Supplementary Table S2 Characteristics of included studies [ordered by date of
publication]
Sun 2006
Methods
Mainland China;
A randomized, controlled trial;
The patients were then randomized via the envelope method
(the random allocation sequence was generated by simplified
randomization using a computer-generated random number to
decide the allocation of a patient) by a coordinator or doctor who
was blinded to the patient’s name and condition, to determine
which treatment should be given to the patient.
On the basis of data from literature and our study, the 3-year
disease-free survival was between 20 and 48% (Belghiti et al.
1991; Lai et al. 1998; Lau et al. 1999; Lin et al.2000); the
estimated 3-year disease-free survival in the control group was
35%, and the expected 3-year disease-free survival in the IFN a
treatment group was 55%. The significance level was set to be
0.05, and the testing power was 0.80. Therefore, 100 patients in
each group were needed to detect the difference (Dupont and
Plummer 1990). The sample size was enlarged to 115, because
we expected that approximately 15% of the patients might not
follow the treatment protocol. From May 1999 to December
2002, 236 patients after curative resection of HBV-related HCC
were randomized into two groups; each group had 118 patients.
All analyses were performed by the intent-to-treat.
By the end of November 2004, the median observation time was
36.5 months.
Participation
From May 1999 to December 2002, at Liver Cancer Institute
and Zhong Shan Hospital(China);
Entry criteria: received curative resection for HCC; a positive
serum HBV profile but a negative test for anti-HCV antibody;
have a serum bilirubin level ≤34 mmol/l (normal value, ≤17
mmol/l), alanine aminotransferase (ALT) and aspartate
transaminase (AST) ≤2 times the upper limit of the normal
value, white blood cell (WBC) count≥2,500·109/l, and a platelet
count ≥40·109/l.
Exclusion criteria: residual cancer be found in the liver
according to the results of postoperative ultrasonography, that
the serum alpha fetoprotein (AFP) level be not within normal
limits at the time of enrollment, and that major organ (heart, lung
and kidney) function was abnormal.
Curative resection:(1) the complete resection of all tumor
nodules and the cut surface being free of cancer by histological
examination; (2) no cancerous thrombus was found in the portal
vein (main trunk or two major branches), hepatic veins or bile
duct; (3) the number of tumor nodules did not exceed three; and
(4) no extrahepatic metastasis was found.
118 patients in IFN-α group (male/female: 106/12, mean age:
52.2 years); 118 patients in control group (male/female: 102/16,
mean age: 50.4 years).
Interventions
Treatment group: received IFN a1b (Sinogen, Kexing
Bioproducts Co., Shenzhen, P. R. China), which was started at a
pilot dose of 3 million units (mu) two times a week by
intramuscular injection for 2 weeks, then 5 mu three times a
week for 18 months. The above treatments were terminated
when recurrence was confirmed.
Control group: no anti-cancer treatment.
Outcomes
Disease-free survival; overall survival.
Notes
Up through November 2004, IFN-a treatment was terminated in
11 patients because of intolerable adverse effects; 9 patients in
the IFN-a treatment group and 18 in the control group refused to
follow the protocol after randomization and received adjuvant
TACE when their tumors did not recur. One patient from the
control group was lost to follow-up after the first visit.
Risk of bias (RCT)(Unclear)
Authors’ judgment
Support for judgment
Low risk
The random allocation sequence was
generated by simplified randomization
using a computer-generated random
number to decide the allocation of a
patient
Allocation concealment
(selection bias)
Unclear risk
Patients were randomized via the
envelope method but it’s not clear
whether it’s a continuous sealed
envelope.
Blinding of participants
and
personnel
(performance bias)
Low risk
The outcome is not likely to be
influenced by lack of blinding.
Blinding of outcome
assessment (detection
bias)
Low risk
The outcome is not likely to be
influenced by lack of blinding.
Incomplete
outcome
data (attrition bias)
Low risk
One patient from the control group
was lost to follow-up after the first
visit.
Selective
reporting
(reporting bias)
Low risk
It is clear that the published reports
include all expected outcomes.
Unclear risk
One possible source of bias may
Bias
Random
generation
bias)
Other bias
sequence
(selection
come from the average tumor size in
the control group, which was slightly
larger than that in the IFN group and
may have contributed to the poorer
outcome in the control group.
Nine patients in the IFN group and 18
in the control group refused to follow
the protocol after randomization and
received adjuvant TACE when their
tumors did not recur. It’s not clear
whether these factors will lead to
some kinds of bias.
Lo 2007
Methods
Hong Kong, single center;
Open-label, randomized trial;
Randomization was performed with stratification according to
International
Union
Against
Cancer
pathologic
tumor-node-metastasis (pTNM) stage (5th edition, 1997) on
histology (pTNM stages I/II and III/IVA) by drawing
consecutively numbered sealed envelopes and implementation
was ensured by a research assistant.
The use of placebo to maintain double blinding was considered
impractical because of the almost universal side effect of flu-like
syndrome during initial interferon treatment.
It was decided that a sample size of 40 patients per treatment
group would provide the study with a statistical power of 80% at
the 0.05 level of significance to detect a reduction in recurrence
rate from 60% to 30%. The sample size per treatment group
was 40.
Follow-up was continued through January 1, 2005 when all
surviving patients had a minimum follow-up of 30 months. No
patient was lost to follow-up.
Comparison between groups was made on an intention-to-treat
basis.
Participation
From February 1999 to June 2002 at the Department of
Surgery, the University of Hong Kong at Queen Mary Hospital;
Inclusion criteria: curative resection of HCC with clear
microscopic margin and no residual tumor detected on imaging
1 month after surgery, HBV (+),age 18-75 years;
Exclusion criteria: if they refused to participate or had one or
more of the following criteria: history of previous treatment by
regional or systemic chemotherapy, hormonal therapy or
immunotherapy, history of psychiatric illness, poor hepatic
function, serum creatinine level over 180 mol/L, absolute
neutrophil count ＜ 1.5 x 109/L or platelet count ＜ 75 x 109/L,
or poor performance status (ECOG performance status rating
grade 3 or 4);
40 patients in IFN group (Male/female: 31/9, mean age: 49
years); 40 in control group (male/female: 34/6, mean age: 54
years).
Interventions
Treatment group: interferon alpha-2b (Intron-A,
Schering-Plough, Kenilworth, NJ) 10 MIU/m2 subcutaneously 3
times weekly starting with 2 doses each of one third and then
two thirds of full dose escalating to full dose by the fifth dose for
16 weeks (IFN-I group).
Starting time: immediately after randomization within 60 days
after surgery;
The median interferon dosage was 16.7 MIU (range, 14 –19.4
MIU) per dose;
Control: no treatment.
Outcomes
Recurrence free survival (RFS); overall survival (OS); patient
tolerance, virologic response, and liver function.
Notes
98% of the control group and 95% of the IFN-I group were
positive for at least one of the serum markers for HBV. Only 2
patients (5%) of the control group and 1 (3%) of the IFN-I group
were seropositive for antibody against hepatitis C virus.
Approximately half of all the study patients were of pTNM stage
III or IVA. Nineteen patients (48%) of each group had histologic
evidence of cirrhosis in the nontumorous liver
Risk of bias (Unclear)
Bias
Random
generation
bias)
Authors’ judgment
Support for judgment
sequence
(selection
unclear risk
No enough information.
Allocation concealment
(selection bias)
Low risk
Consecutively
envelopes
Blinding of participants
and
personnel
(performance bias)
Low risk
The outcome is not likely
influenced by lack of blinding.
to
be
Blinding of outcome
assessment (detection
bias)
Low risk
The outcome is not likely
influenced by lack of blinding.
to
be
Incomplete
outcome
data (attrition bias)
Low risk
No patients lost to follow-up.
Selective
reporting
(reporting bias)
Low risk
It is clear that the published reports
include all expected outcomes.
Other bias
Low risk
No.
numbered
sealed
Kubo 2007
Methods
Japan, single center;
Cohort study.
Follow-up: The median follow up from operation until the
detection of HCC recurrence or the study endpoint (30 April
2006) in this study was 759 days (34–2053). The median follow
up for each group was 1117 days (187–2037) for patients
receiving lamivudine and 224 days (34–2053) for the controls.
Participants
From November 2000 to October 2005, at Osaka City University
Hospital ;
Curative resection of HCC was performed in 24 patients
seropositive for HB surface antigen (HBsAg) who were negative
for anti-hepatitis C virus antibody and had high serum
concentrations of HBV DNA. The patients had not received any
lamivudine therapy before the operation. The serum
concentration of HBV DNA was at least 3.7 logarithms of the
genome equivalent (LGE) per milliliter. Lamivudine therapy was
started in the 14 who then agreed to this therapy and gave their
informed consent (lamivudine group); control group consisted of
the other 10 patients who declined treatment with the drug
because of the possibility of adverse events or the necessity of
long-term administration of the drug.
14 patients in treatment group (Male/female: 10/4, mean age:
55 years); 10 in control group (male/female: 7/3, mean age: 55
years).
Interventions
Treatment group: lamivudine therapy (100 mg/day), beginning 2
weeks to 2 months after surgery. The period of lamivudine
administration was 6 months to 65 months (mean, 32 months).
Adefovir dipivoxil was used if lamivudine failed to control the
viral hepatitis.
Control group: no antiviral therapy.
Outcomes
Changes in serum HBV DNA concentration and remnant liver
function, HCC recurrence
Notes
In four patients YMDD mutant viruses were detected after
beginning lamivudine administration.
Assessment of Study Quality (COHORT)(7 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
From November 2000 to October
2005, curative resection of HCC was
performed at Osaka City University
Hospital in 24 patients seropositive for
HB surface antigen (HBsAg) who
were negative for anti-hepatitis C
virus antibody and had high serum
concentrations of HBV DNA. The
patients had not received any
lamivudine therapy before the
operation.
2. Did the non-exposed
cohort draw from the
same community?
yes
All patients received curative resction
at the same hospital.
3. Ascertainment
exposure?
of
yes
Medical records.
4. Outcome of interest
was not present at start
of study?
yes
Curative resection was defined as a
complete
resection
of
all
macroscopically
evident
tumors.
Absence of tumor cells along the
parenchymal transection line was
confirmed histologically. No remaining
tumor was detected in the remnant
liver by computed tomography
(dynamic study) 3–4weeks after
surgery.
5A. Study controls for
age?
yes
Age,
gender
distribution,
the
proportion of patients with HBeAg
positivity, viral load, the results of
laboratory tests, and Child–Pugh
classification did not differ between
groups.
5B. Study controls for
any additional factor?
yes
Age,
gender
distribution,
the
proportion of patients with HBeAg
positivity, viral load, the results of
laboratory tests, and Child–Pugh
classification did not differ between
groups. Type of resection, tumor size,
tumor number, differentiation of main
tumor, prevalence of portal invasion,
cancer stage according to UICC
classification, severity of active
hepatitis as well as degree of hepatic
fibrosis in non-cancerous hepatic
tissue showed no difference between
groups.
6.
Assessment
of
outcome by record
linkage?
yes
Serum α-fetoprotein concentrations
were measured every three months.
Ultrasonography,
computed
tomography, magnetic resonance
imaging, chest radiography, or a
combination of these was performed
every three months. When tumor
recurrence was suspected on the
basis of a tumor marker, radiologic
studies, or both, angiography or
biopsy was performed to obtain a
definitive diagnosis.
7.
Follow-up
enough?
long
no
The median follow up from operation
until the detection of HCC recurrence
or the study endpoint (30 April 2006)
in this study was 759 days (34–2053).
The median follow up for each group
was 1117 days (187–2037) for
patients receiving lamivudine and 224
days (34–2053) for the controls.
8. Adequacy of Follow
Up of Cohorts?
no
No statement.
Kuzuya 2007
Methods
Japan, single center;
Retrospective cohort.
Follow-up: 32.6 ± 18.9 months in control group; 38.0 ± 21.6
months in treatment group
Participation
Between December 1998 and December 2004,at the
Department of Gastroenterology, Nagoya University School of
Medicine or the Department of Gastroenterology, Ogaki
Municipal Hospital;
inclusion criteria: (i) patients with chronic HBV infection were
diagnosed as having initial HCC (not recurrence);(ii)patients
who did not receive lamivudine therapy prior to diagnosis of
initial HCC; (iii) patients who underwent hepatic resection or
RFA for initial HCC treatment; and (iv) patients who were judged
as having complete curative response 1 month after initial HCC
treatment. (v)Positive for hepatitis B surface antigen (HBsAg)
and were not positive for hepatitis C virus antibody.
16 patients in treatment group (Male/female: 14/2, mean age:
59.8 years); 33 in control group (male/female: 27/6, mean age:
51.1 years).
Interventions
Treatment group: lamivudine (Zeffix, Glaxo-Smith-Kline, UK) at
a dose of 100 mg/day (lamivudine group) for as long as
possible.
Treatment duration: mean period was 22.7 ± 14.2 months
(range 6.3–54.8).
Control group: no lamivudine therapy.
Outcomes
Changes in remnant liver function, HCC recurrence and survival
Notes
There was a significant difference with respect to HBV-DNA
among the two groups. Median HBV-DNA levels in the
lamivudine group (6.2 log copies/mL, range 2.8–8.3) were
significantly higher than those in the control group (4.1 log
copies/mL, range 2.6–7.1) (P = 0.003).
The emergence of YMDD mutants was observed in five of 16
patients in the lamivudine group (31.6%). There were no serious
adverse effects during lamivudine therapy.
Assessment of Study Quality (COHORT)(8 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
Between December 1998 and
December 2004, a total of 105
patients with chronic HBV infection
were diagnosed as having initial HCC
(not recurrence) and were treated at
the Department of Gastroenterology,
Nagoya University School of Medicine
or
the
Department
of
Gastroenterology, Ogaki Municipal
Hospital. Of 105 patients, 49 patients
meeting the inclusion criteria were
enrolled.
2. Did the non-exposed
cohort draw from the
same community?
yes
All patients were from the same
hospital.
3. Ascertainment
exposure?
of
yes
Medical records.
4. Outcome of interest
was not present at start
of study?
yes
Dynamic computed tomography (CT)
was performed at 1 month after initial
treatment of HCC in all patients in
order to assess the therapeutic
effects; no enhancement in the
treated area was considered to
indicate complete curative response.
5A. Study controls for
age?
yes
There were no significant differences
among the two groups with regard to
age, sex, HBeAg, ALT, PT, albumin,
total bilirubin, platelet count, presence
of ascites, hepatic encephalopathy,
Child–Pugh score, stage of initial
HCC, initial HCC treatment and
follow-up period.
5B. Study controls for
any additional factor?
yes
There were no significant differences
among the two groups with regard to
age, sex, HBeAg, ALT, PT, albumin,
total bilirubin, platelet count, presence
of ascites, hepatic encephalopathy,
Child–Pugh score, stage of initial
HCC, initial HCC treatment and
follow-up period.
6.
Assessment
of
outcome by record
linkage?
yes
All patients were followed primarily
with abdominal US and liver function
tests, as well as measurement of
tumor markers, serum a-fetoprotein
and
des-gamma-carboxy
prothrombin, at 1- to 3-month
intervals after initial treatment for
HCC. When suspicious findings on
US or tumor markers were detected,
dynamic CT was performed in order
to
examine
recurrent
HCC.
Angiography assisted CT was
performed whenever possible.
7.
Follow-up
enough?
long
yes
Follow-up: 32.6 ± 18.9 months in
control group; 38.0 ± 21.6 months in
treatment group.
8. Adequacy of Follow
Up of Cohorts?
no
No statement.
Yoshida 2008
Methods
Japan, single center;
Retrospective cohort.
Follow-up: 47 ± 22 months in the nontreatment group; 33 ± 20
months in the LAM group
Participation
Between January 2000 and December 2005, at Department of
Gastroenterology, University of Tokyo, Japan;
Inclusion criteria: (i) HBs antigen was positive; (ii) received
curative RFA therapy, as judged by subsequent imaging studies.
Exclusion criteria: non curative treatment or combine with
chemo therapy.
33 patients (male/female: 23:10; mean age: 57 years) received
LAM after ablation therapy. The rest 71 patients (male/female:
55:16; mean age： 59 years) did not.
Interventions
The decision to prescribe LAM, which became available in
Japan from November 2000, after RFA treatment was at the
discretion of each patient and the physician in charge on
discussing merits and demerits of the therapy. When indicated,
LAM was given at a dose of 100 mg per day orally after
obtaining written informed consent.
Treatment duration: not reported.
Control group: no LAM treatment.
Outcomes
Antiviral efficacy of lamivudine; Changes in liver function;
Overall and Recurrence-free survival
Notes
Reactivated hepatitis, defined as redetection of HBV-DNA and
elevation of ALT level higher than 2 × the upper normal limit,
was seen in four. Two of them received adefovir treatment,
which was effective in achieving negative HBVDNA and normal
ALT. No adverse effects attributable to LAM were recorded.
Assessment of Study Quality (COHORT)(8 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
Between
January
2000
and
December 2005, a total of 1050
patients were admitted to our hospital
for RFA treatment of HCC. HBs
antigen was positive in 110 patients
and 104 of them received curative
RFA
therapy, as judged by
subsequent imaging studies (Fig.1).
In this study, the medical records of
these 104 patients were reviewed.
2. Did the non-exposed
cohort draw from the
same community?
yes
All patients were from the same
hospital.
3. Ascertainment
exposure?
of
yes
Medical records.
4. Outcome of interest
was not present at start
of study?
yes
The effectiveness of ablation was
evaluated with contrast-enhanced
computed tomography in each
patient.
5A. Study controls for
age?
yes
The propensity score for LAM
administration was calculated by
using a logistic regression model with
LAM administration as the dependent
variable and sex, age, liver function
(represented by Child-Pugh score),
and HCC stage as the independent
variables. On the basis of the
propensity score, one matched
control was selected for each patient
who received LAM, allowing the
maximum difference of 0.1 in the
score.
5B. Study controls for
any additional factor?
yes
The propensity score for LAM
administration was calculated by
using a logistic regression model with
LAM administration as the dependent
variable and sex, age, liver function
(represented by Child-Pugh score),
and HCC stage as the independent
variables. A control was selected for
each patient who received LAM by
using the propensity score as the
matching variable, the maximum
distance of which was set at 0.1.
6.
Assessment
of
outcome by record
linkage?
yes
Recurrence of HCC was monitored
with ultrasonography and computed
tomography every 3–4 months, and
RFA was repeated when necessary.
Blood tests and imagings were also
applied to those patients who did not
choose to receive LAM.
7.
Follow-up
enough?
long
yes
Follow-up: 47 ± 22 months in the
nontreatment group; 33 ± 20 months
in the LAM group
8. Adequacy of Follow
Up of Cohorts?
no
No statement.
Chuma 2009
Methods
Japan, single center;
Retrospective cohort.
Follow-up: 49.2 (12–89) months in control group; 35.5 (12–67)
months in antiviral group.
Participation
Between January 2001 and December 2007, at Department of
Gastroenterology, Sapporo Municipal Hospital, Japan;
Inclusion criteria: (1) hepatic resection or RFA for initial HCC
treatment; (2) three or fewer lesions, each 3 cm or less in
diameter; (3) no extra hepatic metastasis or vascular invasion;
(4) curative treatment and no local recurrence after treatment;
(5) no recurrence 3 months after treatment; (6) liver function of
Child-Pugh class A or B; (7) no excessive alcohol intake ([65
g/day); and (8) no evidence of any other active neoplastic
site;(9) High serum HBV DNA levels (>4 log10 copies/mL) when
HCC was diagnosed.
20 patients in treatment group (men/women: 14:6; age:
55.7±7.9years); 30 patients in control group (men/women: 22:8,
age: 55.6±8.3 years).
Interventions
Seventeen patients received antiviral therapy within 1 month
after HCC treatment. The remaining three patients received
antiviral therapy from diagnosis of active viral hepatitis B; the
intervals between HCC treatment and the commencement of
nucleotide analogue in these three patients were 12, 15, and 22
months. Seven patients received lamivudine only (100 mg/day).
Entecavir alone (0.5 mg/day) was used in five patients. Adefovir
dipivoxil (10 mg/day) was used together with lamivudine to
suppress lamivudine-resistant hepatitis B virus (HBV) in eight
patients.
Treatment duration: not reported.
Control group: no antiviral therapy.
Outcomes
Recurrence free survival (RFS); Overall survival (OS);
Notes
Adefovir dipivoxil (10 mg/day) was used together with
lamivudine to suppress lamivudine-resistant hepatitis B virus
(HBV) in eight patients.
Assessment of Study Quality (COHORT)(8 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
Between
January
2001
and
December 2007, a total of 196
patients who were diagnosed with
HBV-related HCC at our liver unit
underwent hepatic resection or RFA
as a primary treatment. HCC was
diagnosed based on the American
Association for the Study of Liver
Disease (AASLD) guidelines. Of the
196 patients who were assessed
initially, 103 fulfilled the following
criteria and were enrolled。
2. Did the non-exposed
cohort draw from the
same community?
yes
Hospital controls.
3. Ascertainment
exposure?
of
yes
Medical records.
4. Outcome of interest
yes
Inclusion criteria: curative treatment
was not present at start
of study?
and no local recurrence after
treatment; no recurrence 3 months
after treatment.
5A. Study controls for
age?
yes
There were no significant differences
among the four groups with regard to
gender; age; HBeAg; levels of ALT,
PT, albumin, PIVKA-II, AFP, or
bilirubin; platelet count; Child-Pugh
score; tumor size; tumor number;
stage of HCC; initial HCC treatment;
or follow-up period.
5B. Study controls for
any additional factor?
yes
There were no significant differences
among the four groups with regard to
gender; age; HBeAg; levels of ALT,
PT, albumin, PIVKA-II, AFP, or
bilirubin; platelet count; Child-Pugh
score; tumor size; tumor number;
stage of HCC; initial HCC treatment;
or follow-up period.
6.
Assessment
of
outcome by record
linkage?
yes
During follow-up, clinical evaluations
and
biochemical
tests
were
performed
every 1–3 months.
Patients
underwent
triphasic
computed tomography of the liver
every 3 months. The endpoint used in
this study was the recurrence of HCC.
7.
Follow-up
enough?
long
yes
The mean follow-up period for all
patients was 40 (12–92) months.
8. Adequacy of Follow
Up of Cohorts?
no
No statement.
Koda 2009
Methods
Japan ,single center;
Cohort study;
The mean follow-up period in all patients was 28.6 ± 16.7
months for the nucleotide analog group and 36.3 ± 21.6 for the
control group.
Participation
Between January 2002 and December 2006, at Tottori
University Hospital, Japan.
We administered nucleotide analogue to patients who met
following conditions: 1) HBV-DNA in serum more than 3.7
LGE/mL, 2) serum ALT more than 40 IU/L, 3) patients wish to
have nucleotide analogue treatment after curative treatment. 62
patients with chronic HBV infection were diagnosed with HCC.
Exclusion criteria: negative (less than 3.7 LGE/mL) for serum
HBV-DNA or had normal serum ALT levels (less than 40 IU/L)
during observation periods.
30 patients in treatment group (men/women: 24/6; mean age:
59 years); 20 patients in control group (men/women: 15/5, mean
age: 60 years).But for patients who received curative treatment,
22 in the treatment group and 14 in control group.
Interventions
Treatment group: Lamivudine (100 mg/day) or entecavir (0.5
mg/day) .When the emergence of YMDD mutants in patients
who were administered lamivudine were observed, they were
additionally administered adefovir depivoxil or were changed
from lamivudine to entecavir.
Treatment duration: these patients continued to take nucleotide
analog during the observation period
Control group: no nucleotide analog treatment.
Outcomes
Changes in liver function, HCC recurrence and survival rate
Notes
Only the data for patients who received curative treatment for
HCC were extracted.
Assessment of Study Quality (COHORT)(7 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
We administered nucleotide analogue
to patients who met following
conditions: 1) HBV-DNA in serum
more than 3.7 LGE/mL, 2) serum ALT
more than 40 IU/L, 3) patients wish to
have nucleotide analogue treatment.
Between
January
2002
and
December 2006, 62 patients with
chronic
HBV
infection
were
diagnosed with HCC, of which
30(48.4%) orally received nucleotide
analog daily after HCC treatment
because they met all three conditions.
2. Did the non-exposed
cohort draw from the
same community?
yes
Hospital controls.
3. Ascertainment
exposure?
of
yes
Medical records.
4. Outcome of interest
was not present at start
of study?
no
No description.
5A. Study controls for
age?
yes
There were no significant differences
in baseline virological and clinical
characteristics between the groups.
5B. Study controls for
any additional factor?
yes
There were no significant differences
in baseline virological and clinical
characteristics between the groups.
6.
Assessment
of
outcome by record
linkage?
yes
We examined the clinical features
such as ascites and hepatic
encephalopathy by physical findings
and laboratory tests every 1-3
months. All patients were followed
using abdominal sonography or
computed tomography (CT) every 3
months as well as the measurement
of
tumor
markers,
serum
alpha-fetoprotein
(AFP)
and
des-gamma-carboxyl
prothrombin
(DCP) every 1-3 months.
7.
Follow-up
enough?
long
no
The mean follow-up period in all
patients was 28.6 ± 16.7 months for
the nucleotide analog group and 36.3
± 21.6 for the control group.
8. Adequacy of Follow
Up of Cohorts?
yes
All patients were followed using
abdominal sonography or computed
tomography (CT) every 3 months as
well as the measurement of tumor
markers, serum alpha-fetoprotein
(AFP)
and
des-gamma-carboxyl
prothrombin (DCP) every 1-3 months.
Qu 2010
Methods
China, single center;
Retrospective cohort;
Median observation period of 53.3 months (from 3.5 to 74
months).
Participation
Between 2004 and 2006, in the Department of Liver Surgery,
Zhongshan Hospital, Fudan University;
Inclusion criteria: HBV-related HCC patients who had received
curative resection of pathologically proven HCC;
Exclusion reasons: died in hospital due to postoperative hepatic
failure; early recurrence within 3 months after surgery
(suggesting preexisting metastases before HCC resection); data
were lacking for 17 patients.
Curative resection was defined as: (1) complete resection of all
tumor nodules and the surgical free margin of more than 5 mm
by pathological examination; (2) no cancerous thrombus found
in the portal vein (main trunk or two major branches), hepatic
veins, or bile duct; (3) the number of tumor nodules did not
exceed three; and (4) no extrahepatic metastasis found.
101 patients in treatment group (male/female: 86/15, mean age:
50.98 years); 467 patients in control group (male/female:
407/60, mean age: 52.65 years).
Interventions
Patients with postoperative IFN-a therapy had a serum bilirubin
level≤34 mmol/L, alanine aminotransferase and aspartate
transaminase≤2 times the upper limit of the normal range, white
blood cell (WBC) count≥2,500*109/L, platelet count ≥40*109/L,
the serum AFP level be within normal limits at the time of
recruitment, and that major organ (heart, lung, and kidney)
function was normal.
Treatment group:IFN-a1b (Sinogen, Kexing Bioproducts Co.,
Shenzhen, PR China) therapy, which was started at a pilot dose
of 3 million units (mu) two times a week by intramuscular
injection for 2 weeks, then 5 mu three times a week for 18
months.
Duration: Administration of IFN-a therapy was started 4–6
weeks after curative resection.The IFN-a therapy was
terminated when recurrence was confirmed.
Control group: no IFN treatment.
Outcomes
Disease-free; Overall survival rates
Notes
We did not monitor the HBV-DNA level and could not detect the
difference of the IFN-a therapy in the patients with different
HBV-DNA levels.
We did not have the information on the use of oral antiviral
agents (nucleoside analogues) among these patients.
3(3.0%) in IFN group and 10 (2.1%) in control group had
coexisting HCV infection.
Assessment of Study Quality (COHORT)(8 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
Between 2004 and 2006, 1,045
patients with HBV-related HCC
underwent tumor resection by the
same surgical team in the Department
of Liver Surgery, Zhongshan Hospital,
Fudan University. 622 HBV-related
HCC patients who had received
curative resection of pathologically
proven HCC were retrieved. A total of
568 patients were finally entered into
the analyses
2. Did the non-exposed
cohort draw from the
same community?
yes
Hospital control.
3. Ascertainment
exposure?
of
yes
101 patients received IFN-a1b
(Sinogen, Kexing Bioproducts Co.,
Shenzhen, PR China) therapy for 18
months. Administration of IFN-a
therapy was started 4–6 weeks after
curative resection.
4. Outcome of interest
was not present at start
of study?
yes
21 patients who had early recurrence
within 3 months after surgery
(suggesting preexisting metastases
before
HCC
resection)
were
excluded.
5A. Study controls for
age?
yes
There was no statistical difference
between patients with postoperative
IFN-a therapy or not in terms of these
factors.
5B. Study controls for
any additional factor?
yes
There was no statistical difference
between patients with postoperative
IFN-a therapy or not in terms of these
factors.
6.
Assessment
of
outcome by record
linkage?
yes
All 568 patients were followed up by
determination of monthly AFP and
ultrasonography (US), as well as 3
monthly computed tomography (CT)
or magnetic resonance imaging (MRI)
scan for 1 year. Then, all patients
were screened by AFP and US every
3 months and helical CT or MRI every
6 months thereafter, and hepatic
angiography when recurrence was
suspected.
7.
Follow-up
enough?
long
yes
Median observation period of 53.3
months (from 3.5 to 74 months)
8. Adequacy of Follow
Up of Cohorts?
no
No statement.
Li 2010
Methods
China, single center;
Prospective cohort;
Median follow-up: 12 months.
Participation
From January 2004 to June 2007; in the Eastern Hepatobiliary
Surgery Hospital;
Inclusion criteria: (1) underwent elective curative hepatic
resection for HCC; (12) a preoperative diagnosis of HCC with no
previous treatment, (3) absence of other malignancies, (4)
serum hepatitis B virus DNA (HBV DNA) greater than 104
copies/ml.
Exclusion criteria: refused to participate or had one or more of
the following criteria: concurrent hepatitis C virus or hepatitis
delta virus infection, drug abuse, pregnancy, or associated
serious medical illness (such as myocardial infarction,
cerebrovascular event, or transient ischemic attack within 6
months prior to this hospitalization) ;with operative death; lost to
follow-up.
In deciding whether patients would receive or not receive
adjuvant antiviral therapy, we considered the wish of the
patients. Of course, economic conditions of the patients were
also involved in the decision-making process.
43 patients in treatment group (male/female: 34/9, mean age:
46 years); 36 patients in control group (male/female: 30/6, mean
age: 45 years).
Interventions
Treatment group: Lamivudine [Heptodin, GlaxoSmithkline
(China) Investment Co. Ltd.] was used at a dosage of 100 mg
orally per day, starting within the first postoperative week. If
YMDD mutation was confirmed, adefovir dipivoxil tablets
[Hepsera, GlaxoSmithkline (China) Investment Co. Ltd.] at a
dosage of 10 mg per day was given.
The HBV DNA level was rechecked after a 3-month combination
therapy. If HBV DNA level had decreased, lamivudine was
withdrawn.
Control group: no antiviral therapy.
Antiviral duration: not reported.
Outcomes
Primary outcome measures included recurrence, disease free
survival, and overall survival rates. Secondary outcome
measures included patient tolerance, virologic response, liver
function, and liver volume.
Notes
The operating time was longer in the control group because
there were more patients, though statistically not significant,
who received major hepatectomy than in the treatment group
(63.9% vs. 53.5%), (P=.241).
17 (39.5%) in the treatment group and 22 (61.1%) in the control
group were pTNM stage III.
Assessment of Study Quality (COHORT)(7 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
yes
From January 2004 to June 2007,
of the exposed cohort?
753
consecutive patients with
advanced HCC were seen by our
surgical team in the Eastern
Hepatobiliary Surgery Hospital. Of
these, 88 patients met the selection
criteria. Finally, 43 patients in the
treatment group received lamivudine
with or without adefovir dipivoxil, and
36 patients in the control group were
followed up and analyzed.
2. Did the non-exposed
cohort draw from the
same community?
yes
Hospital control.
3. Ascertainment
exposure?
of
yes
Lamivudine
[Heptodin,
GlaxoSmithkline (China) Investment
Co. Ltd.] was used at a dosage of 100
mg orally per day, starting within the
first postoperative week. Follow-up
visits were done every month.
4. Outcome of interest
was not present at start
of study?
no
No description.
5A. Study controls for
age?
yes
There was no statistically significant
difference in the parameters of
baseline characteristics and operative
data.
5B. Study controls for
any additional factor?
yes
There was no statistically significant
difference in the parameters of
baseline characteristics and operative
data.
6.
Assessment
of
outcome by record
linkage?
yes
All patients were followed up at the
outpatient clinic every monthly in the
first 2 years and then with increasing
intervals. When tumor recurrence or
metastases
were
suspected,
investigations
with
computed
tomography (CT), or magnetic
resonance imaging (MRI) were
carried out. Fine needle biopsies were
carried out when necessary.
7.
Follow-up
enough?
long
no
Median follow-up:12 months.
8. Adequacy of Follow
Up of Cohorts?
yes
6 patients who were lost to follow-up
were excluded from analysis.
Chan 2011
Methods
Hong Kong, single center;
Retrospective cohort;
The last census date for this study was June 30, 2009. All
patients were available for follow-up.
Participation
From September 1, 2003, through December 31, 2007, in the
Department of Surgery of Queen Mary Hospital, Hong Kong;
136 patients with chronic HBV infection underwent hepatectomy
for HCC. Preoperative clinical data were retrieved from our
prospectively collected database. Only patients who underwent
major hepatectomy, which was defined as anatomical resection
of more than 2 Couinaud segments, were selected for this study.
Initiation of antiviral therapy within 12 months after hepatectomy
was based on the following criteria: (1) alanine
aminotransferase level more than 2 times the upper limit of
reference values, with or without a serum HBV DNA level
greater than 105 copies/mL; (2) serum alanine aminotransferase
level greater than the upper limit of the reference value but less
than 2 times the value, with serum HBV DNA level greater than
105 copies/mL; or (3) liver biochemistry findings within the
reference range, with serum HBV DNA levels greater than 105
copies/ mL only. None of the patients developed tumor
recurrence before the initiation of antiviral therapy.
Patients who received antiviral therapy after hepatectomy were
categorized as the treatment group, and those who did not were
categorized as the control group.
42 patients in treatment group(male/female:31/11,mean age: 57
years); 94 patients in control group(male/female:74/20,mean
age: 55 years)
Interventions
Treatment group: during the early study period, lamivudine (100
mg/d); in recent years, entecavir (0.5 mg/d).
Antiviral therapy was started in 42 patients (lamivudine in 38
and entecavir in 4) at a median of 8 days (range, 0-12 months)
after hepatectomy.
Treatment duration: not reported.
Control group: no antiviral treatment.
Outcomes
Disease-free ;Overall survival rates
Notes
There were significantly more patients with Child-Pugh class B
cirrhosis in the control group.
The higher serum AFP level in the control group implied a
greater tumor load that might also confound the survival benefit
of antiviral treatment.
Assessment of Study Quality (COHORT)(8 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
From September 1, 2003, through
December 31, 2007, 379 patients
underwent hepatectomy for HCC in
the Department of Surgery at our
institution. Among them, 136 patients
had chronic HBV infection.
2. Did the non-exposed
cohort draw from the
same community?
yes
Patients who received antiviral
therapy after hepatectomy were
categorized as the treatment group,
and those who did not were
categorized as the control group.
3. Ascertainment
exposure?
of
yes
Antiviral therapy was started in 42
patients (lamivudine in 38 and
entecavir in 4) at a median of 8 days
(range,
0-12
months)
after
hepatectomy.
4. Outcome of interest
was not present at start
of study?
yes
None of the patients developed tumor
recurrence before the initiation of
antiviral therapy.
5A. Study controls for
age?
yes
There was no significant difference in
the age, distribution of sex, and the
incidence of screening-detected HCC
between the 2 groups of patients.
5B. Study controls for
any additional factor?
No
There were significantly more patients
with Child-Pugh class B cirrhosis in
the control group.
6.
Assessment
of
outcome by record
linkage?
yes
Computed tomography of the liver
was performed at 1 month after
hepatectomy to confirm complete
tumor clearance and then every 3
months for surveillance. Blood tests
for liver biochemistry values, clotting
profile,
complete
hematological
profile, and serum AFP levels were
also determined at 1 month after
hepatectomy and then at 3-month
intervals. Liver biochemistry findings
at the time of tumor recurrence were
recorded.
7.
Follow-up
enough?
yes
The 1-, 3-, and 5-year disease-free
survival rates in the treatment group
were 66.5%, 51.4%, and 51.4%,
long
respectively; in the control group,
48.9%,
33.8%,
and
33.8%,
respectively.
8. Adequacy of Follow
Up of Cohorts?
yes
All patients
follow-up.
were
available
for
Wu 2012
Methods
Taiwan, nationwide cohort；
Follow-up: for untreated cohort: mean (SD) of 2.18 (1.77) years
and a median (interquartile range [IQR]) of 1.57 (0.77-3.15)
years; for treated cohort, mean (SD) of 2.64 (1.74) years and a
median (IQR) of 2.18 (1.21-3.69) years.
Participation
Retrieving data from Taiwan’s National Health Insurance
Research Database (NHIRD) and pharmacy prescription
database;
Inclusion criteria: patients who were admitted with a primary
diagnosis of HBV-related HCC for the first time and received
curative liver resection between October 1, 2003, and
September 30, 2010;
Exclusion criteria: if diagnosed with hepatitis C, other viral
hepatitis, malignant tumor, or if they received antiviral
treatments for more than 3 months before the index admission;
if they received liver resection, transarterial chemoembolization,
percutaneous ethanol injection, radiofrequency ablation, or liver
transplantation before the index hospitalization;
518 patients in treatment cohort(male/female:435/83;mean age:
54.4 years); 4051 patients in control group (male/female:
3335/716 ; mean age:54.6 years)
Interventions
Treated cohort: 487 patients received only 1 nucleoside
analogue, including 159 patients who received lamivudine, 292
patients who received entecavir, and 36 patients who received
telbivudine. The remaining patients received more than 1
nucleoside analogue.
The mean (SD) interval to start of antiviral therapy after liver
resection was 1.19 (1.38) years; The mean (SD) duration of
nucleoside analogue use in treated patients was 1.45 (1.38)
years and the median (IQR) was 0.95 (0.48-1.94) years.
Untreated cohort: no treatment;
Outcomes
Recurrence free survival (RFS); Overall survival (OS);
Notes
The treated cohort had a significantly higher prevalence of liver
cirrhosis (48.6%) when compared with the untreated cohort
(38.7%) (P<0.001).
Information about adverse events of nucleoside analogues was
not available from the NHIRD. In the present study, we did not
have data regarding a patient’s HBV viral load or liver function.
Assessment of Study Quality (COHORT)(8 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
We identified all hospitalized patients
who were admitted with a primary
diagnosis of HCC for the first time and
who received curative liver resection
between October 1, 2003, and
September 30, 2010.
2. Did the non-exposed
cohort draw from the
same community?
yes
Patients who were newly diagnosed
with HBV-related HCC and who
received curative liver resection were
divided into 2 cohorts based on their
use of nucleoside analogues. The
untreated cohort comprised patients
who never received nucleoside
analogues and the treated cohort was
patients who received nucleoside
analogues for at least 90 days.
3. Ascertainment
exposure?
of
yes
Information
regarding
patients’
medications was retrieved from the
pharmacy prescription database.
Reliability of the retrieved information
was verified independently by 2
statisticians.
4. Outcome of interest
was not present at start
of study?
yes
Patients with HCC recurrence in the
first 3 months after the index
hospitalization for liver resection were
excluded.
5A. Study controls for
age?
yes
To determine the independent risk
factors
for
HCC
recurrence,
multivariable analyses and stratified
analyses using hazard ratios (HRs)
were carried out with modified Cox
proportional hazards models in the
presence of competing risk event
after adjusting for age, sex, resection
modality, liver cirrhosis, diabetes,
propensity score, and use of statins,
NSAIDs or aspirin, and metformin.
5B. Study controls for
any additional factor?
yes
To determine the independent risk
factors
for
HCC
recurrence,
multivariable analyses and stratified
analyses using hazard ratios (HRs)
were carried out with modified Cox
proportional hazards models in the
presence of competing risk event
after adjusting for age, sex, resection
modality, liver cirrhosis, diabetes,
propensity score, and use of statins,
NSAIDs or aspirin, and metformin.
6.
Assessment
of
outcome by record
linkage?
yes
Hepatocellular carcinoma recurrence
was defined as rehospitalization with
a primary diagnosis of HCC after the
index admission date and a treatment
modality for HCC recurrence, such as
surgery,
transarterial
chemoembolization,
percutaneous
ethanol injection, radiofrequency
ablation, or liver transplantation
during the study period.
7.
Follow-up
enough?
long
no
The median follow-up durations for
the untreated cohort were 2.18 years
and for the treated cohort, 1.57 years.
8. Adequacy of Follow
Up of Cohorts?
yes
It is nearly impossible for these HCC
patients to withdraw from the NHI
program before death. Therefore,
there were no missing data or loss of
follow-up in our study population.
Chen 2012
Methods
Taiwan, multicenter;
Observation-controlled, multicenter, randomized phase III study;
Randomization was performed via telephone to the central
office of the TCOG. Patients were stratified according to the
underlying viral etiology of HCC, HBV-related (HBsAg-positive)
or HCV-related (HBsAg-negative/anti-HCV-positive), and then
randomly assigned to receive either adjuvant IFNα-2b treatment
(IFNα-2barm) or observation alone (control arm) within each
stratum, for which the assignment was permuted and balanced
between strata for every block size of 50 for HBsAg-positive
stratum and 10 for HBsAg-negative/anti-HCV positive stratum.
With the assumption of the 2-year recurrence-free rate of 50% in
the control arm and 70% in the treatment arm, the estimated
median RFS time (the primary endpoint) based on the
exponential survival assumption was 2 and 3.89 years,
respectively. With a 2-sided 5% significance level and 90%
power, the required sample size was 134 per arm.
Follow up: median follow-up of 63.8 (95% confidence interval
[CI] 60.8–66.9) months. Only 2 patients in the IFN arm were lost
to follow up.
All patients who underwent randomization were included in the
intent-to-treat (ITT) population
Participation
Between October 1st, 1997, and April 30th, 2003 in 10 Taiwan
Cooperative Oncology Group (TCOG)-affiliated institutions in
Taiwan;
Inclusion criteria: curative resection of HCC with gross resection
margin > 1 cm, performance status of Eastern Cooperative
Oncology Group (ECOG) score < 2, Pugh-Child‘s Score < 7,
serum total bilirubin level are < 2 mg/dl, platelet count > 10 x 104
/ mm3, prothrombin times are < 3 sec above normal control,
serum creatinine < 1.5 mg/dl, HBsAg (+) or anti-HCV (+);
Exclusion criteria: age > 70 years, vascular involvement in
radiography, leukocyte < 3000/mm3, with advanced second
primary malignancy, with pregnancy or breast-feeding, with
severe cardiopulmonary diseases, with clinically significant
psychiatric disorder, had antineoplastic chemotherapeutic or
immuno-thetic drugs or corticosteroids within 6 weeks;
133 patients in IFN group (male/female: 108/25; mean age: 50
years); 135 patients in control group (male/female: 112/23;
mean age: 49 years).For HBV-HCC, 106 in IFN arm and 109 in
control arm.
Interventions
Treatment group: IFNα-2b, (Intron A, Schering-Plough Corp,
Kenilworth, NJ, USA), was administered intramuscularly, 5 days
perweek for 5 weeks with the dosage escalated from 1 MU to 5
MU during the first week and held at 5 MU for the next 4 weeks,
and then administered thrice weekly for an additional 48 weeks,
or until HCC recurrence, presence of unacceptable toxicity or
patient refusal to continue.
Duration of treatment: 53 weeks;
Control: no treatment;
Outcomes
Recurrence free survival (RFS); overall survival (OS); toxicity
Notes
A significantly greater number of patients in the treatment arm
had high hepatitis activity (including active cirrhosis, moderate
to severe chronic active hepatitis in histology) in non-tumor liver
(63.9% vs. 51.1% in control arm; P = 0.040, χ2-test).
Among the 130 patients treated with IFNα-2b, 33 (24.8%)
required dose reduction, and 5 (3.8%) patients were
subsequently taken off study because of treatment-related
toxicity.
Only data of HBV-HCC were extracted for meta-analysis.
Risk of bias (unclear)
Bias
Random
generation
bias)
Authors’ judgment
Support for judgment
sequence
(selection
Low risk
Permuted block randomization
Allocation concealment
(selection bias)
Low risk
Probably done. (Randomization was
performed via telephone to the central
office of the TCOG.)
Blinding of participants
and
personnel
(performance bias)
Low risk
The outcome is not likely to be
influenced by lack of blinding.
Blinding of outcome
assessment (detection
bias)
Low risk
The outcome is not likely to be
influenced by lack of blinding.
Incomplete
outcome
data (attrition bias)
Low risk
The proportion of missing outcomes
was not enough to have a clinically
relevant impact on the intervention
effect estimate. (Only 2 patients from
the treatment group were lost to
follow-up.)
Selective
reporting
(reporting bias)
Low risk
It is clear that the published reports
include all expected outcomes.
Unclear risk
A significantly greater number of
patients in the treatment arm had high
hepatitis activity (including active
cirrhosis, moderate to severe chronic
active hepatitis in histology) in
non-tumor liver (63.9% vs. 51.1% in
control arm; P = 0.040, χ2-test).
Other bias
Yang 2012
Methods
Mainland China, single center;
A prospective cohort study;
The median follow-up duration was 47.2 months (range,
4.7-112.7 months) in the high viral load group.
Participation
From January 2002 to December 2008, in the Department of
Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital,
Second Military Medical University;
Inclusion criteria: (i) received curative resection for HCC; (ii)
positive for HbsAg; (iii) didn’t receive any preoperative
anti-tumor therapy.
Exclusion criteria: with concurrent infection with HCV, without
HBV DNA test, died in hospital or within 3 months following
surgery, or lost to follow-up.
Curative resection definition: macroscopically complete removal
of the tumor with a pathologically tumor-free surgical margin.
Ultimately, 631 patients were enrolled in this prospective study.
Out of 358 patients with HBV DNA level >10,000 copies/mL, 330
were enrolled in the subgroup analysis, 142 in the oral antiviral
treatment group and 188 in the control group.
Interventions
Treatment group: lamivudine 100 mg, adefovir dipivoxil 10 mg,
or entecavir 0.5 mg orally daily started within a week after
operation or after discharge for some patients in the high viral
load group. For patients with renal insufficiency, the daily
lamivudine or adefovir dipivoxil dose was adjusted according to
creatinine clearance.
Control group: no antiviral therapy.
Treatment duration: not reported.
Outcomes
Recurrence free survival (RFS); overall survival (OS);
Notes
The study did not collect full information on the fluctuation of
viral load, including degree of suppression by antiviral
treatment, presence of HBeAg seroconversion, virus resistance,
or mutation, which may be associated with long-term prognosis
after curative resection.
Assessment of Study Quality (COHORT)(6 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
From January 2002 to December
2008, two surgical teams from the
same department in our hospital
performed 808 consecutive curative
resections for HCC, defined as
macroscopically complete removal of
the tumor with a pathologically
tumor-free surgical margin. Among
them, 716 patients were positive for
HBsAg
2. Did the non-exposed
cohort draw from the
same community?
yes
Out of 358 patients, 330 were
enrolled in the subgroup analysis,
including 188 patients who had not
received any antiviral drugs after
surgery or discharge from hospital,
and 142 patients who received the
regular administration of oral antiviral
drugs.
3. Ascertainment
exposure?
No
No description.
of
4. Outcome of interest
was not present at start
of study?
yes
From January 2002 to December
2008, two surgical teams from the
same department in our hospital
performed 808 consecutive curative
resections for HCC, defined as
macroscopically complete removal of
the tumor with a pathologically
tumor-free surgical margin.
5A. Study controls for
age?
no
No description for this subgroup.
5B. Study controls for
any additional factor?
no
No description for this subgroup.
6.
Assessment
of
outcome by record
linkage?
yes
Patients were followed up in our clinic
every 2 months during the first
postoperative year and at least every
3-4 months thereafter.
7.
Follow-up
enough?
long
yes
The median follow-up duration was
47.2 months (range, 4.7-112.7
months) in the high viral load group.
8. Adequacy of Follow
Up of Cohorts?
yes
Patients who were excluded included
those with concurrent infection with
HCV, those without HBV DNA test,
those who died in hospital or within 3
months following surgery, and those
lost to follow-up.
Ke 2013
Methods
Mainland China,single center;
A retrospective cohort study;
Follow-up: mean follow-up of 24 months for control group and
23 months for treatment group.
Participation
From January 2007 to December 2011，in Hepatobiliary Surgery
Department, Tumor Hospital of Guangxi Medical University,
China；
Inclusion criteria: (1) the initial radical hepatectomy of HCC was
performed in the Tumor Hospital of Guangxi Medical University.
Diagnosis was verified by postoperative pathology; (2) serum
Hepatitis B surface antigen (HBsAg) was positive for all
patients; (3) Child-Pugh score was from 5 to 6; (4) Eastern
Cooperative Oncology Group score was 0; (5) informed consent
was signed.
Exclusion criteria: (1) received transarterial chemoembolization
(TACE) or other antitumor therapies before operation; (2)
received antiviral therapy (including interferon treatment) in the
past year; (3) received prophylactic TACE or other antitumor
therapies after operation; (4) combined infection of human
immunodeficiency virus, hepatitis C virus, or hepatitis D virus;
(5) suffered from other malignant tumors or other severe
diseases simultaneously; (6) alcoholism; (7) drug abuse; and (8)
pregnant or lactating women.
141 patients in treatment cohort(male/female:129/12;mean age:
48.9 years); 141 patients in control group (male/female:127/14;
mean age:49.7 years)
Interventions
Indications for antiviral therapy followed the Guideline of
prevention and treatment for chronic hepatitis B (2010
Version)16: (1) for Hepatitis B e Antigen (HBeAg)-positive
patients, the value of HBV DNA ≥105 copies/mL (equivalent to
20,000 IU/mL); or for HBeAg-negative patients, HBV DNA ≥104
copies/mL (equivalent to 2,000 IU/mL); and alanine
aminotransferase (ALT) ≥ two folds the upper limit of normal; (2)
for patients with compensated cirrhosis, HBV DNA ≥104
copies/mL for HBeAg-positive patients, and HBV DNA ≥103
copies/mL for HBeAg-negative patients, which does not matter
whether the level of ALT is high or low; (3)For patients with
cirrhosis in the decompensation period, they should receive
antiviral therapy once HBV DNA is detected.
Treatment group: Lamivudine [Heptodin, from GlaxoSmithKline
(China) Investment Co. Ltd.] orally taken by the patients once
they had left the hospital or from the first week after the
operation for the following one year, with a dosage of 100 mg/d.
Control: no treatment;
Treatment duration：Not reported.
Outcomes
Recurrence free survival (RFS); Overall survival (OS);
Notes
To avoid the interference of measured confounding factors,
PSM was adopted in making group matches. Exactly 141 pairs
were matched successfully.
Information about adverse events of nucleoside analogues was
not available .The complete information on the resistance rate of
the virus and gene mutation rate were not collected.
Assessment of Study Quality (COHORT)(6 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
A total of 478 patients meeting the
aforementioned requirements were
collected from January 2007 to
December 2011.
2. Did the non-exposed
cohort draw from the
yes
Among these patients, 141 treated by
lamivudine after operation were
same community?
3. Ascertainment
exposure?
integrated into the treatment group,
and the remaining 337 patients
without lamivudine treatment were
integrated into the control group. To
avoid the interference of ensured
confounding factors, PSM was
adopted in making group matches.
Exactly 141 pairs were matched
successfully.
of
no
No description.
4. Outcome of interest
was not present at start
of study?
yes
Patients of both groups underwent
radical hepatectomy for HCC. This
procedure followed the Diagnosis
management and treatment of HCC
(2011 Version) of the Ministry of
Health of the People’s Republic of
China.
5A. Study controls for
age?
yes
To avoid the interference of ensured
confounding factors, PSM was
adopted in making group matches.
Exactly 141 pairs were matched
successfully. After matching, the
covariants were balanced.
5B. Study controls for
any additional factor?
yes
To avoid the interference of ensured
confounding factors, PSM was
adopted in making group matches.
Exactly 141 pairs were matched
successfully.
6.
Assessment
of
outcome by record
linkage?
yes
Patients were followed up every two
or three months after the operation for
their serum HBV immune markers,
HBV DNA, liver function, prothrombin
time (PT), alpha-fetoprotein (AFP),
ultrasonography,
computed
tomography or magnetic resonance
imaging, and so on. Postoperative
recurrence (including intrahepatic and
extrahepatic
recurrence)
was
confirmed through the appearance of
intrahepatic or extrahepatic lesions
meeting the features of HCC in any
imaging examination.
7.
no
Mean follow-up of 24 months for
Follow-up
long
enough?
8. Adequacy of Follow
Up of Cohorts?
control group and 23 months for
treatment group.
no
No statement.
Su 2013
Methods
Taiwan, single center
Retrospective cohort study;
With a median follow-up of 45.9 months.
Participation
From 1990 to 2007, in Taipei Veterans General Hospital;
607 consecutive treatment-naı¨ve HBV-related HCC patients
who underwent curative resection surgery.
Inclusion criteria:(a) positive hepatitis B surface antigen
(HBsAg) in sera; (b) liver function of A or B by Child’s
classification, with an indocyanine green 15-minute retention
rate (ICG-15R),30%; (c) tumors involving no more than three
Healey’s segment without portal vein main trunk involvement;
(d) absence of other major diseases that might complicate
surgery; (e) absence of extra-hepatic tumor dissemination； (f)
No other forms of adjuvant anti-tumor therapy such as local
ablation therapy, chemoembolization, or molecular target
therapy, were performed before or after resection until the
emergence of tumor recurrence.
Exclusion criteria: with concurrent infection of hepatitis C virus
(HCV) or hepatitis D virus (HDV).
As the demographic characteristics were not perfectly match
between patients with and those without antiviral therapy after
resection, we further assessed the efficacy of anti-viral therapy
stratified by tumor stage to diminish the impact of confounding
factors on prognosis.
182 BCLC stage A patients (40 in treated group, 142 in control
group)
Interventions
The criteria for the indication of reimbursed antiviral therapy for
chronic hepatitis B in Taiwan were as the followings: (1) for
cirrhotic patients, serum HBV DNA levels > 2000 IU/mL
irrespective of serum alanine aminotransferase (ALT) levels; (2)
for non-cirrhotic patients, serum ALT levels > 80 U/L in addition
to serum HBV DNA levels > 20000 IU/mL in HBeAg-positive
patients and HBVDNA levels > 2000 IU/mL in HBeAg-negative
patients, respectively.
Treatment group: received antiviral agents included lamivudine,
entecavir and pegylated interferon.
Control group: no antiviral therapy.
Outcomes
Recurrence free survival (RFS); overall survival (OS);
Notes
Only data of BCLC stage-A patients were extracted.
Assessment of Study Quality (COHORT)(6 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
There
were
607
consecutive
treatment-naı¨ve HBV-related CC
patients who underwent curative
resection surgery in Taipei Veterans
General Hospital from 1990 to 2007.
Among them, 333 patients who had
stored serum samples available for
virological analysis were enrolled in
this study.
2. Did the non-exposed
cohort draw from the
same community?
Yes
As reimbursed anti-viral therapy was
implemented in Taiwan since 2003;
therefore, only 62 (18.6%) patients
received anti-viral therapy after
resection.
3. Ascertainment
exposure?
of
no
No description.
4. Outcome of interest
was not present at start
of study?
yes
No other forms of adjuvant anti-tumor
therapy such as local ablation
therapy,
chemoembolization,
or
molecular target therapy, were
performed before or after resection
until the emergence of tumor
recurrence.
5A. Study controls for
age?
no
The mean age in treatment group is
52 and in control group is 58
(P=0.014).
5B. Study controls for
any additional factor?
no
There are still several other
imbalanced
factors
such
as
Microscopic venous invasion, tumor
size.
6.
Assessment
of
outcome by record
linkage?
yes
After
surgery,
patients
visited
outpatient clinics regularly every three
months and assessed by testing
serum liver biochemistries and AFP
levels, and ultrasonography.
7.
Follow-up
enough?
long
yes
With a median follow-up of 45.9
months.
8. Adequacy of Follow
Up of Cohorts?
yes
No evidence to say no, such as
checking the kaplan-meier curve.
Yan 2013
Methods
Mainland China;
A retrospective cohort study;
Follow-up duration was not available.
Participation
Between January 2005 and June 2008, 226 consecutive
patients underwent curative resection of hepatitis B-related
HCC in our hospital.
Inclusion criteria: (1) underwent local or regional liver resection
for hepatitis B-related HCC; (2) tumors, either single, <8 cm in
size or no more than 3 for size <3 cm; (3) macroscopic complete
resection of tumor judged by surgeon’s gross inspection, clear
resection margin >1.0 cm on pathological examination; (4) no
residual tumor thrombus in portal vein or hepatic artery; (5) no
lymph node involvement or distant metastasis; and (6) HBV
DNA levels in excess of 105 copies/ml and 104 copies/ml,
together with ALT levels more than two times the upper limit of
normal, have been proposed as thresholds for treatment of
HBeAg-positive and HBeAg-negative hepatitis respectively.
Exclusion criteria: had been given gene or immune therapy to
prevent occurrence or with concurrent drug abuse, pregnancy,
or other serious medical illness that might interfere with this trial.
35 patients in antiviral group(male/female:33/2;mean age: 45
years);26 patients in control group (male/female: 23/3; mean
age:47 years)
Interventions
Antiviral group: All the patients met the antiviral therapy criteria
of Asian Pacific Association for the Study of the Liver (APASL)
recommendation. Lamivudine 100 mg q.d., and switched to
adefovir 10 mg q.d. or entecavir 0.5–1.0 mg q.d. for those
resistant to lamivudine.
HBV DNA levels in excess of 105 copies/ml and 104 copies/ml,
together with ALT levels more than two times the upper limit of
normal, have been proposed as thresholds for treatment of
HBeAg-positive and HBeAg-negative hepatitis respectively.
Control: no treatment;
Duration: no reported.
Outcomes
Disease free survival (DFS);Recurrence;
Notes
Only data of control group and isolated antiviral group were
extracted.
Assessment of Study Quality (COHORT)(6 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
Of the 226 patients, 120 who met the
inclusion and exclusion criteria were
included and fell into following four
groups
according
to
their
postoperative adjuvant treatment:
2. Did the non-exposed
cohort draw from the
same community?
yes
120 were included and fell into
following four groups according to
their
postoperative
adjuvant
treatment:
control
group
(no
post-operative adjuvant therapy),
antiviral therapy group (patients
received
postoperative
antiviral
therapy), and TACE group (patients
received
postoperative
TACE
therapy).
3. Ascertainment
exposure?
of
no
No description.
4. Outcome of interest
was not present at start
of study?
yes
Obviously yes from the Kaplan-Meier
curve: no recurrence during the first
several
months
after
curative
treatment.
5A. Study controls for
age?
yes
There was no significant difference in
their age, gender ratio, Child-Pugh
class, tumor size, tumor number, AFP
level, HBe-Ag positive rate, HBV-DNA
level, and the kind of liver resection
between the groups.
5B. Study controls for
any additional factor?
yes
There was no significant difference in
their age, gender ratio, Child-Pugh
class, tumor size, tumor number, AFP
level, HBe-Ag positive rate, HBV-DNA
level, and the kind of liver resection
between the groups.
6.
Assessment
of
outcome by record
linkage?
yes
All patients were followed-up at the
outpatient clinic every one to two
months for the first year and then with
increasing intervals. At each visit to
the clinic, blood tests were taken for
DNA
level,
biochemical
tests,
alpha-fetoprotein
(AFP),
and
ultrasonography.
Patients
with
suspected recurrent disease would be
investigated by further imaging
studies,
further
histological
or
cytological confirmation would be
obtained if possible.
7.
Follow-up
enough?
no
No statement.
long
8. Adequacy of Follow
Up of Cohorts?
no
No statement.
Yin 2013
Methods
Mainland China, single center；
Two-stage longitudinal study that included a randomized clinical
trial (RCT) and a cohort study;
The RCT was an open-label RCT.The study statistician
generated 200 randomization codes. The ratio of test to control
was 1:1 and the block size was 4. Patients were randomly
assigned to either antiviral or control arms according to
enrollment sequence.
Sample size was estimated on the basis of 2-year recurrence
rates of 77% in the control group and 52% in the antiviral group
in our nonrandomized cohort, with patients recruited from May
2006 to June 2007 as the expected difference. The minimum
sample size was 75 for each group (two-sided α = 0.05; β =
0.10; power, 90%).
The median follow-up duration was 23.83 months for all patients
(interquartile range, 13.29 to 32.15 months) in cohort study and
39.93 months (interquartile range, 27.27 to 47.80 months) in
RCT.
Participation
From May 2006 to July 2009, at the Department of
Comprehensive Surgery, Eastern Hepatobiliary Surgery
Hospital;
A total of 1,096 consecutive patients with HCC who received
radical hepatectomy were invited to join either the
nonrandomized cohort study or the RCT. The patients enrolled
onto the RCT were not included in the nonrandomized cohort.
For cohort:
Inclusion criteria: with consecutive HCC;seropositive for HbsAg
and HBV DNA ≥ 500 copies/ml;received radical hepatectomy;
previously untreated;
Exclusion criteria: coinfected with HCV, recurred within 1 month
after surgery, or lost to follow-up (contact information was lost
for 91.5% of these patients).
215 patients in antiviral group(male/female:194/21;mean age:
50.06 years);402 patients in control group (male/female: 336/66;
mean age:50.25 years)
For RCT:
Inclusion criteria: 1. Age 18~70years, without gender stricture;
2. HBsAg (+) and HBV-DNA>500 copies/mL; 3. Liver function:
Child A or B; 4. Without surgical contradiction and life span is
longer than half a year; 5. Without HCV, HIV or syphilis infection;
6. After redial excision; 7. Participants attend the trial of their
own free will and sign the informed consent form before
recruiting.
Exclusion criteria：1. Pregnant or breast-feeding women or
possible to conceive again; 2. With mental disorder or central
nervous abnormality or episode; 3. With abnormal ECG or heart
disease including congestive heart failure, coronary heart
disease, arrhythmia and myocardial infarction; 4. With serious
infection, sepsis, diabetes and metabolic disorder; 5. With active
digestive ulcer and defect of defect of absorption; 6. History of
malignant or metastatic tumor in other sites in last 5 years; 7
Patients who is participating in other trials; 8. Other conditions
are not proper for the trial.
We recruited 180 patients for this RCT, with 90 in each arm.
Some patients were excluded from the survival analysis due to
lost of follow-up or discontinuation of intervention (9 in treatment
group and 8 in control group).
Interventions
Treatment group: began receiving oral NAs within 1 week after
surgery until HBsAg seroconversion. Lamivudine (100 mg per
day; GlaxoSmithKline, Beijing, China). Adefovir dipivoxil (10 mg
per day; GlaxoSmithKline) plus lamivudine or entecavir (0.5 mg
per day; Sino-American Squibb, Shanghai, and China) was
used if the patients were drug resistant. The dosage was
adjusted in some patients according to their creatinine
clearance rates.
Control group: no antiviral treatment.
Outcomes
Recurrence free survival (RFS); Overall survival (OS); Side
effect.
Notes
No serious adverse effects caused by NA treatment were
reported in the cohort study.
No adverse effects caused by NA treatment were reported,
except one patient who received adefovir dipivoxil plus
lamivudine treatment had transient anorexia. None of the
participants discontinued participation in the RCT because of
the adverse effects.
Cirrhosis, tumor encapsulation, tumor differentiation, HBeAg
seropositivities, and AFP were imbalanced between the antiviral
and control arms. We stratified the study patients by each of the
five imbalanced variables between the antiviral and control arms
and evaluated the effect of antiviral treatment on postoperative
prognosis in each stratum. It was found that antiviral treatment
was significantly associated with increased RFS and OS after
stratification with cirrhosis, tumor encapsulation, and HBeAg;
whereas antiviral treatment did not significantly increase RFS
and OS in those with grade 1 to 2 tumor differentiation and OS
in those with AFP≤20 ng/mL.
Assessment of Study Quality (COHORT)(7 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
A total of 1,096 consecutive patients
with HCC who received radical
hepatectomy at the Department of
Comprehensive Surgery, Eastern
Hepatobiliary Surgery Hospital, from
May 2006 to July 2009.
2. Did the non-exposed
cohort draw from the
same community?
yes
617 previously untreated patients with
HCC with serum HBV DNA of more
than 500 copies/mL were enrolled
onto this stage. Of those, 215
received
postoperative
NA
treatments.
3. Ascertainment
exposure?
of
yes
All patients enrolled onto this study
were re-examined at our hospital
within 1 month after surgery. The
follow-up examination was performed
at our outpatient clinic every 3 to 6
months or sometimes at outpatient
clinics at local hospitals if the patients
had related symptoms, according to
standard epidemiologic procedure.
4. Outcome of interest
was not present at start
of study?
yes
We excluded the patients coinfected
with HCV, those who recurred within
1 month after surgery, and those lost
to follow-up
5A. Study controls for
age?
yes
Most of the parameters were
consistent between the two groups,
except that the antiviral group had
higher ratios of men, cirrhosis, and
HBeAg positivity and higher levels of
viral load and ALT.
5B. Study controls for
any additional factor?
no
Most of the parameters were
consistent between the two groups,
except that the antiviral group had
higher ratios of men, cirrhosis, and
HBeAg positivity and higher levels of
viral load and ALT.
6.
Assessment
of
outcome by record
yes
All patients enrolled onto this study
were re-examined at our hospital
linkage?
within 1 month after surgery. The
follow-up examination was performed
at our outpatient clinic every 3 to 6
months or sometimes at outpatient
clinics at local hospitals if the patients
had related symptoms, according to
standard epidemiologic procedure.
Computed
tomography
and/or
magnetic resonance imaging were
conducted for our patients every 6
months or if HCC recurrence was
suspected to confirm the diagnosis.
7.
Follow-up
enough?
long
no
The median follow-up duration was
23.83 months for all patients
(interquartile range, 13.29 to 32.15
months) in cohort study.
8. Adequacy of Follow
Up of Cohorts?
yes
We excluded those lost to follow-up
(contact information was lost for
91.5% of these patients).
Authors’ judgment
Support for judgment
Low risk
The study statistician generated 200
randomization codes. The ratio of test
to control was 1:1 and the block size
was 4.
Allocation concealment
(selection bias)
Unclear risk
Patients were randomly assigned to
either antiviral or control arms
according to enrollment sequence.
But the details were not fully reported.
Blinding of participants
and
personnel
(performance bias)
Low risk
The outcome is not likely to be
influenced by lack of blinding.
Blinding of outcome
assessment (detection
bias)
Low risk
The outcome is not likely to be
influenced by lack of blinding.
Incomplete
outcome
data (attrition bias)
Unclear risk
8 patients in treatment group and 9
patients in control group were ruled
out during the analysis. Though the
reasons were similar between groups,
the influence was unclear.
Selective
reporting
(reporting bias)
Low risk
It is clear that the published reports
include all expected outcomes.
Unclear risk
There were five imbalanced factors
(Table 1) between the two arms of the
Risk of bias (RCT)(Unclear)
Bias
Random
generation
bias)
Other bias
sequence
(selection
RCT despite strict randomization.
Nishikawa 2013
Methods
Japan, single center;
Retrospective cohort study;
Median observation periods: 4.9 years (range, 0.2–11.9) for NA
group and 4.0 years (range, 1.1–10.4) for control group.
Participation
Between January 2001 and November 2012, in Osaka Red
Cross Hospital, Japan;
Inclusion criteria: treatment-naïve HBV-related HCC patients
received curative therapy; positive for hepatitis B surface
antigen (HBsAg) and negative for anti-HCV (HCVAb).
Curative therapy was defined as therapy resulting in no
apparent viable tumor on dynamic computed tomography (CT)
performed within 1 month after initial treatment for HCC.
Patients were classified into two groups: control group patients
did not receive NA therapy for the following reasons: (i)
sustained low HBV viral load during the follow-up period (n=20);
(ii) informed consent for NA therapy was not obtained due to
economic reasons (n=7); and (iii) unknown reasons (n=5).
Patients in the treated group received NA at the time of initial
treatment for HCC (n=65).
65 patients in the treated group(male/female:47/18,mean
age:56.1 years);32 patients in the control group ( male/female:
47/18, mean age:60.7 years)
Interventions
44 patients were treated with ETV monotherapy; 5 patients were
treated with LAM monotherapy; 3 patients were treated with
ETV monotherapy switched from LAM monotherap; 13 patients
were treated with ADV, add-on treatment was converted from
LAM monotherapy;
Duration of antiviral treatment was not available.
Control group: no NA therapy.
Outcomes
Recurrence free survival (RFS); Overall survival (OS);
Notes
In the current study, the baseline characteristics in the two
groups were not well balanced for survival analysis, leading to
bias.
Assessment of Study Quality (COHORT)(7 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
A total of 131 treatment-naïve
HBV-related HCC patients received
curative therapy at our institution
between
January
2001
and
November 2012. All patients were
positive for hepatitis B surface antigen
(HBsAg) and negative for anti-HCV
(HCVAb).
2. Did the non-exposed
cohort draw from the
same community?
yes
Hospital controls.
3. Ascertainment
exposure?
of
yes
The present study comprised a
retrospective analysis of patient
records registered in our database,
and all treatments were conducted in
an open label manner.
4. Outcome of interest
was not present at start
of study?
yes
Curative therapy was defined as
therapy resulting in no apparent
viable tumor on dynamic computed
tomography (CT) performed within 1
month after initial treatment for HCC
5A. Study controls for
age?
yes
P value comparing the two groups
was 0.08.
5B. Study controls for
any additional factor?
no
Obviously not.
6.
Assessment
of
outcome by record
linkage?
yes
Follow up after each therapy
consisted of periodic blood tests and
monitoring
of
tumor
markers,
including a-fetoprotein (AFP) and
des-g-carboxy prothrombin (DCP),
using chemiluminescent enzyme
immunoassays(Lumipulse
PIVKAII
Eisai; Eisai, Tokyo, Japan).Dynamic
CT scans and/or MRI were obtained
every 2–4 months after each therapy.
7.
Follow-up
enough?
long
yes
The median observation periods were
4.9 years (range, 0.2–11.9) for NA
group and 4.0 years (range, 1.1–10.4)
for control group.
8. Adequacy of Follow
Up of Cohorts?
no
No statement.
Hann 2014
Methods
USA,single center;
A cohort study;
Follow up: We have observed their clinical course for the past
22 years (1991 to May 2013); Two patients are alive without
recurrence for over 12 years (152 and 151 months,
respectively).
Participation
From 1991 to 2013, in tertiary Liver Disease Prevention Center,
Division of Gastroenterology and Hepatology,USA;
Inclusion criteria: (i) with initial HCC diagnosis;(ii)a single
tumor<7 cm in diameter;(iii)had not received antiviral therapy
prior to HCC diagnosis;(iv)HbsAg positive and negative for
anti-HCV;(v)chose the local tumor ablation as the first option.
Tumor elimination was considered successful when previously
identified contrast enhancement was no longer identified.
Nine untreated patients were all men with a median age of 53
years (48–66 years). Of the 16 anti-HBV treated patients, 14
were men and two were women with a median age of 57 years
(20–73 years).
Interventions
Nine HCC patients were identified between 1991 and 1999.
They did not receive antiviral therapy due to unavailability of the
drug (designated “the untreated”).
From year 2000 to present, 16 patients were eligible for study.
They were started on antiviral therapy immediately after
diagnosis of HCC (designated “the treated”).
The majority received LAM as the first-line therapy in early 2000
and later TLV in two patients. ADV or TDF were later added.
For those with low baseline HBV DNA, one drug was started
and as long as they remained with undetectable HBV DNA, the
medication was not changed.
Outcomes
Recurrence; Recurrence free survival; Overall survival (OS).
Notes
Three patients developed virological breakthrough with LAM at
months 22, 24 and 27, respectively, and were placed on
combination therapy with TDF or ADV.
The patients in untreated group were historical controls, which
might introduce a certain degree of bias.
Only data of patients who received resection or percutaneous
tumor ablation as initial curative treatment were extracted.
Assessment of Study Quality (COHORT)(9 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
Of those, 25 with a single HCC≤7 cm
in diameter were included in the
study. They were Asian American
patients and had never received
antiviral therapy prior to diagnosis of
HCC.
2. Did the non-exposed
cohort draw from the
same community?
yes
Nine HCC patients were identified
between 1991 and 1999. They did not
receive antiviral therapy due to
unavailability of the drug (designated
“the untreated”).
3. Ascertainment
exposure?
of
yes
From year 2000 to present, 16
patients were eligible for study. They
were started on antiviral therapy
immediately after diagnosis of HCC
(designated “the treated”). All patients
on antiviral therapy have maintained
undetectable HBV DNA levels and
were followed at three to four monthly
intervals.
4. Outcome of interest
was not present at start
of study?
yes
All patients with a single HCC (≤7 cm)
lesion underwent local tumor ablative
procedures. Tumor elimination was
considered
successful
when
previously
identified
contrast
enhancement
was
no
longer
identified.
5A. Study controls for
age?
yes
Mean age was 53 (46–60) in
untreated group and 57 (20–73) in
treated group was (P 0.61).
5B. Study controls for
any additional factor?
yes
There were no significant differences
between the untreated and the
treated in the following factors:
median tumor size, baseline HBV
DNA level, AFP, albumin, and platelet
count.
6.
Assessment
of
outcome by record
linkage?
yes
We have observed their clinical
course for the past 22 years (1991 to
May 2013) with a follow-up magnetic
resonance imaging (MRI) at 1 month
following
tumor
ablation,
subsequently at three monthly
intervals and later every 6 months
throughout.
7.
Follow-up
enough?
long
yes
Patients were followed by the same
group of physicians at the clinic for
over 12 years. Two patients are alive
without recurrence for over 12 years
(152 and 151 months, respectively)
8. Adequacy of Follow
Up of Cohorts?
yes
Patients’ compliance was excellent
except one patient (Pt. no. 13) who
after 1 year following TACE and
antiviral therapy was lost in follow-up
for a year. He returned 2 years later
with recurrent HCC with the high HBV
DNA level.
Zhang 2014
Methods
Mainland China, single center;
Retrospective cohort study;
Median follow-up: 31 months.
Participation
Between January 2008 and January 2013, in the Department of
Surgery,Shanghai Jiao Tong University Affiliated Sixth People’s
Hospital, China;
Inclusion criteria: underwent curative liver resection for
HBV-related HCC.
Exclusion criteria: underwent any preoperative treatment, such
as antiviral therapy, transhepatic artery chemoembolization,
percutaneous ethanol injection, or chemotherapy.
Curative resection was defined as complete removal of all
macroscopically evident tumors. The absence of tumor cells
along the parenchymal transection line was confirmed
histologically. Computed tomography (CT) performed 3–4
weeks after surgery showed no remaining tumor.
87 patients were included in the present study. Among these, 36
patients (male/female: 22/14) had a tumor up to 3 cm, of whom
17 patients received entecavir after surgery. Fifty-one
(male/female: 35/16) had a tumor greater than 3 cm among
these, of whom 23 patients received entecavir after surgery.
Interventions
Post curative antiviral criteria: (a) preoperative diagnosis of
HCC; (b) no previous treatment; (c) absence of other
malignancies; and (d) alanine transminase (ALT) levels more
than two times the upper limit of the reference value, with or
without a serum HBV-DNA level greater than 104 copies/ml; or
serum HBVDNA greater than 104 copies/ml, irrespective of ALT
levels;(e) agreed to receive antiviral therapy.
Treatment strategy: entecavir treatment started 14 days after
HCC resection. Treatment duration was not reported.
Control group: no antiviral therapy.
Outcomes
Disease-free survival (DFS); Overall survival (OS).
Notes
Our study has a number of limitations, including a small sample
size, the biases inherent to a retrospective analysis, and
non-standardized selection criteria for antiviral treatment.
Assessment of Study Quality (COHORT)(6 stars)
Items
Authors’ judgment
Support for judgment
1. Representativeness
of the exposed cohort?
yes
Between January 2008 and January
2013, 251 consecutive HCC patients
were treated by our surgical team. Of
these, 87 patients were included in
the present study.
2. Did the non-exposed
cohort draw from the
same community?
yes
Patients who received antiviral
therapy after hepatectomy were
categorized as the antiviral subgroup
and those who did not were
categorized as the nonantiviral
subgroup.
3. Ascertainment
exposure?
of
no
No description.
4. Outcome of interest
was not present at start
of study?
yes
Curative resection was defined as
complete
removal
of
all
macroscopically evident tumors. The
absence of tumor cells along the
parenchymal transection line was
confirmed histologically. Computed
tomography (CT) performed 3–4
weeks after surgery showed no
remaining tumor.
5A. Study controls for
age?
yes
There was no difference between the
treated and the untreated subgroups
in the two tumor size groups at
baseline.
5B. Study controls for
any additional factor?
yes
There was no difference between the
treated and the untreated subgroups
in the two tumor size groups at
baseline.
6.
Assessment
of
outcome by record
linkage?
yes
For detection of HCC recurrence,
serum levels of α-fetoprotein (AFP)
and protein induced by vitamin K
absence were measured 1 month
after surgery and at 3-month intervals
thereafter. Ultrasound, CT, MRI, and/
or chest radiography were performed
1 month after surgery and at 3-month
intervals thereafter.
7.
Follow-up
enough?
long
no
Probably no; The last census date for
this study was 1 September 2013.
8. Adequacy of Follow
Up of Cohorts?
no
No description.
Huang 2014
Methods
Mainland China;
Prospective, single-center, randomized, open-label study;
Eligible patients were randomly assigned in a 1:1 ratio via
computer generated allocation to either the antiviral group or
control group. A block size and strata were used in the
randomization. The stratification factor was BCLC stage. On the
basis of the previous data, it was estimated that approximately
53.2% of patients in the control group would develop HCC
recurrence at 3 years after surgery, and the corresponding rate
was 35.3% in the antiviral group. The hazard ratio (HR) of
antiviral treatment was estimated to be 0.7. Consequently, a
sample size of 86 patients in each group was calculated using α
of 0.05 and 90% power. Assuming the possibility of some
violation from protocol and loss to follow up after randomization,
100 patients were randomized into each study arm.
Follow-up was continued until April 2013 when all surviving
patients had a minimum follow-up of 60 (range 4–70 months)
months.
Participation
From May 2007 to April 2008, at our liver unit (Eastern
Hepatobiliary Surgery Hospital, China);
Consecutive patients with newly diagnosed HBV-related HCC
who had received R0 liver resection were eligible for enrollment.
Inclusion criteria for this study were as follows: (1) age 18 to 70
years; (2) positive test for Hepatitis B surface antigen (HBsAg)
and negative test for antibody to hepatitis C virus (HCV-Ab) or
human
immunodeficiency
virus;
(3)
serum
HBV-deoxyribonucleic acid (HBV-DNA) level greater than 2000
IU/mL; (4) Barcelona Clinic Liver Cancer stage 0, A or a solitary
tumor with diameter greater than 5 cm; (5) no extrahepatic
metastasis; (6) no radiologic evidence of invasion into major
portal/hepatic venous branches; (7) good liver function with
Child-Pugh Class A and baseline serum alanine
aminotransferase (ALT) level less than 2 times the upper limit of
normal (reference range<40 IU/L), with no history of
encephalopathy, ascites refractory to diuretics, esophagogastric
variceal bleeding; (8) good renal function (a serum creatinine
level <133μmol/L); (9) no previous treatment of HCC; (10) no
previous history of antiviral therapy; (11) negative resection
margin (R0 resection); and (12) histopathological result of the
resected specimens being HCC.
Eligible patients were excluded if they refused to participate.
100 untreated patients (male/female: 90/10; mean age: 50.6
years); 100 treated patients (male/female: 89/11; mean age:
50.5 years).
Interventions
Treatment group: adefovir tablets (Hepsera, GlaxoSmithKline)
10 mg/d orally starting from 4 to 7 days after surgery; Antiviral
treatment was continued unless there was unacceptable toxicity
or withdrawal of consent.
In the antiviral group, 3 patients developed primary
nonresponse and 15 patients developed viral resistance to
adefovir. The therapy was then switched to entecavir.
Three patients stopped taking antiviral treatment without
authorization from the clinicians. Except these 3 patients, all the
patients in the antiviral group and all the patients who were
treated with antiviral treatment for hepatitis due to HBV
reactivation in the control group were continued with antiviral
treatment until the end of study census
Control: no antiviral treatment.
Outcomes
Recurrence and Overall survival; Patient tolerance of antiviral
treatment, virologic response, and liver function.
Notes
There were no patients who accepted antiviral therapy
developed adverse effects on follow-up.
Risk of bias (RCT)(Unclear)
Bias
Random
generation
bias)
sequence
(selection
Authors’ judgment
Unclear risk
Support for judgment
No enough information to judge.
Allocation concealment
(selection bias)
Low risk
Eligible patients were randomly
assigned in a 1:1 ratio via computer
generated allocation to either the
antiviral group or control group.
Blinding of participants
and
personnel
(performance bias)
Low risk
The outcome is not likely to be
influenced by lack of blinding.
Blinding of outcome
assessment (detection
bias)
Low risk
The outcome is not likely to be
influenced by lack of blinding.
Incomplete
outcome
data (attrition bias)
Low risk
Six patients were lost to follow-up (3
patients in the antiviral group and 3
patients in the control group). All
analyses were performed on an
intention-to-treat basis.
Selective
reporting
(reporting bias)
Low risk
It is clear that the published reports
include all expected outcomes.
Other bias
Low risk
No additional biases
Table 1 Other characteristics of included RCTs[ordered by date of publication]
TB
(T/C)
(μmol/
L)
ALT
(T/C)
( U/L)
AST
(T/C)
( U/L)
ALB
(T/C)
(mg/d
L)
NA
%Chi
ld-Pu
gh
class
A
(T/C)
NA
%Chi
ld-Pu
gh
class
B
(T/C)
NA
Sun2006
NA
NA
NA
Lo2007
10/11
39/39
NA
39/38
NA
NA
Chen201
2
Yin 2013
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
98.8/
100
NA
1.2/0
52.6/5
1.4
35-55:
77/81
40.5/4
0.5
Huang20
14
14.4/1
4.5
NA
%Mu
ltiple
nodu
les(T
/C)
AFP(n
g/ml)(T
/C)
%Micro
vessel
invasio
n(T/C)
%
HBeA
g+
(T/C)
13.6/
12.7
17/2
7
NA
76.3/75
.4
48/35
20.3/2
0.3
18/25
30.8/24
.4
18.5/8.
5
26.0/28
.0
12.8/8
.9
50.6/3
1.7
51.0/5
0.0
22.6/
14.8
12.3/
22.0
17.0/
16.0
Median
:126/2
3
NA
NA
226.2/
149.0
Abbreviations: T, treated; C, control; NA, not available; TB, Total bilirubin; ALT, alanine
aminotransferase; AST, aspartate aminotransferase; ALB, serum albumin; HBeAg+,
hepatitis B virus e antigen positive; AFP:α-feto protein;NA: not available.
Table 2 Other characteristics of included cohort studies [ordered by date of publication]
Kubo
2007
TB (T/C)
(μmol/L)
ALT (T/C)
( U/L)
AST
(T/C)
( U/L)
ALB
(T/C)
(mg/dL)
%Ch
ild-P
ugh
class
A
(T/C)
%Chil
d-Pug
h
class
B
(T/C)
%
Multi
ple
nodu
lars(
T/C)
13.7/13.7
53/56
44/40
38/37
78.6/
80
21.4/2
0
35.7/
50
%
Mic
rov
ess
el
inv
asi
on(
T/C
)
28.
6/4
0
AF
P(n
g/m
l)
%
HBeAg
+ (T/C)
NA
78.6/50
Kuzuya
2007
Yoshida
2008
13.7/15.4
56.6/54.2
NA
37/37
NA
NA
NA
NA
NA
25/6.1
25.7/15.4
54/36
NA
34/38
60.7/
71.8
NA
NA
NA
24/15
Chuma
2009
15.4/15.4
43.1/37.7
NA
40/39
85/9
0
15/10
25.0/
23.3
NA
Koda
2009
Qu 2010
25.7/22.2
78/54
77/56
33/35
NA
50.25/53.
60
NA
42.37/41.
94
33.3/1
5
0/2.8
NA
16.48/17.
33
63.3/
80
100/
97.2
16/
12
(*1
04)
26.
7/2
0.7
NA
12.9/
14.6
Li 2010
17.6/18.2
NA
NA
40.6/41.6
65.1/
58.3
32.6/3
3.3
NA
25.
7/2
6.6
NA
Chan
2011
12.0/12.0
58.0/42.5
66.5/5
54.5
39/41
100/
89.4
0/10.6
NA
Wu 2012
NA
NA
NA
NA
NA
NA
Yang
2012
Ke 2013
NA
NA
NA
NA
NA
13.5/13.3
39/42
37/39
40.4/40.6
15.4/15.4
45/42
NA
NA
41.5/35.8
Yin 2013
NA
Nishika
wa 2013
50/43.3
36.7/40
NA
34.7/32.
1
88.4/70
NA
59.
5/5
4.3
NA
171
.1/2
88.
1
26/
303
.5
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
41/40
NA
NA
27.7/
24.2
22.6/
46.9
NA
38.8/36.5
57.1/
60
42.9/4
0
NA
52.
5/6
9.7
65.
7/6
8.0
37.
4/4
8.0
234
/24
7
10.6/11.
3
15.0/10.
2
NA
NA
35-55:20
8/380
97.2/
97.7
2.8/2.
5
14.4/
12.7
NA
37.2/24.
9
14.9/15.7
52.8/40.0
49.8/4
0.5
39.4/41.8
NA
NA
38.5/
28.1
36.
7/3
3.1
NA
33.8/12.
5
Hann201
4
NA
NA
NA
42/42
85.7/
80
14.3/2
0
NA
NA
Yeh2014
NA
NA
NA
NA
NA
NA
NA
NA
155
8.5/
178
7.7
19.
7/4
84
NA
Su 2013
Yan
2013
NA
NA
54.3/72.
0
NA
NA
Zhang20
14
17.46/18.
16
48.59/45.
53
47.59/
41.16
41.5/42.3
94.1/
89.5
5.9/10
.5
11.8/
15.8
Zhang20
14
19.43/21.
4
58.04/56.
11
49.22/
51.61
37.0/36.7
73.9/
71.4
26.1/2
8.6
34.8/
35.7
17.
6/2
1.1
60.
9/5
7.1
NA
NA
NA
NA
Abbreviations: T, treated; C, control; NA, not available; TB, Total bilirubin; ALT, alanine
aminotransferase; AST, aspartate aminotransferase; ALB, serum albumin; HBeAg+,
hepatitis B virus e antigen positive;AFP:α-feto protein;NA: not available.