, p<0.001

Median survival (wk)88 vs 26 (p<0.001)Survival (%) at 1yr: 65.6 vs 35.5 2yr: 49.4 vs 21.1 

Adjustedk HR 

0.66 (95% CI 0.48-0.92)Survival (%) at 2yr: 49.4 in the screening group; correcting for lead-time bias in the non-screening group, by tumor doubling time: 26.7 (p=0.0035) 60-day28.6 (p=0.035) 90-day 32.2 (p=0.18) 120-day 

 % ≥50: 

 vs 65.9 

e: 

 vs 79.3 

HBV: 67.7 vs 53.57 HCV: 43.9 vs 31.3

Cirrhosis: 91.9 vs 68.2, Ascites: 10.1 vs 21.9

TNMS I: 66.2 vs 19.3 II: 27.2 vs 37.2 III: 3.7 vs 28.9 IV: 2.9 vs 14.6 (p<0.0001)

Hepatic resection: 53.5 vs 34 (p<0.0001) TACE: 35.1 vs 29.9

Unadjusted OR (95% CI) of survival at 1yr: 3.57 (5.26–2.38) 2yr: 3.70 (5.26–2.56) 3yr: 3.57 (5.26–2.44) 

Adjustedl OR (95% CI) of 

survival at1yr: 1.72 (2.86–1.03)2yr: 2.22 (3.70-1.35) 3yr: 2.27 (3.85–1.37)

 otherwise specified; NS = nonsignificant(ly).

 examined but an adjusted hazard ratio was not reported.

HCC, year of diagnosis, age, race, MELD, psychosis, ascites, varices, encephalopathy 

Child-Pugh 

 alcohol use, stage 

tumor, absence of portal vein thrombus, stage, surgical resection 

ter, hepatology assessment before diagnosis, early stage, receipt of potentially curative treatment. 

s, treatment received 

s A, platelets per log10 increase, AST per log10 increase 

AFP, and lead time adjustment. 
43

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9CONTENTS 34

methods for potential sources of bias in cohort studies of screening for hepatocellular carcinoma in patients with chronic 

 screening group distinguished 

rom non-screening?

Was this definition 

objective and replicable?

Loss to follow-up, 

difference in loss to 

follow-up between 

screened and 

unscreened?

Selection bias - are screening and 

nonscreening groups drawn from 

similar populations?

Ascertainment of 

outcomes adequately 

described and similar 

between surveilled 

and non-surveilled 

groups?

p were patients prospectively 

eening program. Non-screening 

red - possible that some of these 

creened, but no data

Yes, for the screening group, not for the non-screening group. 

Data for screening group only: Mean follow-up months: 56 7.7% lost to follow-up

Compared patients at an institution to referral patients. 

Unclear

ng screening vs those who refused Objective, but not valid. NR No - non-screening group were those 

that refused intervention. 

Probably yes (national death registry)

nd CPT codes to determine receipt 

ounds. Used an algorithm to 

her AFP or US were performed for 

based on lab data and ICD-CM 

Yes NR, but unlikely that there 

was differential or high loss to follow-up as included all VA patients and they conducted sensitivity analyses using Medicare data for older patients

Yes Yes - the date of death 

was obtained from the VA vital status file.

ening defined as having AFP, 

n 3 years prior to HCC diagnosis. 

eview used to assess intent of 

rmed for acute symptoms, during 

or to assess a mass were not 

ening. 

Yes NR Yes Yes

p defined as those who were 

-up for cirrhosis. Control patients 

atients or had tests done at "non

vals"

No NR Unclear - control patients had tests 

done at "non-scheduled intervals" but it was unclear whether this meant they were enrolled in cirrhosis clinic but failed to present for testing or were not enrolled in a screening program. 

No

p were those treated by 

y unit, which used regular 

ear how unit of treatment was 

No - it is not clear how patients were chosen for treatment by gastroenterology unit

Unclear No - groups defined by treating unit 

which may treat different patient populations. 

Unclear

p had AFP and US done as part of 

am and repeated within one year. 

ad HCC diagnosed because of 

 part of another work-up, but it is 

ey differentiated groups based on 

No NR Unclear - not enough detail about 

both groups. Unclear whether control patients were referred from outside institutions and why they would not have received screening. 

Yes - national mortality dataset

creening group were those who 

r imaging in year prior to diagnosis 

ve reason for testing was apparent 

w. 

Yes NR, but unlikely that there 

was differential or high loss to follow-up as included all VA patients 

Yes Yes - VA patients
44

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9CONTENTS 34

 screening group distinguished 

rom non-screening?

Was this definition 

objective and replicable?

Loss to follow-up, 

difference in loss to 

follow-up between 

screened and 

unscreened?

Selection bias - are screening and 

nonscreening groups drawn from 

similar populations?

Ascertainment of 

outcomes adequately 

described and similar 

between surveilled 

and non-surveilled 

groups?

p were patients seen in Liver Unit 

as part of their regular screening 

creening group were either patients 

agnosed with HCC because of 

agnosed with HCC at the time of 

sis

No, it is unclear why some patients attending a screening program and others didn't. Also unclear procedures for cirrhosis work-up.

28 out of 290 patients were lost to follow-up but did not differentiate between screened and unscreened

No - some non-screening patients were referred from outside institutions and others at the institution did not attend screening program for unclear reasons.

Yes, through registry

ning group patients were part of a 

am. Non-screening patients had 

ecause of symptoms (12%), as a 

creening (11%), incidentally during 

20%), and referred from outside 

No - unclear how symptomatic detection was determined retrospectively and unclear how referral patients were surveilled. 

None Unclear - probably not, the majority of 

non-screening patients were referred from outside institutions with little detail about care at these institutions. 

Unclear

creening group presented with 

unclear how this was determined in 

view

No Loss to follow-up - unclear 

Median follow-up months: 41.3 vs 29.6

Unclear - does not specify whether these were consecutive patients with HCC. All were from single institution, but unclear why some patients received routine screening while others did not. 

Unclear

creening group was referred from 

nfo on screening among non

p. 

NR NR Unclear - non-screening patients 

presented to clinic with HCC. No information about their prior care. 

Source of death data NR

mptomatic presentation was 

No 5 vs 4 vs 9 No - Most patients treated at study 

center were part of screening program, while referral patients were not. 

unclear

tails about how symptomatic or 

diagnoses were categorized in the 

No 0 vs 2 vs 2 No - Most patients treated at study 

center were part of screening program, while referral patients were not. In fact, treating center was independently associated with survival. 

unclear

p pts enrolled in a screening 

creening group was referred - 

me of these patients were screened, 

e assumed that these patients did 

lar follow-up or screening with AFP 

e HCC was an

g."

No NR 

Data for screening group only: median duration of follow-up 184 weeks (range 61–363 weeks). 

No - non-screening group defined as being all referral patients

Unclear

ted. Screening group: tumors 

ng routine follow-up US, no 

ency. The nonscreening group 

 opportunistic and symptomatic 

unistic group: tumors were found 

alth checkup or other nonhepatic 

 liver-associated symptoms 

oup - visited hospital because of  symptoms. 

No NR Unclear - not enough information 

about how groups were defined

Yes - linked to Taiwan mortality data
45

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d trials comparing TACE to supportive care in patients with hepatocellular carcinoma

usion and exclusion criteria

Sample 

characteristics; 

liver disease 

etiology 

(% T vs C)

Liver disease 

stage 

(% T vs C)

Survival

(%T vs C)

Adverse events

C with AFP >250ng/ml, 

uded patients who were 

idates for surgery, previous 

ment, severe liver disease, 

ular contraindications 

emoembo, increased 

tinine, extrahepatic mets.

Mean age 63 vs 65 Male 96 vs 96 EtOH 76 vs 73 HBV 4 vs 7HCV 9 vs 10Primary hemochromatosis 11 vs 10

Okuda I 94 vs 84.8 Okuda II 6 vs 15.2

Unadjusted RR of death: 0.7, (95% CI 0.45-1.11, P=0.13) 1-year: 62 vs 43.5 2-year: 37.8 vs 26 Adjusted RR of death: 0.77 (95% CI 0.48-1.25, P=0.31)adjusted for Karnofsky score, ascites, bilirubin, albumin, tumor type, tumor mass, portal obstruction AFP, chemoembolization

Trial stopped due to deaths in both groups (liver failure, GI hemorrhage, SBP). Chemoembolization led to <50% increase in survival after 8 months, therefore trial stopped. Abdominal pain 80% Vomiting 80% Fever 76% Death 2% Ascties 10% Encephalopathy 2% GI hemorrhage 8% Cholecystitis 4% Elevated AST/ALT ≥ 5x ULN 3 days after treatment 54% Increase in serum bilirubin ≥ 0.9mg/dL 58%Other complications 18%

ents with unresectable 

C. Excluded: poor hepatic 

tion, elevated creatinine, 

ry of prior tumor treatment 

cute tumor rupture, presence xtrahepatic metastasis 

ascular contrainidcations 

emoembolization, poor 

ormance status

Mean age 62 vs 63 Male 90 vs 87 HBsAg pos 85 vs 74

Okuda I 47.5 vs 46.1, Okuda II 52.5 vs 53.9

Unadjusted:1-year : 57 vs 322-year: 31 vs 113-year: 26 vs 3RR of death 0.50 ( 95%CI 0.31-0.81, p=0.005) Adjusted RR of death: 0.49 (95% CI 0.29-0.81, p=0.006), adjusted for symptoms, portal vein obstruction, Tumor size, Okuda, treatment with TACE

38 patients had treatment stopped because of progressive disease (12 patients), death (7 patients), poor liver function (6 patients), adverse effects (6 patients), patient refusal (3 patients), arteriovenous shunting (2 patients),and hepatic artery thrombosis (2 patients). The most common clinical adverse effect was a self-limiting syndrome consisting of fever, abdominal pain, and vomiting. 

secutive patients with 

C were included. Excluded: 

ctable HCC, patients with 

taneous encephalopathy 

associated poor survival 

s, non-embolizable HCC 

to portal vein thrombosis, 

evious porto-caval 

stamosis.

Age 64 vs 66 Male 91 vs 86 EtOH 71.4 vs 66.7Non-EtOH 28.6 vs 33.3

Okuda I 28.6 vs 23.8 Okuda II 53.4 vs 52.4 Okuda III 19 vs 23.8

Unadjusted: 6 month 33 vs 52 1 year 24 vs 31 (no statistical difference)

Two severe complications of chemoemoblization: death from acute renal failure in one patient, and a gastrointestinal hemorrhage from acute gastroduodenal ulcerations
46

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methods for potential sources of bias in randomized trials of TACE in patients with early-stage hepatocellular carcinoma 

uence 

ration Allocation concealment

Blinding of participants, 

personnel and outcome 

assessor

Incomplete 

outcome data

Selective outcome 

reporting

Other sources 

of bias

Summary 

assessment: 

Risk of Bias

domized Yes, centralized 

telephone center

Can't answer, no mention of blinding 

Yes Yes Yes Low

No – sealed, but not necessarily opaque envelopes, not centralized

Can't answer, blinding not discussed

Yes, ITT. Censored patients lost to F/U

Yes Yes Unclear

Probably yes, randomization and assignment done centrally at one center

Can't answer, no mention of blinding of radiologists and others that could have been blinded

can't answer, No mention of loss to follow-up

Yes Yes Unclear
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ring resection, RFA, TACE, and OLT to supportive care in patients with hepatocellular carcinoma 

ve 

ment 

ities

Cohort definition

Sample characteristics; 

liver disease etiology

(% T vs C)

Liver disease 

stage, Child-Pugh, 

or MELD

(% T vs C)

Stage at 

Diagnosis

(% T vs C)

Survival 

(% T vs C)

Adverse 

events

All patients with diagnosis of HCC within Milan criteria on the liver transplant waiting list or listed patients who developed HCC while waiting liver transplant at a single transplant center in Toronto. Patients were stratified into RFA (n = 77) and No Treatment groups (n = 93). 

Age 56 vs 55 Male 86 vs 81 Female 11 vs 18 HBV: 22 vs 19 HCV: 64 vs 56 EtOH: 12 vs 26 NASH/Cryptogenic 4 vs 4 Other: 1 vs 5

MELD (14 vs 15) Mean number 

1.33 vs 1.35 Max size 2.5 vs 2.4

Among non-transplanted patients (waiting list drop-off events) Unadjusted: 1-year: 87 vs 71 3-year: 76 vs 39 5-year: 55 vs 30 (P=0.009) Adjusted RR not reported

n=77, No 

major events, 

2 minor 

events (L 

portal vein 

thrombosis, 

vasovagal 

reaction)

n

ve/ 

edical 

Consecutive patients with HCC at 10 institutions forming the ITA.LI.CA (Italian Liver Cancer) group, of whom 228 were eligible for OLT.

OLT eligible (n=228):Male 77.6

Child-Pugh class:A 52.2B 47.8

Single lesion: 62.2Up to 3 nodules: 37.7

Among pts eligible for OLT, median survival in months:OLT (mean) 143.7 Resection 56RFA 44TACE 34Supportive 23(p=0.001)Adjusted HR not for each modality not reported.

No

n; 

CE; 

c 

erapy

All patients diagnosed with HCC at a single center in Korea. Excluded patients with inadequate data, prior initial treatments for HCC at other hospitals, or interruption to follow up. The survival of the patients was analyzed on the basis of the initial treatment adopted in patients with Child-Pugh class A or B. For initial treatment, 17 patients (6.6%) underwent surgical resection, 19 (7.4%) underwent RFA, 135 (52.5%) underwent TACE, 2 (0.8%) received systemic chemotherapy, and 84 (32.7%) received supportive care.

Age <50 16, ≥ 50 84Male 77, Female 23 Serum AFP levels > 400 ng/mL 41.2 HBV 66 HCV 5 HBV/HCV 1 EtOH 19 Unknown 9

Childs A 41Childs B 40 Childs C 19

TNM I 7 TNM II 37 TNM III 31 TNM IV-a 16 TNM IV-b 9

Unadjusted survival in patients with TNM I & II disease: Resection vs RFA vs TACE vs Conservative: 1-year: 100 vs 81.8 vs 73 vs 25 3-year: 91.7 vs 36.4 vs 33 vs 8.3 5-year: 75 vs 27.3 vs 19 vs 8.3 (P<0.01) Adjusted RR not reported

No
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ve 

ment 

ities

Cohort definition

Sample characteristics; 

liver disease etiology

(% T vs C)

Liver disease 

stage, Child-Pugh, 

or MELD

(% T vs C)

Stage at 

Diagnosis

(% T vs C)

Survival 

(% T vs C)

Adverse 

events

n All histologically confirmed HCC, 

patients considered resection candidates with a ≤5cm solitary lesion confined to a single lobe of the liver and no medical contraindications to surgery (e.g. cirrhosis), based on SEER data. Excluded patients with contraindications to surgery, and patients who received local therapy (e.g., cryoablation) or underwent transplantation.

Age 60.9 vs 66.8 White 51.5 vs 47.9 Black 4.8 vs 13.8 Asian 30.1 vs 28.2 Hispanic 13.5 vs 10.1 Not reported

Not reported, no cirrhosis in this cohort

Mean tumor size 3.0 vs 3.7

Unadjusted: 1-year: 72.7 vs 40.9 5-year: 32.5 vs 7.3 Median survival 47.1 vs 17.9 month, p<0.001 Adjusted HR 0.45 (95% CI 0.34-0.59, p<0.01), adjusted for resection, age, size, gender, race

No

on-al 

(RFA, 

EI)

All patients diagnosed with HCC at a single center. Patients were divided into those who received locoregional therapies and those who received supportive care.

M/F 81/19 vs 74/26Age (mean) 60 vs 58 Caucasian 59 vs 76 Asian 32 vs 17 Other 9 vs 7 HCV 50 vs 46 HBV 25 vs 22 Combined 2 vs 0 EtOH 14 vs 20 Other 9 vs 7

Childs A 57.0 vs 23.5 Childs B 30.5 vs 24.2 Childs C 10.1 vs 17.4 non-cirrhotic 3 vs 3 Ascites 29 vs 53 Tumor symptoms 23 vs 38

CLIP 0: 16 vs 5 CLIP 1-2: 73 vs 51 CLIP 3-6: 10 vs 34 Tumor extending >50% of liver 5 vs 17 Portal vein thrombosis 5 vs 29 

Unadjusted HR for death 0.48 (95%CI 0.35-0.65, p=0.001 Adjusted HR for death 0.59, 95% CI 0.41-0.83, p=0.03, adjusted for CLIP score, AFP, Alk Phos, Bilirubin

No

T 

n; n + 

FA 

CE 

A 

 

her

ve 

Asian American patients with HCC who were referred to a single tertiary Liver Cancer Center during a 7-year period

Mean age 61.5 (SD 11.7) Males 78.1 Ethnicity: Chinese 52.5 Korean 17.3 Vietnamese 14.0 Japanese 13.3 Other 2.9 Hepatitis B 57.9 Hepatitis C 33.1 HBV and HCV 1.4 Hemochromatosis 1.1 Alcoholic liver disease 0.7 Nonalcoholic steatohepatits 0.4 Von Gierke Disease 0.4 Unknown etiology 4.7

Child Turcotte Pugh A 70.3 B 19.1 C 2.9 Mean MELD score 15.6 (SD 7.8)

Within Milan criteria 56.8 Macrovascular invasion 11.2 Metastasis (11 lung, 3 bone) 5

Unadjusted 1/3/5 year survival: OLT 65/53/53 OLT and TACE or RFA 96/58/50 Resection 66/59/- RFA only 87/63/49 TACE only 49/19/- RFA and TACE 96/48/21 Chemotherapy 17/-/- Supportive 12/12/- Adjusted RR not reported

No

lbumin >3 g/dL, and bilirubin <3 mg/dL; Stage II: moderately advanced (one or 2 of the signs of advanced disease are present; Stage III: very advanced.
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methods for potential sources of bias in cohort studies of resection, OLT, RFA, and TACE in patients with hepatocellular 

Comparability of groups? 

Confounding by indication? 

on of the non-exposed cohort drawn from the 

ame community as the exposed cohort?

Outcome assessment bias? 

Difference in loss to follow-up 

between treated and controls?

Adequate adjustment for 

potential confounders?

ing by indication an issue as no details were given 

 certain OLT candidates would receive RFA and 

uld not, groups are generally comparable

No bias in outcome assessment. No difference in loss to follow-up

Unclear which variables were modeled in the multivariable analysis of overall survival with RFA versus control

all patients who would be potentially eligible for 

e basis of age, tumor stage, and liver disease 

ut did not account for other factors that would 

e surgical candidacy so confounding by indication 

sent. 

No discussion of loss to follow-up Yes 

ing by indication present, unable to assess the 

stics of treatment group as compared to the 

oup, other than by stage

No description of loss to follow-up Unclear multivariable analysis 

for survival

 patients who would be surgical candidates, 

ere comparable. Registry data on surgical 

cations originated from chart review, but unable to 

or patient comorbidities that may have influenced 

o perform surgery. 

No discussion of loss to follow-up No liver disease variable, but 

did not include cirrhotic

groups were not similar, confounding by indication 

No Yes

 groups drawn from the same community, but 

ng by indication present

Loss to follow-up not discussed Yes adjusted for confounders
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ervational studies of OLT, RFA, and TACE in patients with hepatocellular carcinoma

N

Liver disease etiology %

Treatment 

modality Long-term survival % Harms and other findings

5626HBV 26HCV 71HBV/HCV 3

OLT 5-year: 61-72

10-year: 45-66

NR

5776HBV 8HCV 61EtOH 9

OLT 4-year: 67-73 NR

902NR

OLT 5-year: 56 NR

121HBV 45.5

RFA • 1-year: 92.5

2-year: 78.53-year: 67.2

9.9% of patients experienced major complications, namely hemothorax, pneumoperitoneum, persistent intrahepatic biliary dilatation, branch portal vein thrombosis, and peritoneal seeding.

218HCV 83.9HBV 7.3HCV-HBV 4.1Alcohol 3.2Unknown 1.3

RFA 3-year: 76

6-year: 55

1.8% experienced major complications regarded as treatmentrelated: peritoneal bleeding, hemothorax, neoplastic seeding, hyperbilirubinemia lasting for 1 month.

48HCV 35.4HBV 4.2NASH 8.3Alcohol 33.3other 10.4

TACE 1-year: 72

3-year: 284-year: 12

Post-embolization syndrome: 40-50%Hepatic abscess: 2%Transient decompensation with ascites: 8%Quality of life was measured (WHOQOL-BREF) at baseline and after the treatment period. No statistically significant temporal trends were detected for any of the 4 health domain QOL measures (physical, psychological, social relationships, and environmental well-being).
51

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, APASL, and EASL-EORTC guidelines for screening for hepatocellular carcinoma

is 

Screening modality Timeframe for screening Levels of evidence used in guidelines Strength of recommendation levels used in guidelines

ients 

e level 

) 

plant 

Ultrasound (evidence level II; recommendation NR)

6 month intervals (evidence level II; recommendation NR) The screening interval does not need to be shortened for patients at higher risk of HCC (evidence level III; recommendation NR)

Levels of evidence were assigned according to study design:II Randomized controlled trialsII-1 Controlled trials without randomizationII-2 Cohort or case control analytic studiesII-3 Multiple time series; dramatic uncontrolled experimentsIII Opinion of respected experts; descriptive epidemiology

NR

CV 

e 2a, 

Ultrasound and a-fetoprotein (evidence 2a; recommendation B)

6 month intervals (evidence 2a; recommendation B)

The quality of existing evidence was ranked 1 (highest) to 5 (lowest) according to the Oxford system of evidence-based approach for developing the consensus statements.

The strength of recommendations ranked from A (strongest) to D (weakest) according to the Oxford system of evidence-based approach for developing the consensus statements.

 

y 

ce 

1 for 

ce 

C1 for 

ced 

r 

ce 

B2 for 

D; 

Ultrasound performed by experienced personnel (evidence 2D; recommendation 1B)

6 month intervals (evidence 2D; recommendation 1B)

(adapted from National Cancer Institute*)Level 1: Randomized controlled clinical trials or meta-analysesof randomized studies*(i) Double-blinded(ii) Non-blinded treatment deliveryLevel 2: Non-randomized controlled clinical trialsLevel 3: Case series(i) Population-based, consecutive series(ii) Consecutive cases (not populationbased)(iii) Non-consecutive casesStrength of evidence according to endpoints:A. Total mortality (or overall survival from a defined time)B. Cause-specific mortality (or cause-specific mortality from adefined time)C. Carefully assessed quality of lifeD. Indirect surrogates(i) Event-free survival(ii) Disease-free survival(iii) Progression-free survival(iv) Tumor response rate

(adapted from the GRADE system)Grading of evidenceA -High quality: Further research is very unlikely to change our confidence in the estimate of effectB -Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimateC- Low or very low quality: 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. Any estimate of effect is uncertain.Grading recommendation1-Strong recommendation warranted: Factors influencing the strength of the recommendation included the quality of the evidence, presumed patientimportant outcomes, and cost2-Weaker recommendation: Variability in preferences and values, or more uncertainty: more likely a weak recommendation is warranted. Recommendation is made with less certainty: higher cost or resource consumption

of evidence for adult and pediatric cancer treatment studies. Bethesda, MD: National Cancer Institute. http://www.cancer.gov/cancertopics/pdq/levels-evidence

ciation for the Study of Liver Diseases; APASL = Asian Pacific Association for the Study of the Liver; EASL-EORTC = European Association for the Study of the 

ch and Treatment of Cancer; NR = not reported
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sessment of guidelines for screening for hepatocellular carcinoma

AASLD APASL EASL-EORTC

is guideline 2 3 3

1 (strongly disagree) – 7 (strongly agree)

 guideline is (are) specifically described. 6 6 7

d by the guideline is (are) specifically described. 6 6 7

d by the guideline is (are) specifically described.* 6 6 7

oup includes individuals from all relevant professional groups.* 2 5 3

 the target population (patients, public, etc.) have been sought.* 1 1 1

ne are clearly defined.* 4 4 6

ed to search for evidence.* 2 3 4

vidence are clearly described. 1 1 1

of the body of evidence are clearly described. 1 2 3

he recommendations are clearly described.* 2 3 3

cts, and risks have been considered in formulating the recommendations.* 2 2 2

en the recommendations and the supporting evidence.* 2 3 4

nally reviewed by experts prior to its publication.* 2 5 1 

guideline is provided.* 1 1 1

ecific and unambiguous. 5 5 5

agement of the condition or health issue are clearly presented.* 4 4 5 

sily identifiable.* 4 5 6 

ators and barriers to its application. 2 2 2

 and/or tools on how the recommendations can be put into practice. 2 2 2

ations of applying the recommendations have been considered. 2 2 2

oring and/or auditing criteria. 1 1 1

y have not influenced the content of the guideline.* 1 1 1 

ne development group members have been recorded and addressed.* 3 1 1 

ciation for the Study of Liver Diseases; APASL: Asian Pacific Association for the Study of the Liver; EASL-EORTC: European Association for the 

r Research and Treatment of Cancer 
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R REVIEW COMMENTS AND RESPONSES

Comment Response

ives, scope, and methods for this review clearly described?

essive.

ods section pertaining to inclusion of systematic reviews of comparative 

studies is a little unclear—at first it says these studies were excluded, 

s you included reviews of comparative effectiveness studies (if I’m 

 correctly). I didn’t really see anything in the results comparing one active 

nother so it seems to me that it would be clearer to just say that studies 

 active treatments were excluded—unless there was some specific 

ason that you included them, and then just say “we included systematic 

dies that compared active treatments and reported xx outcomes” or 

 that—which I think would be more straightforward.

We agree. We initially had looked at these studies to gather more information about treatment-specific harms, but we agree that the majority of harms data we report are from cohort studies. We’ve clarified that studies that compared active treatments were excluded. 

ent)ent)

f HCC surveillance on mortality in pts with chronic liver disease

ent)

 the objectives, scope, and methods for this review are clearly described, 

ecifically address issues related to the situation in the Veterans Health 

. In an e-mail dated 19 February 2013 to the ESP, I had indicated that this 

of major interest to my office.

The scope of the review was broad enough to have captured studies both directly and indirectly relevant to VA. We did include a section (in Results) specifically focused on VA studies. In our edits, we added more detail to our discussion of the 3 VA observational studies and more about current screening practices in VA. We agree that the background should have included VA-specific information – we’ve added some information about change in prevalence of HCV and HCC diagnoses in VA over time. 

of bias in our synthesis of the evidence?

nt)nt)nt)nt)

xclusion of articles not in English

nt)

e to consider the natural history of HCC introduces a serious 

flaw that biases the results towards the finding that there is not evidence 

tment of early HCC . The implicit assumption that HCC is similar in its 

ior to malignancies such as prostate cancer – where patients may survive 

thout treatment – is incorrect (please see comments 3 and 4 infra). If 

-small cell lung cancer, the approach used here would likely conclude that 

cient evidence to support resection of stage 0 or stage 1A NSCLC.

We agree that the natural history of HCC is important contextual information. In the initial draft, we did consider natural history in the discussion, albeit briefly. In our edits, we 

have expanded our discussion of natural history and the implications of natural history on the overall balance of risk/benefit for HCC screening. Much of the information about the natural history of early-stage HCC is several decades old. What information there is suggests that the natural history of early-stage HCC varies. 

 failure to include trials that compare 2 different modalities systematically 

ence that supports treatment of early HCC.

Throughout the report, we have clarified that we evaluated treatment studies only as a way to indirectly evaluate the effects of screening. Because this review was focused on screening, we looked for evidence of the effects of treating screen-detected (or earlystage HCC) compared to no treatment. Studies comparing 2 or more active treatments would not have provided evidence about the effects of treating screen-detected disease. 
54

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Comment Response

 discussion of harms from evaluation of liver lesions detected via 

iled to note that the diagnosis of HCC is most often made by imaging 

psy. This consideration was communicated in my e-mail of 19 February 

addressed in this document.

The initial draft’s discussion section did include a statement about diagnoses most often occurring as a result of imaging rather than biopsy. Nevertheless, we have re-written the screening harms section to clarify that, in considering harms, we considered the harms of the initial screening tests themselves as well as the harms of additional testing done in response to initial positive screening test results. We agree that liver biopsy is not commonly performed for the diagnosis of HCC, but it is performed sometimes and the harms are important to consider. In our re-drafted section, we clarify that few studies reported testing actually performed. The 2 studies that reported rates of liver biopsy used in HCC diagnosis reported 33 and 80% of patients had liver biopsy performed. We also clarified in the summary of evidence table that there was limited directness of information about harms (since most had to do with needle track seeding and biopsy is not often used in current practice).

ch methodology is well explained and most of the relevant direct 

been captured. There are however several problematic issues. 

eview, there is a large body of observational studies that consistently 

ciation between HCC surveillance and HCC diagnosis at an early 

e receipt of resection or transplant, and increased survival. This is 

y not grade 1 evidence but it is grade 2. Expressing the data as “there is 

s inaccurate. Rather, there is evidence of grade 2 level that consistently 

c. 

We disagree that we characterized the data as “there is no evidence”. We graded the evidence as “insufficient” because it is impossible to know whether the improved survival observed in these studies among screen-detected patients was related to a true effect of screening or, rather, to lead-, length-, and selection biases common to the studies. There are also important inconsistencies among studies – 3 of 4 studies that attempted to correct for lead-time found survival advantages attenuated with longer tumor doubling time assumptions. Nevertheless, we agree that readers could misinterpret the term “insufficient” as “there is no evidence”. Therefore, we elected to use GRADE terminology to summarize the strength of evidence rather than the AHRQ terminology we originally used. Using GRADE, we believe the strength of evidence would be “very low”. We have used this term in place of insufficient in our edited draft and hope this will better communicate that there are indeed studies, but that any conclusions drawn from this body of evidence are very tenuous. 

be “kitchen sink” approach of piling disadvantages of the two RCT, but not 

through as to the possible consequences of the disadvantages. A couple 

e low screening rates, and inclusion of non cirrhotics would bias the 

the null (not the opposite). 

We agree that this section could have been more thoughtfully presented. We’ve rewritten to include a more precise discussion of how various deficiencies might affect the results. 

y seem to ignore the meta analyses of RCT (and observational studies) 

trate statistically significant benefit in survival. 

there is no mention! It is the only RCT proven efficacious intervention for py of HCC. 

These studies were not included because we were focused on screening efficacy and, therefore, focused only on studies evaluating the effects of treating early-stage HCC (since the effects and rationale for screening is most likely to increase the detection of earlier stage disease). The TACE meta-analysis included the 3 trials we included plus a fourth (the Llovet Lancet trial) that we excluded because it included only patients with advanced stage disease. Likewise, sorafenib has only been evaluated inpatients with advanced stage disease. We have clarified throughout the report that we were focused on this specific subgroup of treatment studies. We agree that, though this language was in the initial draft, readers might have missed that we were not evaluating HCC treatment in general. We also include an additional statement in the limitations section that this review applies only to early-stage disease and not advanced stage, and we acknowledge that some patients undergoing screening could have newly discovered advanced stage disease. 

 not get into the many studies that report survival of patients who were 

ansplanted compared to those listed and transplanted (at the same stage). 

We included comparative and non-comparative observational studies of OLT if they included patients with early-stage disease. 

y, there is no numerical emphasis on worst case scenario against HCC 

or example mentioning the point estimate of the meta analysis for tumor 

t the 95% CI or the more recent study described in the body of the 

ng term survival (which is quiet good) with resection and transplant is 

out numbers. 

We have included the long-term survival numbers, the CI information, and we also note in the table the most recent needle-track seeding study. 
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Comment Response

ummary of the document is not accurate or supported by the data: consistent 

de 2 is not the same as insufficient evidence to draw conclusions. 

See response to comment #18. 

ethics of RCT need also to be addressed in light of existing studies that 

atients are unlikely to accept such a trial when (nothing is one of the arms).

We have included this as an important area for future research. 

ces 

Farrell GC, Strasser SI, Lee AU, McCaughan GW, George J. Feasibility 

a randomized control trial for liver cancer screening: is a randomized 

for liver cancer screening feasible or still needed? Hepatology. 2011 

8-2004. doi: 10.1002/hep.24581. PubMed PMID: 21800340. 

Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M, Brú C, Rodés 

ural history of untreated nonsurgical hepatocellular carcinoma: rationale 

and evaluation of therapeutic trials. Hepatology. 1999 Jan;29(1):62-7. 

: 9862851. 

Duan Z, McGlynn KA, El-Serag HB. Utilization and outcomes of palliative 

patocellular carcinoma: a population-based study in the United States. 

nterol. 2012 Jan;46(1):71-7. doi: 10.1097/MCG.0b013e318224d669. 

: 22157221; PubMed Central PMCID:PMC3832893. 

F, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, 

survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009 

485-91. doi: 10.1200/JCO.2008.20.7753. Epub 2009 Feb 17. PubMed 

38; PubMed Central PMCID: PMC2668555. 

E, Smith DD. Trends in local therapy for hepatocellular carcinoma and 

mes in the US population. Am J Surg. 2008 Jun;195(6):829-36. doi: 

urg.2007.10.010. Epub 2008 Apr 23. Review. PubMed PMID: 18436176. 

B, Siegel AB, Davila JA, Shaib YH, Cayton-Woody M, McBride R, 

Treatment and outcomes of treating of hepatocellular carcinoma among 

ients in the United States: a population-based study. J Hepatol. 2006 

66. Epub 2005 Nov 2. PubMed PMID: 16290309. 

B, Mason AC, Key C. Trends in survival of patients with hepatocellular 

ween 1977 and 1996 in the United States. Hepatology. 2001 

. PubMed PMID: 11124821. 

l-Serag HB. Racial differences in survival of hepatocellular carcinoma 

tates: a population-based study. Clin Gastroenterol Hepatol. 2006 

0; quiz 4-5. PubMed PMID: 16431312. 

hu AX, Gordon FD, Pratt DS, Mithoefer A, Garrigan K, Terella A, Hertl M, 

ung RT. Liver transplantation outcomes for early-stage hepatocellular 

ults of a multicenter study. Liver Transpl. 2004 Nov;10(11):1343-54. 

: 15497158.

Most of these provide background or contextual information. We have reviewed all these studies and included them in background or discussion as appropriate. We have re-written the background to include more information on changing HCC incidence (including the Altekreuse reference). We did examine the Leung study for inclusion as a comparative observational study. However, it compared HCC patients receiving OLT to patients receiving OLT for non-malignant disease. Because there were several large national OLT cohorts, we only examined noncomparative OLT studies with > 500 patients. The 5-year survival reported in this smaller cohort was quite similar to the survival we report from the larger cohorts. 

 or unpublished studies that we may have overlooked?

nt)

m aware of.

know of.

nt)

 I am aware of
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Comment Response

ese are only a small portion of the literature that could be cited that 

 findings in this document, particularly with regard to treatment of early 

m JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials 

lar carcinoma treated with percutaneous ablation therapies. Hepatology. 

):453-9.

B, Siegel AB, Davila JA, Shaib YH, Cayton-Woody M, McBride R, 

Treatment and outcomes of treating of hepatocellular carcinoma among 

ients in the United States: a population-based study. J Hepatol. 2006 

66. 

Real MI, Montaña X, Planas R, Coll S, Aponte J, Ayuso C, Sala 

Solà R, Rodés J, Bruix J; Barcelona Liver Cancer Group. Arterial 

r chemoembolisation versus symptomatic treatment in patients with 

epatocellular carcinoma: a randomised controlled trial. Lancet. 2002 May 

1734-9. 

J, Bulkow L, Harpster A, Snowball M, Lanier A, Sacco F, Dunaway E, 

reening for hepatocellular carcinoma in Alaska natives infected with 

is B: a 16-year population-based study. Hepatology. 2000 Oct;32(4 Pt 

Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal 

rcutaneous ethanol injection for small hepatocellular carcinoma in 

-analysis of randomized controlled trials. Am J Gastroenterol. 2009 

4-24.

E, Smith DD. Trends in local therapy for hepatocellular carcinoma and 

mes in the US population. Am J Surg. 2008 Jun;195(6):829-36.

We had reviewed most of these studies. They were excluded for following reasons:Cho – comparative effectiveness studiesEl-Serag – no outcomes specific to patients with early-stage disease. Llovet – trial included only patients with advanced stage disease. McMahon – we excluded observational screening studies with historic controls (because there were plenty of studies with contemporary controls and the use of historic controls would have introduced one more source of bias). Orlanda – comparative effectivenessSchwarz – no outcomes information specific to patients with early-stage disease. 

on based US data on survival of patients with HCC who were 

There are several publications based on UNOS data that show excellent 

ear recurrence free survival) survival among HCC patients who received 

s.

We included several large OLT cohorts including a large UNOS cohort. We agree longterm survival was good and we reported this. 

iple publications from population based US based cohorts (plus the 

ble SEER data) that show stage specific survival of patients with HCC, 

rly showing remarkable improvement with transplant and resection 

atients with similar stages who did not get transplanted/resected. These 

nal studies but the magnitude of differences is dramatic. 

In initial draft, we did not include the comparative numbers in the summary of evidence (only in the text) – we’ve now added this to the table. We reported that survival in patients selected for surgery is quite good and markedly better than patients not selected for surgery. We have added more to the discussion about the potential explanations for such findings – unclear whether this is a true treatment effect or whether this difference reflects careful patient selection and confounding by indication. 

 publications of US based population based cohorts that show unfirmly 

 of untreated patients with HCC (irrespective of stage if one looks at 5 

Compare with 5 year survival of transplant/resection. 

See above

emarkably deficient and biased. There is mention of harms of biopsies for 

nd harms of different treatments, but nothing about ultrasound of the liver 

 (for AFP). This is akin to talking about the harms of colorectal resection 

py but not colonoscopy or FIT (for CRC screening) or harms of breast 

t mammography). Both ultrasound and blood draws (which is the method 

 AFP) for all kinds of indications have been around for decades and there 

e safety data on both.

We have re-written the screening harms section to clarify that, in considering harms, we considered the harms of the initial screening tests themselves as well as the harms of additional testing done in response to initial positive screening test results. We acknowledge that ultrasound and blood draws are, themselves, likely quite safe. Nevertheless, it is still important to consider the harms of testing done in response to initial positive screening test. 
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Comment Response

f discussion on TACE (which is appropriate) but there is a remarkable 

he one palliative therapy that has grade 1 evidence of efficacy from multiple 

 modern RCTs, namely sorafenib. This agent can only be applied (and 

tested in those with compensated cirrhosis (mostly Child A) and mostly 

mildly symptomatic patients. Surveillance even if it does not detect early 

reated with potentially curative therapy, will detect asymptomatic cancer 

 treated with efficacious palliative treatment. The days of removing patients 

ndidates for liver transplant from surveillance consideration are gone. 

See response to #20. While it is true that some patients undergoing screening will have asymptomatic advanced stage disease identified, the intent and results of screening are to increase the detection of early-stage disease. Trials evaluating screening intervals found, in both groups, that screening mostly increased the number of early-stage small tumors. While we acknowledge that our review does not cover the detection and treatment of advanced stage disease, we believe a focus on early-stage disease is appropriate for the discussion of screening. 

ally four RCT of TACE/TAE (check recent meta analyses) See above #20. 

suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report.

ost of CT and MR that precluded their inclusion in the AASLD PG. I was 

ttee when the issue came up. Everyone I know uses AFP to screen 

nsensical “firing of the AFP” by that PG. I have seen MANY advanced 

e missed on u/s and obvious on CT. CT as performed in the US for HCC 

eadfully insensitive. 

Noted. We searched for any screening studies using any of these potential screening modalities. Most studies included patients who were detected with U/S and/or AFP. 

 of places the report refers to radiofrequency ablation but doesn’t 

 as another “active” treatment. These are not the same thing so both 

tioned.

We cover both RFA and TACE. 

n describing the RCT’s of screening vs. no screening there is some 

e Chinese staging system which might warrant some revision. The 

at the Chinese system doesn’t consider liver disease severity which is not 

undice/ascites/cachexia etc are markers of disease severity (and to my 

such clinical markers are now included in the Barcelona and other staging 

nk the more accurate critique would be to note that the Chinese studies used 

ng system than currently used in the U.S. and Europe that didn’t include 

 tumor size, number of lesions, and location of lesions, and focused on 

s of disease severity (if I’m stating this accurately) and leave it at that.

We have re-written the trial results section to be more precise about the effects of each flaw, including the staging system. 

n on screening vs. no screening it would be helpful to at least report 

y of the difference in survival reported in the observational studies. I 

n adjusted estimates only and report the median difference with the 

ow there is really no quantitative report of the results so it’s hard for 

w what to make of it. Even if the data are unreliable providing some 

give readers some sense of the potential magnitude of effect, whether 

 likely to explain much or all of the results, inconsistency, etc.

We have re-drafted the screening observational studies table to make it easier to find the survival and HR data. We have also created a new figure displaying comparative survival information. Finally, we have included a summary of this information in the relevant parts of the results section. 

e section on active treatments vs. conservative treatments—for the 

est reporting the actual results from the two studies that didn’t report 

 effect on survival and for the observational studies reporting some 

garding the differences between treatment and no treatment.

This information is included in the treatment studies table. 

– well done review.

resses internal validity (risk of bias) of the trials quite well. I wonder if a 

ut external validity (applicability/generalizability) might not also be useful. The 

many Hep C providers use the Chinese trial of patients with hep B as the 

mending screening/surveillance for HCC in hep C patients. Clearly that trial 

 for recommending screening, even for hep B patients, but there may be an 

e with extrapolating the results (however interpreted) to hep C patients. 

We included such a statement in our revisions. 
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Comment Response

traction, in addition to mode and frequency of surveillance it would be 

eview technical limitations of surveillance. A main limitation of ultrasound 

 the poor visualization of the liver parenchyma in patients with more 

osis and fatty change. In these patient populations, the detection of 

d particularly smaller HCC lesions, is limited. These limitation would likely 

t on surveillance efficacy. 

This was beyond the scope of our review. However, an AHRQ review is currently being completed that covers just this topic. 

reat job going through a large number of studies. The draft report 

n and well structured to present results at different levels of detail, 

the reader’s specific needs. 

 surveillance means looking for recurrence of a prior cancer; thus, the 

 should not use that term but rather screening for HCC. Screening 

ancer in those without a prior diagnosis of cancer. This is more than 

he continued misuse of the term surveillance tends to separate HCC 

m a wealth of knowledge about cancer screening which seems to be 

context. This sentence seems to highlight the problem: “However, 

ons for HCC surveillance remain controversial in part because of 

 the quality and paucity of existing evidence, and because there have 

 raised about overdiagnosis and patient harms in other cancer screening 

s too easy for some to ignore this sentence because HCC surveillance 

 screening program. At the very least you should include a definiton of 

r statement that HCC ”surveillance” is in fact a type of cancer screening 

r surveillance as would be done after surgical resection of HCC. 

We agree – we have changed the terminology to screening from surveillance. 

tive summary, it would be helpful to separate the review of the two RTCs 

RTCs. In particular, the latter RTC seems to have flaws that were not 

the guideline writing groups and may not be well known to the end users 

port who read only the Executive Summary. 

We have done so. 

sider including overdiagnosis bias as another confounder for non RTCs 

ing, and perhaps comment on the magnitude of overdiagnosis in the two 

We have included more in the discussion about natural history and about uncertainty regarding the potential for overdiagnosis in screen-detected HCC. We could not estimate the magnitude of overdiagnosis in the RCTs, but we do make note of the trials comparing screening intervals in which more early-stage patients were found and treated in the intensive screening group without an improvement in survival. 

e paper probably reaches the right conclusion, the whole paper seems 

at disjointed and a bit frustrating to read. A reader gets the sense of 

y” about how studies were not well-done. While that may be generally 

if the authors could be more constructive to the field with some more 

e and assessment and suggestion. For example:

‘best evidence’ and how good is it? 

n’t really explain what you are looking for, regarding “quality of evidence” 

of effect.” Later you will describe weaknesses of many studies, but the 

re described for several studies at a time rather than individual studies, 

was left wondering “is there a baby somewhere in this bathwater; is there 

t qualifies at ‘best’ and is that ‘good enough’”. My hunch is that the 

or example both the Chinese RCTs have major deficiencies. But if that’s 

maybe be clear about it.

We agree. As reported above, we revised the results section to be clearer about the flaws and their implications. We also reconfigured the observational studies results section and discuss the 3 “best” studies earlier. 
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Comment Response

above observational studies, you’ve just finished a 2-page review of 

u write no summary of what you think of the 2 pages you have written. 

dication that you’ve synthesized or evaluated this entire group of studies. 

arly done in the Discussion either). You simply end with critique of 

happened to be last. In contrast, a reader would like to know “What 

 line about this whole class of studies, about what you have just told 

ome close to being satisfactory to draw a conclusion? Is the quality of 

ory? Can we take away any idea about magnitude of any impact, or is 

(or magnitude so low) that we can’t? 

We agree. We have included a summary paragraph at the beginning of both the screening and treatment sections. 

owing sections have the same problem: You write paragraphs about 

es or groups of studies, but you don’t summarize at the end of each 

ou have described and what you think it means. For example look at 

agraph on p14; there’s no summary, just diffuse anxiety (again probably 

t the whole process looks like you are just throwing up your hands. Ditto 

 lead-time bias, harms, treatment. 

See above. 

ization

ervational studies, you need to remind the reader “what question were 

 - benefit, harm, other?

We have revised the section headings accordingly

delines

idelines section has the potential to be interesting, to the extent that 

s recommend FOR surveillance. When they do, can you:

at is their recommendation (it’s in the Table);

based on (what evidence; what studies, what statements about benefit 

 of this may be buried in Table 12, but can you distill the essence and 

ou think the problem is?

ge (2).

 seem to rely on saying the guidelines aren’t any good because (p19, first 

ntified several methodological flaws...”. Can you elaborate more on the 

ndix D, Table 12: How strong or weak is an overall quality grade of 2 or 

us are the generally low grades in rigor of development? Enough to be 

Can you say any detail about what specific studies about the evidence 

 seems to rely on - which study, what magnitude of benefit and of harm? 

n the Chinese RCTs, now largely-discredited? Or other? Right now the 

ems somewhat an abstract exercise; can you give it a little more detail 

rpreting/summarizing the data in the Tables and in your text summary? 

We have revised this section accordingly. 

es

ara in Future Studies, you could provide much more help to the field by 

ecific about what you think should be done in the future, based on what you 

om your reviews. The recommendations for “consecutive patients” and 

collected .... about adverse effects” seems somewhat generic. In earlier text 

ed lead-time bias, trying to adjust for it, and other sources of problems. Can 

s section, try to tell future-researchers how to improve what they are doing.

We agree. We now included a future studies table that pairs study suggestions with the evidence gap they are meant to address. 
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Comment Response

e 1 - The statement that the 5 year survival for HCC is 16.5% is incorrect. 

cited statistics from references 1-2 refer to the SEER category of “liver and 

ductal bile duct cancers,” not HCC. In addition, reference 1 specifically 

s incomplete reporting of VA cancer registry data to state cancer registries, 

ctor that makes relevance of the cited data to VA unclear.

ion-based study of 2,963 HCC patients based on the linked SEER

 dataset found a median survival of 104 days with a 3 year survival rate 

not the 16.5% rate cited in this review (El-Serag et al. 2006).

There are issues with all long-term survival estimates we found. The SEER data is the most current though we agree it is flawed in that there are some non-HCC cases included. However, HCC are likely to be the majority. We added an additional reference and present the mortality as a range. We believe this shows there is a range, while underscoring the original point which was that long-term survival is poor. The SEERMedicare data includes mostly (91%) patients > 65 so it is not surprising the long-term survival reported here was lower. 

e 1 - The statement that “the National Cancer Institute recommends 

nst surveillance” is incorrect. The source relied on for this statement, 

rence 8, explicitly states that “The summary reflects an independent 

ew of the literature and does not represent a policy statement of NCI or 

National Institutes of Health (NIH).

We have taken this out. 

tatement that “recommendations for HCC surveillance remain 

s based solely on reference 12, an opinion piece (not an original study) 

VA authors who failed to disclose that they were attempting to secure VA 

port a placebo-controlled study of surveillance.

We have consolidated the background section and added additional references. 

e 8 - No statistical justification is provided for the arbitrary sample size of 

patients required for inclusion of studies involving OLT.

We did not use a sample size limit for observational studies comparing treatment to no treatment. The sample size of 500 patients applied to noncomparative observational studies – as such, there is no statistical testing. Rather, we included such studies both as a way to understand harms of treatment as well as long-term survival. The sample size of 500 was chosen because there were several, large noncomparative observational studies of OLT and we felt these would provide more generalizable data regarding long-term survival and harms. The smaller, noncomparative observational studies we examined had similar findings and would not have changed the results – good long-term survival and poor reporting of harms. 

e 8 – The rationale for not including studies that compared two or 

e active treatments was not provided. Active-controlled studies are well 

gnized as a valid mechanism for establishing efficacy of an intervention, cularly when ethical considerations preclude a placebo or no-treatment 

 Of note, the PCORI methodology relied on by the review (reference 23) 

citly endorses active comparator studies; PCORI standard RQ-5 states 

“non-use (or no specific treatment) comparator groups should be avoided 

ss no specific treatment is a likely option in standard care.”

The PCORI causal inference standards to which we refer apply to observational studies. The active-controlled studies guidance applies to situations in which the benefits of treatment have been established. The strength of evidence for HCC screening depends in part on the balance of benefits and harms of treating screen-detected disease. Screening is likely to detect additional small, early-stage HCC. The efficacy of treating such screen-detected tumors compared to watchful waiting is the question that applies most directly to the HCC screening and we were tasked – after discussion with a group of topic-specific and screening-methodology experts - with finding and examining such studies. Examining active comparator studies would not have contributed substantially to the strength of evidence for HCC screening. We have clarified that our approach to the treatment literature was meant to examine the relative benefits of treating screen-detected disease and that our review does not examine the issue of HCC treatment as a whole. 

e 9 – The statement that there is no widely accepted standard for quality 

essment of observational studies” is incorrect. The Strobe (Strengthening 

Reporting of Observational Studies in Epidemiology; www.strobe

ement.org) is referenced by the Uniform Requirements for Manuscripts 

mitted to Biomedical Journals by the International Committee of Medical 

nal Editors and by the Cochrane Collaboration, and endorsed by the 

als of Internal Medicine, British Medical Journal, and Lancet.

The STROBE statement summarizes the elements an observational study manuscript should report – it is not a standard for quality assessment of observational studies. It is akin to the CONSORT statement for trials. There is no widely accepted quality assessment tool for observational studies (see AHRQ methods guide for effectiveness and comparative effectiveness reviews, Chapter 4). There are various tools for assessing the quality of observational studies and we drew from several as appropriate to this topic. 
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Comment Response

11-15: The discussion of surveillance did not include the population study 

cMahon et al. (2000), which demonstrated a survival benefit in Alaska 

ves with chronic hepatitis B. 

We examined the McMahon study, but it was excluded because the use of historic controls was a pre-specified exclusion criteria. This was an exclusion criterion because of the potential for additional confounding from secular trends in overall management of liver disease patients. We included a large body of observational studies and many, as we describe, found that screen-detected patients had longer survival. Whether screening truly prolonged survival or screen-detected patients appeared to live longer because of lead-time and other biases is not clear. The McMahon study would have provided findings and methodologic issues similar to the many other observational studies we examined. We did revise our presentation of observational study results in the table and narrative portions to make the precise survival data and hazard ratios easier to follow. 

15-8 – The conclusions regarding the effects of OLT, resection, RFA, and 

E do not reflect the following data, which were not included in the review:

El-Serag et al. (2006) used data on HCC patients from SEER and Medicare claims to construct a Cox proportional hazards model to identify predictors of outcome; the model incorporated tumor size and extent. The type of therapy received was a significant predictor of survival.

See #32 

A similar study by Schwartz and Smith (2008), adjusting for disease extent and vascular invasion among other factors, found risk ratios of 0.56 for transplantation and 1.53 for ablation. As noted below, ablation is associated with increased survival compared to other modalities.

See #32

Although cited in this document, the data from reference 18 (Mazzaferro et al. 1996) were not compared with historic controls for early stage HCC; the survival rates in this study far exceed those observed in patients with untreated early disease (see references listed under Comment 3).

See #62

Although cited in this document, the results from reference 49 (Liu et al. 2004), which found that HCC resection was associated with a mortality reduction of 55%, are dismissed with statements about “confounding by indication” and concerns about performance status as a confounding. There is no evidence that the natural history of HCC is significantly affected by etiology (assuming that that was what the authors meant). Liu et al. excluded patients from their study who had medical contraindications to surgery, which makes confounding by performance status unlikely.

We have rewritten this part. We agree that the Liu study is probably the best of the comparative observational studies and we describe the results as low-strength evidence. As Liu et al themselves acknowledge, they did not have information on comorbidities and other confounding factors. 

Cho et al. (2009) conducted a meta-analysis of trials comparing ablation with percutaneous ethanol injection in patients with early HCC and found a significant survival advantage for ablation. Similar results were obtained by Orlando et al. (2009)

See #32

Llovet et al. (2002) conducted a landmark prospective RCT comparing TACE to TAE to conservative therapy in patients with early stage HCC. TACE was associated with a significant survival benefit.

See #32

e 21 – Discussion

ment that “Our focus on studies comparing active treatment to 

tive management admittedly may have missed important effects of 

eatments for HCC since many have been evaluated in the context of 

ive effectiveness studies” is an understatement. If there was a question 

ether treatment of early HCC is effective, inclusion of controlled trials 

periority design would have been absolutely appropriate. These do not 

 “comparative effectiveness” studies, as suggested in the text.

See #16