Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma

Transarterial (chemo)embolisation for unresectable

hepatocellular carcinoma (Review)

Oliveri RS Wetterslev J Gluud C

This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011 Issue 3

httpwwwthecochranelibrarycom

Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma (Review)

Copyright copy 2011 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

3OBJECTIVES

3METHODS

Figure 1 5

Figure 2 6

Figure 3 8

8RESULTS

Figure 4 9

Figure 5 11

14DISCUSSION

16AUTHORSrsquo CONCLUSIONS

16ACKNOWLEDGEMENTS

16REFERENCES

21CHARACTERISTICS OF STUDIES

45DATA AND ANALYSES

Analysis 11 Comparison 1 TACE or TAE versus control Outcome 1 All-cause mortality (subgroup risk of selection

bias) 46

Analysis 12 Comparison 1 TACE or TAE versus control Outcome 2 All-cause mortality (subgroup TAE or TACE) 47

Analysis 13 Comparison 1 TACE or TAE versus control Outcome 3 All-cause mortality (subgroup TAE or TACE with

low risk of selection bias) 48

Analysis 14 Comparison 1 TACE or TAE versus control Outcome 4 All-cause mortality (subgroup co-interventions) 49

Analysis 15 Comparison 1 TACE or TAE versus control Outcome 5 All-cause mortality (subgroup low risk of selection

bias trial truncation and co-interventions) 50

Analysis 16 Comparison 1 TACE or TAE versus control Outcome 6 All-cause mortality (subgroup median survival in

control group)) 51

Analysis 17 Comparison 1 TACE or TAE versus control Outcome 7 All-cause mortality (subgroup trial truncation) 52

52APPENDICES

54HISTORY

55CONTRIBUTIONS OF AUTHORS

55DECLARATIONS OF INTEREST

55SOURCES OF SUPPORT

55DIFFERENCES BETWEEN PROTOCOL AND REVIEW

iTransarterial (chemo)embolisation for unresectable hepatocellular carcinoma (Review)


[Intervention Review]

Transarterial (chemo)embolisation for unresectablehepatocellular carcinoma

Roberto S Oliveri1 Joslashrn Wetterslev2 Christian Gluud3

1Department of Oncology The Finsen Centre section 5073 Rigshospitalet Copenhagen Denmark 2Copenhagen Trial Unit Cen-

tre for Clinical Intervention Research Department 3344 Rigshospitalet Copenhagen University Hospital Copenhagen Denmark3Cochrane Hepato-Biliary Group Copenhagen Trial Unit Centre for Clinical Intervention Research Department 3344 Rigshospi-

talet Copenhagen University Hospital Copenhagen Denmark

Contact address Roberto S Oliveri Department of Oncology The Finsen Centre section 5073 Rigshospitalet Blegdamsvej 9

Copenhagen DK-2100 Denmark mafioso_dkyahoodk oliverirhdk

Editorial group Cochrane Hepato-Biliary Group

Publication status and date New published in Issue 3 2011

Review content assessed as up-to-date 15 February 2011

Citation Oliveri RS Wetterslev J Gluud C Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma CochraneDatabase of Systematic Reviews 2011 Issue 3 Art No CD004787 DOI 10100214651858CD004787pub2


A B S T R A C T

Background

Hepatocellular carcinoma (HCC) results in more than 600000 deaths per year Transarterial embolisation (TAE) and transarterial

chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC

Objectives

To assess the beneficial and harmful effects of TACE or TAE

Search strategy

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register The Cochrane Cancer Network register The Cochrane CentralRegister of Controlled Trials (CENTRAL) in The Cochrane Library MEDLINE EMBASE Science Citation Index Expanded and TheLatin American Caribbean Health Sciences Literature (LILACS) from dates of inceptions up to September 2010

Selection criteria

We considered for inclusion all randomised trials that compared TACE or TAE versus placebo sham or no intervention Co-interven-

tions were allowed if comparable between intervention groups Trials with inadequate randomisation were excluded

Data collection and analysis

For all-cause mortality we calculated the log hazard ratio (HR) with standard error as point estimate and pooled them for meta-

analysis using the inverse variance method Sub-group analyses were performed regarding intervention regimen trial truncation or co-

interventions We validated the results with trial sequential analyses We used random-effects model in all meta-analyses in anticipation

of statistical heterogeneity among the trials

1Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma (Review)


Main results

We included nine trials with 645 participants Six trials assessed TACE versus control and three trials assessed TAE versus control Seven

trials had low risk of selection bias based on adequate generation of allocation sequence and concealment - but all these trials had other

risks of bias Three trials were stopped early due to interim inspections and one due to slow accrual For all-cause mortality statistical

heterogeneity between trials was low to moderate (I2= 30) Meta-analysis of trials with low risk of selection bias showed that TACE

or TAE versus control does not significantly increase survival (HR 088 95 CI 071 to 110) Two trials with low risk of selection

bias no early stopping and no co-intervention did not establish any significant effect of TACE or TAE on overall survival (hazard ratio

122 95 confidence interval 082 to 183 P = 033) Trial sequential analysis confirmed the absence of evidence for a beneficial effect

of TACE or TAE on survival indicating the need for future randomisation of up to 383 additional participants Substantial differences

in criteria for assessing tumour response did not allow quantitative analyses One trial investigated quality of life but did not detect any

significant differences between the intervention groups A range of adverse events including post-embolisation syndrome and serious

complications were reported

Authorsrsquo conclusions

There is no firm evidence to support or refute TACE or TAE for patients with unresectable HCC More adequately powered and bias-

protected trials are needed

P L A I N L A N G U A G E S U M M A R Y

Lack of evidence to support or refute transarterial chemoembolisation or transarterial embolisation for patients with unre-

sectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of death from cancer

Several interventions have been tried in order to prolong survival and improve quality of life for such patients During the last 20

years transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have gained considerable attention and have been

advocated as standard loco-regional treatment for unresectable HCC The review included nine trials with 645 participants Six trials

assessed TACE versus control and three trials assessed TAE versus control All trials had risks of systematic errors (rsquobiasrsquo) Contrary to

current practice in many hospitals we could not demonstrate any beneficial effect of TACE or TAE on either survival or tumour growth

in patients with primary liver cancer not suitable for surgical resection Furthermore we calculated that more clinical trials involving a

further 383 trial participants may be needed before firm evidence may become available Importantly TACE or TAE is associated with

a wide range of adverse events some being potentially serious Accordingly we recommend that TACE or TAE should not be used as

standard treatment for liver cancer until firmer evidence is available from randomised clinical trials

B A C K G R O U N D

Hepatocellular carcinoma (HCC) is the fifth most common can-

cer worldwide and the third most common cause of death from

cancer resulting in more than 600000 deaths per year (El-Serag

2007) It has a high incidence in Southeast Asia and sub-Saharan

Africa where it is mainly associated with hepatitis B (Bosch 2004)

However incidences have begun to rise in developed countries

traditionally regarded as low or intermediate areas (El-Serag 1999

McGlynn 2001) and HCC has disproportionately affected age

groups that were not typically affected in the past (El-Serag 2003)

The increase observed in the Western countries is mainly caused

by rising incidence of cirrhosis with especially hepatitis C being a

significant contributor (Davila 2004) and HCC has become the

main cause of death among cirrhotic persons (Sangiovanni 2004)

Early diagnosis of HCC is rare and most persons present with

locally advanced or metastatic disease Prognosis is further com-

plicated by the underlying liver function which in turn affects

the applicability of treatments (Llovet 2003a) Accordingly only

10 to 30 of newly diagnosed HCC persons are eligible for

radical treatment such as resection liver transplantation and per-

cutaneous ablation techniques (ethanol injection radiofrequency

ablation) (Chlebowski 1984 Nagorney 1989 Choi 1990 Paquet

1991)



Transarterial embolisation (TAE) and transarterial chemoemboli-

sation (TACE) have gained considerable attention and have been

advocated as standard loco-regional life-extending treatment for

unresectable HCC The interventions exploit the fact that the

highly vascularised tumours are supplied by the hepatic arteries

whereas the non-neoplastic liver parenchyma has dual blood sup-

ply The tumour-providing branches of the hepatic arteries are

intubated and the application of an embolizing agent results in

ischaemia of the tumour (TAE) This intervention may now po-

tentially be enhanced in TACE by the addition of an emulsified

chemotherapeutic agent to TAE

The implementation of TACE has primarily been based on re-

ported large beneficial effects on survival from in two clinical tri-

als (Llovet [TACE] 2002 Lo 2002) and one sub-sequent meta-

analysis (Llovet 2003b) However number of events remains low

and meta-analytic methodology has undergone developments in-

cluding assessment of risk of bias in the trials based on separate

domains (Higgins 2009a) risks associated with early stopping of

trials (Montori 2005 Bassler 2008) and trial sequential analysis

(TSA) (Brok 2008 Wetterslev 2008 Wetterslev 2009)

O B J E C T I V E S

The primary objective of this review was to conduct a system-

atic review of randomised clinical trials assessing the beneficial

and harmful effect of TACE or TAE in patients with unresectable

HCC using the most rigorous methodology and most recent trial

data available in accordance with the latest Cochrane Collabora-

tion guidelines (Higgins 2009)

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised clinical trials irrespective of language publication sta-

tus or date were considered for inclusion Trials with clear inade-

quate generation of allocation sequence (eg allocation by date of

birth day of the week etc) or inadequate allocation concealment

were not included

Types of participants

Participants diagnosed with HCC according to the definitions of

the individual trials Trials with no explicit definitions were also

included Participants were categorised as having

1 Established HCC present by histology or cytology

2 Likely HCC presence based on nonpathologic para-clinical

diagnosis (typical radiological imaging that could include

ultrasound computed tomography magnetic resonance

imaging or angiogram plus raised alfa-foetoprotein more than

500 ngml with history of chronic liver disease)

Types of interventions

We assessed TACE or TAE versus placebo or sham or no treat-

ment Furthermore TACE or TAE could be employed either alone

or as an adjunct to other co-interventions as long as they were

similar in both arms of the trial

Types of outcome measures

Primary outcome

bull All-cause mortality

Secondary outcomes

bull Tumour response

bull Quality of life according to the measures used in the

individual trials

bull Adverse events (ICH-GCP 1997)

bull Duration of hospital stay

bull Cost-effectiveness

Search methods for identification of studies

We searched The Cochrane Hepato-Biliary Group Controlled TrialsRegister (Gluud 2010) The Cochrane Cancer Network register TheCochrane Central Register of Controlled Trials (CENTRAL) in TheCochrane Library MEDLINE EMBASE Science Citation IndexExpanded and The Latin American Caribbean Health Sciences Lit-erature (LILACS) (Royle 2003) according to the search strategies

and time spans given in Appendix 1


Meta-analyses were conducted according to the recommendations

in The Cochrane Handbook for Systematic Reviews of Interventions(Higgins 2009) and The Cochrane Hepato-Biliary Group Module(Gluud 2010) using the software package RevMan 5 (RevMan

2008) Identified trials were listed and RSO and CG evaluated

whether the trials fulfilled the inclusion criteria Excluded trials

were listed with reasons for exclusion Data were extracted by RSO

and validated by JW and CG Disagreements were resolved by

discussion



Data extraction and management

We extracted general information (title investigators source con-

tact address country publication status language year of publica-

tion and sponsoring of trial) trial characteristics (design sample

size durationfollow-up and quality assessment criteria) partici-

pant-related data (diagnostic criteria eligibility criteria exclusion

criteria baseline characteristics number of persons allocated to

each group numbers at risk) intervention scheme (drug dose

and route for experimental and control interventions) and time-

to-event summary data and statistics (hazard ratio (HR) with 95

confidence interval (CI) log-rank P-value or log-rank χ2 value

and number of events) If essential data were missing in a published

trial we contacted the principal investigators for further details

All-cause mortality

For meta-analyses the natural logarithm (ln) of the HR and its

standard error (SE) were calculated either directly or indirectly

from relevant summary statistics (Parmar 1998 Tierney 2007)

whether reported or provided on our request For direct calcu-

lations we used the crude univariate HR since corrected val-

ues estimated by a regression modelling technique are at risk of

over estimating treatment effects (Deeks 2003) When a trial in-

volved two experimental groups both of which were going into

the same meta-analytic estimation the ln(HR) for each experi-

mental group versus control was left intact but the corresponding

SE(ln(HR)) was multiplied byradic

2 thereby producing two half-

weight contributions to the overall effect estimation (DG Altman

and J Hilden personal communications) All values of ln(HR)

and SE(ln(HR)) were calculated using a specifically developed Ex-

cel spreadsheet (Tierney 2007) All meta-analyses were performed

with Review Manager 50 (RevMan 2008)

The overall pooled HR and 95 confidence interval (CI) were cal-

culated with the inverse variance method (Deeks 2009) We used

the random-effects model in anticipation of clinical and method-

ological diversity between trials (DerSimonian 1986)

For trial sequential analysis the required number of participants

(rsquoinformation sizersquo) for a meta-analysis should be at least as large as

the sample size needed in a single trial with adequate power (Pogue

1998 Brok 2008 Wetterslev 2008) We calculated the required

information size based on a mortality of 80 in the control group

a relative risk reduction (RRR) of 10 an alpha of 5 a beta

of 20 and the estimated diversity (D) in the meta-analysis (

Wetterslev 2008 Wetterslev 2009) To adjust for between-trial

heterogeneity the required information size was corrected with the

factor 1(1-D2) to yield the heterogeneity-adjusted information

size (LBHIS) (Wetterslev 2008 Wetterslev 2009) Cumulative Z-

curves were constructed after including each trial according to

the order of their publication year We assessed the crossing of

the cumulative Z-curves of the naive two-sided boundary of 196

(nominal alpha = 005 beta = 20) and discrete trial sequential

monitoring boundary (TSMB) using the calculated LBHIS All

calculations were performed with Copenhagen Trial Unitrsquos TSA

version 803 software (Wetterslev 2008)

Sub-group analyses were performed with stratification according

to risk of bias TAE or TACE TAE or TACE and low risk of

selection bias trial truncation co-intervention low risk of selec-

tion bias and median survival in the control group Differences in

treatment effects between subgroups were evaluated with the test

of interaction (Altman 2003)

For all calculations a two-tailed P value of less than 005 was

considered statistically significant

Tumour response

In case of uniform assessments of tumour response we planned to

calculate the risk ratio from the proportion of participants reported

as having experienced partial or complete response (rsquorespondersrsquo)

Quality of life

We planned to use the reported means with standard deviation

(SD) for the calculation of the mean difference

Assessment of risk of bias in included studies

We classified trials with adequate randomisation procedure (ie

sequence generation plus allocation concealment) as trials with

low risk of selection bias (Higgins 2009a) Adequate sequence

generation and allocation concealment reduces the risk of selection

bias whereas unclear or inadequate randomisation is associated

with a risk of biased overestimation of treatment effects (Schulz

1995 Moher 1998 Kjaergard 2001 Wood 2008) Accordingly

trials with unclear randomisation were classified as trials with high

risk of bias (Figure 1 Figure 2) We also assessed other components

of bias risk according to the Cochrane Handbook for SystematicReviews of Intervention (Higgins 2009a) and The Cochrane Hepato-Biliary Group Module (Gluud 2010)



Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality

item presented as percentages across all included studies



Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality

item for each included study



Allocation sequence generation- Low risk of bias sequence generation was achieved using com-

puter random number generation or a random number table

Drawing lots tossing a coin shuffling cards and throwing dice are

adequate if performed by an independent adjudicator

- Uncertain risk of bias the trial is described as randomised but

the method of sequence generation was not specified

- High risk of bias the sequence generation method is not or

may not be random Quasi-randomised studies those using dates

names or admittance numbers in order to allocate patients are

inadequate and will be excluded for the assessment of benefits but

not for harms

Allocation concealment- Low risk of bias allocation was controlled by a central and inde-

pendent randomisation unit sequentially numbered opaque and

sealed envelopes or similar so that intervention allocations could

not have been foreseen in advance of or during enrolment

- Uncertain risk of bias the trial was described as randomised but

the method used to conceal the allocation was not described so

that intervention allocations may have been foreseen in advance

of or during enrolment

- High risk of bias if the allocation sequence was known to the

investigators who assigned participants or if the study was quasi-

randomised Quasi-randomised studies will be excluded for the

assessment of benefits but not for harms

Blinding- Low risk of bias the trial was described as blinded the parties

that were blinded and the method of blinding was described so

that knowledge of allocation was adequately prevented during the

trial

- Uncertain risk of bias the trial was described as blind but the

method of blinding was not described so that knowledge of allo-

cation was possible during the trial

- High risk of bias the trial was not blinded so that the allocation

was known during the trial

Incomplete outcome data- Low risk of bias the numbers and reasons for dropouts and

withdrawals in all intervention groups were described or if it was

specified that there were no dropouts or withdrawals

- Uncertain risk of bias the report gave the impression that there

had been no dropouts or withdrawals but this was not specifically

stated

- High risk of bias the number or reasons for dropouts and with-

drawals were not described

Selective outcome reporting- Low risk of bias pre-defined or clinically relevant and reasonably

expected outcomes are reported on

- Uncertain risk of bias not all pre-defined or clinically relevant

and reasonably expected outcomes are reported on or are not re-

ported fully or it is unclear whether data on these outcomes were

recorded or not

- High risk of bias one or more clinically relevant and reasonably

expected outcomes were not reported on data on these outcomes

were likely to have been recorded

Assessment of heterogeneity

Statistical heterogeneity between trials was measured by the I2

statistic which describes the proportion of heterogeneity not as-

cribed to random error (Higgins 2002) Subgroup analyses were

performed according to intervention scheme (TAE or TACE) trial

truncation (early stopping) co-intervention and trial truncation

plus co-intervention

Publication bias

Publication bias was assessed by visual inspection of a funnel plot

(Figure 3) (Egger 1997)



Figure 3 Funnel plot of comparison 1 TACE or TAE versus control outcome 11 All-cause mortality

R E S U L T S

Description of studies

See Characteristics of included studies Characteristics of excluded

studies Characteristics of studies awaiting classification

After performing a sensitive literature search in relevant electronic

databases (Appendix 1) we retrieved 1701 references (includ-

ing doublets) After screening titles we excluded 1161 references

of clear irrelevance We examined 40 references in further detail

(Figure 4) We ended up identifying 13 trials (reported in 13 ref-

erences) eligible for inclusion Pelletier 1990 GETCH 1995 Li

1995 Bruix 1998 Pelletier 1998 Llovet [TACE] 2002 Llovet

[TAE] 2002 Lo 2002 Xiao 2003 Akamatsu 2004 Li 2006

Cheng 2008 and Doffoeumll 2008 However two trials did not re-

port the primary outcome (all-cause mortality) or any secondary

outcomes (Xiao 2003 Li 2006) and one trial did not provide

data adequate for hazard ratio meta-analysis of survival (Li 1995)

We were unable to obtain further information from the authors

Furthermore one trial (Cheng 2008) was excluded due to a later

retraction of the trial based on ldquoconcerns about the integrity of the

data and the veracity of the reportrdquo (DeAngelis 2009)



Figure 4 Flow chart illustrating search strategy and the different phases of the systematic review

Databases were searched from dates of inception to July 2010



The nine trials with quantitative data for survival analysis com-

prised a total of 645 participants (range 42 to 123 participants) of

European Asian or North American origin Three trials investi-

gated TAE and six investigated TACE Three trials had compara-

ble co-intervention in both the experimental and control group

one with radiofrequency ablation or percutaneous ethanol injec-

tion (Akamatsu 2004) and two with tamoxifen (Pelletier 1998

Doffoeumll 2008) Three trials had surgical resections as co-interven-

tion (Li 1995 Xiao 2003 Li 2006) but could not provide data for

the meta-analyses as stated above

Risk of bias in included studies

After the provision of additional information from the responsi-

ble investigators we ended up with seven trials having both ade-

quate sequence generation and adequate allocation concealment

Accordingly these seven trials were classified as trials with low

risk of selection bias (Pelletier 1990 GETCH 1995 Bruix 1998

Pelletier 1998 Llovet [TACE] 2002 Llovet [TAE] 2002 Doffoeumll

2008) and two as having high risk of selection bias (Lo 2002

Akamatsu 2004)

Three trials were stopped early due to repeated interim inspections

using triangular test with discrete monitoring as stopping bound-

aries (GETCH 1995 Llovet [TACE] 2002 Llovet [TAE] 2002)

One trial was stopped due to lack of treatment benefit (crossing the

lower triangular border at the fifth interim inspection) (GETCH

1995) One trial was stopped for treatment benefit (crossing the

upper triangular border at the ninth interim inspection) (Llovet

[TACE] 2002) One trial was stopped prematurely while data were

still accumulating within the triangular borders (rsquounder-runningrsquo)

thus being unable to either accept or reject the null hypothesis

(Llovet [TAE] 2002)

No trial was blinded with regard to participant or care giver due to

the nature of the intervention Regarding tumour response one

trial explicitly reported that the data assessors (eg radiologists)

were blinded

All trials were reported according to the intention-to-treat princi-

ple We did not detect any signs of selective reporting although

some trials indicated vested interest bias

Effects of interventions

All-cause mortality

A funnel plot did not indicate bias Heterogeneity between all nine

trials was low to moderate (I2 = 30) Pooling of HRs from seven

trials with low risk of bias showed no significant effect of TACE

or TAE on survival (overall HR 088 95 CI 071 to 110 P =

027) By contrast the two trials with high risk of bias showed

significant effect (HR 053 95 CI 034 to 083 P = 0005)

(Analysis 11) The difference in HR between the two subgroups

of trials stratified according to risk of bias was significant (test

of interaction P = 0046) Overall meta-analysis of all nine trials

yielded no significant intervention effect (HR 081 95 CI 064

to 102 P = 007)

Based upon an estimated mortality of 80 in the control group

a relative risk reduction of 10 in the TACE or TAE group

an alpha of 5 a beta of 20 and diversity estimated to 13

in all trials in a random-effects model meta-analyses of relative

risk we calculated that the required information size to detect or

reject such an intervention effect as 1028 patients (Figure 5) To

this date only 645 participants have been randomised and the

cumulative Z-score did not cross any trial sequential monitoring

boundaries Accordingly we have only obtained about two thirds

of the required information size to detect (or reject) a 10 relative

risk reduction of mortality



Figure 5 Trial sequential analysis of the cumulative meta-analysis assessing TAE or TACE versus placebo or

no intervention on survival in patients with non-resectable hepatocellular carcinoma The required

information size is based on an event proportion of 80 in the control group a relative risk reduction of 10

an alpha of 5 a beta of 20 and diversity of 13 and equals 1028 patients The cumulative Z-curve (blue)

does not cross the trial sequential monitoring boundaries (red) and only 645 patients have been accrued so far

corresponding to 628 of the required information size

A subgroup analysis stratified according to TACE or TAE showed

no significant effect versus control (Analysis 12) Exclusion of the

two trials with high risk of selection bias (Lo 2002 Akamatsu

2004) just reduced the estimate of the intervention effect and

widened the confidence interval further (Figure 8)

When trials where stratified according to early stopping the trun-

cated trials showed significant intervention effect of TACE and

TAE whereas the non-truncated trials showed no significant in-

tervention effect (Analysis 17) The difference in HR between the

two sub-groups of trials was insignificant (test of interaction P =

038)

When trials where stratified according to the presence or absence

of co-intervention there was no significant intervention effect in

both sub-groups (Analysis 14)

A subgroup analysis stratified according to trial truncation plus

co-intervention showed insignificant effect in the non-truncated

trials without co-intervention (data not shown) When trials with

high risk of selection bias were excluded from the analysis the

meta-analysis of the two remaining non-truncated trials with low

risk of selection bias and without co-interventions (Pelletier 1990

Bruix 1998) resulted in a HR of 122 (95 CI 082 to 183)

whereas the truncated trials with co-interventions showed a HR

of 07)9 (95 CI 063 to 100) (Figure 10) The difference in HR

between these two sub-groups of trials with low risk of bias was

insignificant (test of interaction P = 007)

A further subgroup analysis stratified the trials according to the

50 survival in the control groups was performed as a post-



hoc analysis The 50 survival in the control groups were esti-

mated from the published survival curves by visual extrapolation

if needed The median cut-off value was 12 months We were un-

able to include one trial in this subgroup analysis due to lack of

a survival curve (Llovet [TAE] 2002) Both subgroups yielded no

significant effect of TAE or TACE (Analysis 16) and there was no

difference in HR between the two subgroups (test of interaction

P = 068)

One trial using partial hepatectomy as co-intervention (Li 1995)

did not report overall survival for all participants combined (N

= 140) Instead data were reported as survival percentages for

two subgroups (radical and palliative resections respectively) The

study reported a survival advantage of TACE plus partial hepa-

tectomy versus partial hepatectomy alone which was significant

in both sub-groups (radical resection P = 00014 palliative re-

section P = 00024) Due to the nature of the data figures were

not suitable for meta-analysis of hazard ratios (Characteristics of

included studies)

Tumour response

Seven trials reported evaluation of tumour response However

criteria regarding response evaluation and effect measures varied

substantially between trials (Table 1)

Table 1 Tumour response

Trial Response evaluation Evaluation follow-up Results

Pelletier 1990 Tumour response was evaluated us-

ing both tumour size and α-foeto-

protein levels and was classified in

the following categories

1 Complete response

(disappearance of liver tumour on

both echography and

arteriography and restoration of

normal α-foetoprotein levels)

2 Partial response (Decrease in

tumour size and ge50 decrease

in α-foetoprotein levels)

Not reported In the TACE group complete and

partial tumour response were ob-

served in four (19) and three

(14) participants respectively

Duration of responses lasted be-

tween 2 and 12 months No tu-

mour response was observed in the

control group

GETCH 1995 Tumour response was evaluated us-

ing tumour size andα-foetoprotein

levels separately

Response according to tumour size

was classified as

1 gt50 decrease

2 25-50 decrease

3 lt25 decrease or lt25

increase (stable)

4 ge25 increase

Response according to α-foetopro-

tein levels was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase

Baseline abdominal CT scans and

measurements of serum α-foeto-

protein were carried out before

TACE followed by post-chemoem-

bolisation control measurements

every two months during the first

year and thereafter every four

months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9

Control group (N = 38)

Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50

Bruix 1998 Tumour response was evaluated

using tumour size It is unclear

whether non-enhanced tumoral ar-

eas (reflecting tissue necrosis) were

Tumour size was assessed by dy-

namic CT scan within the first

month after treatment and there-

after every six months

TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35



Table 1 Tumour response (Continued)

excluded from final calculation of

tumour response

Response was classified as

1 Complete response (no

evidence of neoplastic disease)

2 Partial response (gt50

reduction of total tumour load)

3 No change (reduction of

lt50 or increase of lt25)

4 Progressive disease (ge25)

Progression 10


Not reported


ing tumour size and was classified

as

1 Complete response

(complete disappearance of all

tumour lesions)


decrease in tumour size)

Stable disease or progression were

not defined

Not reported Tumour response only available for

45 participants

TACE plus tamoxifen group

Complete response 0

Partial response gt50 9 partici-

pants

Stable disease and progression not

reported

Tamoxifen group

Complete response 0


pants


reported

Llovet 2002 (TAE) Tumour response was evaluated us-


as

Complete response (no evidence of

neoplastic disease)

Partial response (gt50 reduction

of total tumour load)

No change (reduction of lt50 or

increase of lt25)

Progressive disease (ge25)

Tumour size was evaluated by con-

trast-enhanced spiral CT every six

months

14 participants achieved complete

or partial response after TACE

Further details not reported

Llovet 2002 (TACE) Tumour response was evaluated us-


as


neoplastic disease)




increase of lt25)




months


or partial response after TAE Fur-

ther details not reported




Lo 2002 Tumour response was evaluated us-

ing tumour size and -foetoprotein

levels Tumour size was defined as

the product of the two largest di-

ameters of the lesion Response was

classified as

1 Complete response

(complete disappearing of tumour

on imaging or normalization of

alfa-foetoprotein levels)

2 Major response (gt50

decrease in tumour size or AFP

compared to baseline)

3 Minor response (lt50 but

gt25 decrease in tumour size or

AFP compared to baseline)

4 Stabilization (lt 25 decrease

or lt25 increase in tumour size

or AFP compared to baseline)

5 Progression (gt25 increase

in tumour size or AFP compared

to baseline)

Objective response was defined as

the sum of complete and major re-

sponses

CT was performed every three

months and α-foetoprotein levels

were measured every month




TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50

No trial used the RECIST (Response Evaluation Criteria In Solid

Tumours) guidelines (Therasse 2000 Eisenhauer 2009) nor the

guidelines for evaluation of tumour response in HCC developed by

the European Association for the Study of the Liver (EASL) (Bruix

2001) Accordingly meta-analysis was not considered possible

Quality of life

One trial provided details on quality of life (Spitzer index) but

did not detect any significant difference between the two groups

(Doffoeumll 2008)

Adverse events

Descriptions of adverse events were of anecdotal nature and

did not allow meta-analytic calculations Post-embolisation syn-

drome consisting of transient fever abdominal pain and elevated

transaminases was frequently reported among participants under-

going TAE or TACE (about 80) In addition a number of se-

vere albeit rare adverse events were reported including acute re-

nal failure acute gastroduodenal ulcerations ascites encephalopa-

thy transient liver failure cholecystitis bacteraemia and bleeding

from femoral puncture site

Duration of hospital stay and cost-effectiveness

No trial reported data on duration of hospital stay or cost-effec-

tiveness

D I S C U S S I O N

Contrary to current clinical practice we conclude that there is

absence of evidence of TACE or TAE having a beneficial effect

on survival in participants with unresectable HCC Methods of

tumour response evaluation and reporting of adverse events varied

considerably and did not allow meta-analysis of data Only one



trial assessed quality of life systematically but did not observe an

effect of the experimental intervention No trial reported data on

duration of hospital stay or cost-effectiveness

Our systematic review poses a number of methodological advan-

tages compared to previous meta-analyses of the effects of TAE or

TACE (Cammagrave 2002 Llovet 2003b)

First two additional eligible trials have been published (Akamatsu

2004 Doffoeumll 2008) We have also included in the review previ-

ously unidentified trials (albeit the data were not reported in ade-

quate-enough detail to allow us to enter them into the quantitative

analyses of the primary outcome ) (Li 1995 Xiao 2003 Li 2006)

Cochrane reviews should include all identified trials irrespective

of what kind of outcome measures they report In this way one

can get an impression of the risks of outcome measure reporting

bias - a bias component which seems to distort intervention ef-

fects similar to publication bias Accordingly three trials that do

not contribute to our meta-analysis were included (Li 1995 Xiao

2003 Li 2006)

Second we obtained additional relevant data by contacting prin-

cipal investigators of included trials thus reducing the risk of pub-

lication bias ascertainment bias and information bias (Higgins

2009)

Third our assessment of trial quality and hence risk of bias was

based on separate specific domains and not on composite scores

The use of composite scores is discouraged as they are not sup-

ported by any empirical evidence and has several disadvantages in-

cluding unreliable assessments of validity (Emerson 1990 Schulz

1995 Juumlni 1999 Higgins 2009a) In a previous meta-analysis of

TACE and TAE trials (Llovet 2003b) the authors made use of

an ad hoc modified non-validated version of the Jadad composite

score (Jadad 1996) but did not provide any evidence for the va-

lidity of using this modified quality score Importantly the Jadad

score per se is explicitly discouraged by The Cochrane Collabora-

tion (Higgins 2009a) As well as suffering from the generic prob-

lems of scores it does not cover one of the most important poten-

tial biases in randomised trials ie the adequacy of generation of

the allocation sequence and allocation concealment (Schulz 1995

Moher 1998 Kjaergard 2001 Wood 2008)

Fourth we used the HR as the point estimate for all-cause mortal-

ity in our meta-analyses The HR is the most appropriate summary

statistic for survival data since it takes into account both the whole

follow-up period as well as participant censoring (Parmar 1998

Tierney 2007) Nevertheless the use of odds ratios when meta-

analysing survival data is frequently observed including a previous

positive meta-analysis (Llovet 2003b) This approach suffers from

the fact that only a few arbitrary time points are considered for

analysis This problem becomes highly relevant in the case of the

first trial by Pelletier et al (Pelletier 1990) This trial - which we

classified as a trial with low risk of selection bias - did in fact report

a significant 1-year survival rate in favour of the control group

compared with TACE (33 versus 24 respectively) Nonethe-

less after performing a meta-analysis of 1-year survival event rates

showing no significant effect Llovet et al excluded this trial from

a subsequent lsquocore grouprsquo meta-analysis of 2-year survival event

rates due to its shorter follow-up period (Llovet 2003b)

Fifth we considered the impact of randomised trials stopped early

due to interim inspections or slow accrual on our meta-analyses by

performing subgroup analyses Trials stopped early for apparent

benefit are becoming increasingly common but are at risk of re-

porting treatment effects that are substantially larger than typical

interventions that have been definitively studied (Montori 2005)

This phenomenon may be attributed to chance alone (ie stopping

at rsquorandom highrsquo) and is especially relevant if a low number of

events has occurred (Hughes 1992 Montori 2005 Schulz 2005

Bassler 2008) Simulation studies as well as empirical evidence

demonstrate that trials which initially show a significant effect at

interim inspections may later yield no significant effect (Montori

2008 Thorlund 2009) Accordingly methodologists recommend

that relative risk reductions of more than 50 generated in early

stopped trials with fewer than 100 events can easily be disregarded

(Montori 2008) Unfortunately authors of systematic reviews and

meta-analyses frequently neglect the random error risk introduced

from trials stopped early for apparent benefit leading to a sub-

stantial impact on the meta-analysed results (Bassler 2007) In ad-

dition trials stopped early may also cause heterogeneity in meta-

analysis of related trials especially when a random-effects model

is being used (Hughes 1992) Of the nine trials included in our

meta-analysis three were stopped early using triangular test as

stopping rule including the trial yielding the largest relative risk

reductions of mortality (Llovet [TACE] 2002) Like other stop-

ping rules triangular test is at risk of overestimating the treatment

effect (Hulot 2003) Our sub-group analysis of trials stratified ac-

cording to truncation status showed that truncated trials yielded

larger treatment effect sizes than non-truncated trials carrying a

weight of 40 of all trials in the meta-analysis

Sixth we supplemented our meta-analyses with trial sequential

analysis adjusted for trial diversity (Brok 2008 Wetterslev 2008

Wetterslev 2009) Methodological standards for meta-analyses

should not be less rigorous than those for a single trial Therfore

trial sequential monitoring boundaries should be applied to meta-

analyses to reduce the risk of spurious significant findings due to

sparse data and multiplicity Trial sequential analysis addresses the

random errors that may arise from repetitive analyses of accumu-

lating data in cumulative meta-analyses The primary goal of trial

sequential analysis is to provide the required information size for

the meta-analysis (Brok 2008 Wetterslev 2008 Wetterslev 2009)

The secondary goal is to evaluate if the cumulative Z -score cross

the adjacent trial sequential monitoring boundaries (Brok 2008

Wetterslev 2008 Thorlund 2009 Wetterslev 2009) Our trial se-

quential analysis revealed that the total number of accrued partic-

ipants to date (N = 645) is far from the calculated diversity-cor-



rected required information size of 1028 patients (63 accrued

until now) Thus an additional 383 participants may be needed

to demonstrate a potential effect on survival with α = 005 and

80 power (β = 020)

The weaknesses of our meta-analyses are closely related with the

weaknesses in the individual trials We observed a substantial sta-

tistical heterogeneity between trials Besides methodological dif-

ferences related to risk of bias the trials demonstrated substantial

clinical diversity including Okuda stage exclusion criteria aetiol-

ogy and intervention scheme We did not perform meta-regression

due to the low number of available trials (Higgins 2002 Deeks

2009) We observed mostly insignificant differences in treatment

effect sizes between subgroups but it should be recalled that the

test of interaction has limited power to detect interactions even

when the two estimates and P values seem very different (Altman

2003)

One trial in particular draws attention since it has been cited ex-

tensively and forms the basis for the implementation of TACE

due to its reported large beneficial effect based on a total of 46

events (ie deaths) (Llovet [TACE] 2002) Indeed it represented

the largest effect estimate in favour of TACE in our meta-anal-

ysis Besides early stopping for apparent benefit baseline imbal-

ances between the TACE group and the control group might have

contributed further to the observed large beneficial effect An al-

most twice as large proportion (23) of participants in the con-

trol group were classified as advanced (stage C) HCC compared

to the TACE group (13) reflected by higher Child-Pugh scores

number of nodules and inferior performance status Thus it can

be argued that the control group represented a worse prognosis at

baseline due to prognostic imbalance Continuation of the trial

might have reduced the risk of selection bias hence yielding a

more realistic effect estimate

A U T H O R S rsquo C O N C L U S I O N SImplications for practice

There is not sufficient evidence to support or refute TACE or TAE

for patients with unresectable HCC Clinicians should conduct

or await further trials with low risk of bias (rsquosystematic errorrsquo) and

low risk of play of chance (rsquorandom errorrsquo) before using TACE or

TAE as standard loco-regional treatment for unresectable HCC

Implications for research

More adequately powered and bias-protected trials are needed in-

volving up to another 383 participants as calculated by bias- and

heterogeneity-adjusted TSA Only two trials with low risk of selec-

tion bias without co-interventions and without early stopping (ie

lowest overall risk of bias) have been performed one evaluating

TACE (Pelletier 1990) and one evaluating TAE (Bruix 1998) Im-

portantly both trials suggest a possible detrimental effect on sur-

vival Regarding tumour response data assessors should be blinded

and response criteria used should comply with the EASL mod-

ified RECIST criteria since RECIST alone may underestimate

complete and partial responses by not taking the extent of tumour

necrosis into account (Forner 2009)

A C K N O W L E D G E M E N T S

We thank the investigators Drs Bonnetain Cheng Pelletier and

Trinchet who kindly provided us with additional information and

data on our request We also thank Douglas Altman and Joslashrgen

Hilden for useful comments on the pooling of hazard ratios from

trials with two experimental groups Further we thank Bodil Als-

Nielsen and Yan Gong for useful comments to the revised protocol

Dimitrinka Nikolova Sarah Louise Klingenberg and Kate Whit-

field are thanked for their help of identifying trials We acknowl-

edge the work done by Petra Buumlchner-Steudel and colleagues who

prepared an earlier Cochrane Hepato-Biliary Group protocol in

2001-2002 (Buumlchner-Steudel 2002) We however take full re-

sponsibility of the present version of this review

Peer Reviewers Jos Kleijnen The Netherland Tim Meyer UK

Contact Editor Brian Davidson UK

R E F E R E N C E S

References to studies included in this review

Akamatsu 2004 published data only

Akamatsu M Yoshida H Obi S Sato S Koike Y Fujishima T et

alEvaluation of transcatheter arterial embolization prior to

percutaneous tumor ablation in patients with hepatocellular

carcinoma a randomized controlled trial Liver International 2004

24(6)625ndash9

Bruix 1998 published data only

Bruix J Llovet JM Castells A Bru C Montanya X Vilana R et

alTreatment of hepatocellular carcinoma by transarterial

embolization (TAE) A prospective placebo controlled trial

[abstract] Hepatology 1997 Vol 26249Alowast Bruix J Llovet JM Castells A Montana X Bru C Ayuso MC et

alTransarterial embolization versus symptomatic treatment in

patients with advanced hepatocellular carcinoma results of a

randomized controlled trial in a single institution Hepatology199827(6)1578ndash83

Cheng 2004 published data only

Cheng SQ Wu MC Chen H Shen F Yang JH Cong WM et

alTranscatheter hepatic arterial chemoembolization and thymosin



alpha1 in postoperative treatment of hepatocellular carcinoma

Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology] 200426

(5)305ndash7

Doffoeumll 2008 published data only

Doffoeumll M Bonnetain F Bouche O Vetter D Abergel A Fratte S

et alMulticentre randomised phase III trial comparing Tamoxifen

alone or with Transarterial Lipiodol Chemoembolisation for

unresectable hepatocellular carcinoma in cirrhotic patients

(Federation Francophone de Cancerologie Digestive 9402)

European Journal of Cancer 200844(4)528ndash38

GETCH 1995 published data onlylowast Groupe drsquoEtude et de Traitement du Carcinome Hepatocellulaire

A comparison of lipiodol chemoembolization and conservative

treatment for unresectable hepatocellular carcinoma New EnglandJournal of Medicine 1995332(19)1256ndash61

Groupe Francophone drsquoEtude et de Traitement du Carcinome

Hepatocellulaire Treatment of unresectable hepatocellular

carcinoma (HCC) by lipiodol-targeted transcatheter arterial

chemoembolization (TACE) A multicenter randomized trial

[abstract] Hepatology 1993 Vol 1858A

Li 1995 published data only

Li JQ Zhang YQ Zhang WZ Yuan YF Li GH Randomized study

of chemoembolization as an adjuvant therapy for primary liver

carcinoma after hepatectomy Journal of Cancer Research and

Clinical Oncology 1995121(6)364ndash6


Li Q Wang J Sun Y Cui YL Juzi JT Li HX et alEfficacy of

postoperative transarterial chemoembolization and portal vein

chemotherapy for patients with hepatocellular carcinoma

complicated by portal vein tumor thrombosis - a randomized study

World Journal of Surgery 200630(11)2004-11 discussion 2012-3

Li Q Wang J Sun Y Cui YL Juzi JT Qian BY et alPostoperative

transhepatic arterial chemoembolization and portal vein

chemotherapy for patients with hepatocellular carcinoma a

randomized study with 131 cases Digestive Surgery 200623(4)

235ndash40

Llovet [TACE] 2002 published data onlylowast Llovet JM Real MI Montana X Planas R Coll S Aponte J et

alArterial embolisation or chemoembolisation versus symptomatic

treatment in patients with unresectable hepatocellular carcinoma a

randomised controlled trial Lancet 2002359(9319)1734ndash9

Llovet JM Real MI Vilana R Planas R Coll S Aponte J et

alChemoembolization improves survival in patients with

unresectable hepatocellular carcinoma (HH) [abstract] Journal of

Hepatology 2001 Vol 3411

Llovet [TAE] 2002 published data only

Llovet JM Real MI Montana X Planas R Coll S Aponte J et




Lo 2002 published data only

Lo CM Ngan H Tso WK Liu CL Lam CM Poon RT et

alRandomized controlled trial of transarterial lipiodol

chemoembolization for unresectable hepatocellular carcinoma

Hepatology 200235(5)1164ndash71

Pelletier 1990 published data only

Pelletier G Roche A Ink O Anciaux ML Derhy S Rougier P et

alA randomized trial of hepatic arterial chemoembolization in

patients with unresectable hepatocellular carcinoma Journal ofHepatology 199011(2)181ndash4

Pelletier 1998 published data onlylowast Pelletier G Ducreux M Gay F Luboinski M Hagege H Dao T

et alTreatment of unresectable hepatocellular carcinoma with

lipiodol chemoembolization a multicenter randomized trial

Groupe CHC Journal of Hepatology 199829(1)129ndash34

Pelletier G Ducreux M Gay F Luboinski M Hagege H Dao T et

alTreatment of unresectable hepatocellular carcinoma with lipiodol

chemoembolization A multicenter randomized trial [abstract]

Gastroenterology 1996 Vol 110A1292

Xiao 2003 published data only

Xiao E Li D Shen S Zhou S Tan L Wang Y et alEffect of

preoperative transcatheter arterial chemoembolization on apoptosis

of hepatocellular carcinoma cells Chinese Medical Journal 2003

116(2)203ndash7

References to studies excluded from this review

Bhattacharya 1995 published data only

Bhattacharya S Novell JR Dusheiko GM Hilson AJ Dick R

Hobbs KE Epirubicin-Lipiodol chemotherapy versus 131iodine-

Lipiodol radiotherapy in the treatment of unresectable

hepatocellular carcinoma Cancer 199576(11)2202ndash10

Chen 2005 published data only

Chen MS Zhang YJ Li JQ Liang HH Zhang YQ Zheng Y

Randomized clinical trial of percutaneous radiofrequency ablation

plus absolute ethanol injection compared with radiofrequency

ablation alone for small hepatocellular carcinoma Zhonghua Zhong

Liu Za Zhi [Chinese Journal of Oncology] 200527(10)623ndash5


Cheng BQ Jia CQ Liu CT Fan W Wang QL Zhang ZL et

alChemoembolization combined with radiofrequency ablation for

patients with hepatocellular carcinoma larger than 3 cm a

randomized controlled trial JAMA 2008299(14)1669ndash77

Jin 2003 published data only

Jin CB Wu F Wang ZB Chen WZ Zhu H High intensity

focused ultrasound therapy combined with transcatheter arterial

chemoembolization for advanced hepatocellular carcinoma


(4)401ndash3

Koda 2001 published data only

Koda M Murawaki Y Kawasaki H The combination therapy of

transcatheter arterial embolization and percutaneous ethanol

injection for small hepatocellular carcinoma randomized

controlled study [abstract] Journal of Hepatology 2000 Vol 32

issue Suppl 2164lowast Koda M Murawaki Y Mitsuda A Oyama K Okamoto K Idobe

Y et alCombination therapy with transcatheter arterial

chemoembolization and percutaneous ethanol injection compared

with percutaneous ethanol injection alone for patients with small

hepatocellular carcinoma a randomized control study Cancer

200192(6)1516ndash24




Li C Xu D Xu D Li X Zhang W Liu Y Hyperthermal lipiodol

embolization and thermocoagulation for the treatment of primary

hepatocellular carcinoma Zhonghua Gan Zang Bing Za Zhi[Chinese Journal of Hepatology] 200210(3)174ndash6

Liang 2007 published data only

Liang YC Li Z-Y Yang J-Z Lin J Li YZ Ke X Transcatheter

arterial chemoembolization combined with CT-guided

percutaneous intratumor ethanol injection for liver metastases

Chines Journal of Interventional Imaging and Therapy 20074(1)

49ndash51

Lin 1988 published data only

Lin DY Liaw YF Lee TY Lai CM Hepatic arterial embolization in

patients with unresectable hepatocellular carcinoma - a randomized

controlled trial Gastroenterology 198894(2)453ndash6

Liu 2006 published data only

Liu X Wu W Li H The intervention-therapeutic effect of lipiodol-

arsenic emulsion for primary hepatic carcinoma Jie Ry Fang She XueZa Zhi [Journal of Interventional Radiology] 200615(12)716ndash8

Lu 2004 published data only

Lu W Li YH He XF Chen Y Zhao JB Changes of liver function

after transcatheter arterial chemoembolization with use of different

dose of anticancer drugs in hepatocellular carcinoma World

Chinese Journal of Digestology 20041238ndash41


Lu MD Kuang M Liang LJ Xie XY Peng BG Liu GJ et

alSurgical resection versus percutaneous thermal ablation for early-

stage hepatocellular carcinoma a randomized clinical trial

Zhonghua Yi Xue Za Zhi 200686(12)801ndash5

Lygidakis 1996 published data only

Lygidakis NJ Tsiliakos S Multidisciplinary management of

hepatocellular carcinoma Hepato-gastroenterology 199643(12)

1611ndash9

Madden 1993 published data only

Madden MV Krige JE Bailey S Beningfield SJ Geddes C Werner

ID et alRandomised trial of targeted chemotherapy with lipiodol

and 5-epidoxorubicin compared with symptomatic treatment for

hepatoma Gut 199334(11)1598ndash600

Raoul 1997 published data onlylowast Raoul JL Guyader D Bretagne JF Heautot JF Duvauferrier R

Bourguet P et alProspective randomized trial of

chemoembolization versus intra-arterial injection of 131I-labeled-

iodized oil in the treatment of hepatocellular carcinoma Hepatology199726(5)1156ndash61

Raoul JL Guyader D Bretagne JF Heautot JF Duvauferrier R

Bourguet P et alRandomized controlled trial of chemoembolization

vs intraarterial injection of 131 I labeled-iodized oil in the

treatment of hepato-cellular carcinoma (HCC) Preliminary results

[abstract] Gastroenterology 1992 Vol 102A874

Rougier 1993 published data only

Rougier P Roche A Pelletier G Ducreux M Pignon JP Etienne JP

Efficacy of chemoembolization for hepatocellular carcinomas

experience from the Gustave Roussy Institute and the Bicetre

Hospital Journal of Surgical Oncology Supplement 1993394ndash6

Shibata 2009 published data only

Shibata T Isoda H Hirokawa Y Arizono S Shimada K Togashi K

Small hepatocellular carcinoma is radiofrequency ablation

combined with transcatheter arterial chemoembolization more

effective than radiofrequency ablation alone for treatment

Radiology 2009252(3)905ndash13 [PUBMED 19567647]

Shuqun 2004 published data only

Shuqun C Mengchao W Han C Feng S Jiahe Y Wenming C et

alCombination transcatheter hepatic arterial chemoembolization

with thymosin alpha1 on recurrence prevention of hepatocellular

carcinoma Hepato-gastroenterology 200451(59)1445ndash7

Taniai 2006 published data only

Taniai N Yoshida H Mamada Y Kawano Y Mizuguchi Y

Akimaru K et alIs intraoperative adjuvant therapy effective for

satellite lesions in patients undergoing reduction surgery for

advanced hepatocellular carcinoma Hepato-gastroenterology 2006

53(68)258ndash61

Wang 1993 published data only

Wang GM Combination of transcatheter hepatic artery infusion

chemotherapy and embolization with whole liver moving strip

irradiation for primary hepatic carcinoma A randomized trial on

60 patients (abstract) Chinese Medical Journal 1993106638


Wang HL Electrochemical therapy of 74 cases of liver cancer TheEuropean Journal of Surgery Supplement 199457455ndash7

[PUBMED 7531022]


Wang YB Chen MH Yan K Yang W Dai Y Yin SS Quality of life

of primary hepatocellular carcinoma patients after radiofrequency

ablation Ai Zheng [Chinese Journal of Cancer] 200524(7)827ndash33

Wu 1995 published data only

Wu CC Ho YZ Ho WL Wu TC Liu TJ Prsquoeng FK Preoperative

transcatheter arterial chemoembolization for resectable large

hepatocellular carcinoma a reappraisal The British Journal of

Surgery 199582(1)122ndash6


Wu P Li L Zhang Y Transcatheter arterial chemo-embolization

combined with CT-guided percutaneous intratumoral injection of

lipiodol-ethanol for the treatment of primary hepatocellular

carcinoma Zhonghua Zhong Liu Za Zhi [Chinese Journal of

Oncology] 199820(5)391ndash3

Zhou 2006 published data only

Zhou QM Wu PH Zhao M Wang QJ Huang LX Li YQ et

alShort-term curative efficacy of cytokine-induced killer cells

combined micro-invasive treatments on hepatocellular carcinoma

Ai Zheng [Chinese Journal of Cancer] 200625(11)1414ndash8


Zhou Z-T Lin X Li G-H Clinical study of arsenic trioxide-

containing regimen in the treatment of middle or advanced

hepatocellular carcinoma by TACE Chinese Journal of Cancer

Prevention and Treatment 200714(14)1094-6 + 1103

Zhu 1998 published data only

Zhu K Hu G Liang W Percutaneous transfemoral arterial

implantation of drug delivery system for arterial infusion therapy of



advanced primary hepatic carcinoma Zhonghua Zhong Liu Za Zhi

[Chinese Journal of Oncology] 199820(6)457ndash9

References to studies awaiting assessment

Aikata 2006 published data only

Aikata H Shirakawa H Takaki S Uka K Miki D Yamashina K et

alRadiofrequency ablation combined with transcatheter arterial

chemoembolization for small hepatocellular carcinomas

Hepatology 2006 Vol 44 issue 4 (Suppl 1)494A

Bolondi 1996 published data only

Bolondi L Sofia S Piscaglia F Gramantieri L Siringo S Livraghi T

et alEfficacy of transarterial chemoembolization (TACE) associated

to percutaneous ethanol injection (PEI) in the treatment of small

hepatocellular carcinoma (HCC) [Abstract] Journal of Hepatology

199625S118

Dalla Palma 1997 published data only

Dalla Palma L Pozzi MR Sponza M Bartolozzi C Lencioni R

Florio F et alDiagnostic imaging and interventional therapy in

hepatocarcinoma Multicenterstudy of 290 cases La Radiologia

Medica 199794(1-2)30ndash6

Ferrari 2004 published data only

Ferrari FS Stella A Gambacorta D Magnolfi F Fantozzi F

Pasquinucci P et alTreatment of large hepatocellular carcinoma

comparison between techniques and long term results La

Radiologia Medica 2004108(4)356ndash71


Li X-Y Yang LZ Analysis of transcatheter arterial

chemoembolization combined with percutaneous ethanol injection

for hepatoma Chinese Journal of Interventional Imaging andTherapy 20074(4)269ndash72


Wang G Shen W Song M Xu H Results of combined treatment

with transcatheter hepatic arterial chemoembolization and whole-

liver irradiation with the moving strip technique in unresectable

hepatocellular carcinoma International Journal of Clinical Oncology

20005(6)380ndash5

Yang 2008 published data only

Yang P Liang M Zhang Y Shen B Clinical application of a

combination therapy of lentinan multi-electrode RFA and TACE

in HCC Advances in Therapy 200825(8)787ndash94

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Altman 2003

Altman DG Bland JM Interaction revisited the difference

between two estimates BMJ (Clinical Research Ed) 2003326

(7382)219

Bassler 2007

Bassler D Ferreira-Gonzalez I Briel M Cook DJ Devereaux PJ

Heels-Ansdell D et alSystematic reviewers neglect bias that results

from trials stopped early for benefit Journal of ClinicalEpidemiology 200760(9)869ndash73

Bassler 2008

Bassler D Montori VM Briel M Glasziou P Guyatt G Early

stopping of randomized clinical trials for overt efficacy is

problematic Journal of Clinical Epidemiology 200861(3)241ndash6

Bosch 2004

Bosch FX Ribes J Diaz M Cleries R Primary liver cancer

worldwide incidence and trends Gastroenterology 2004127(Suppl

1)S5ndashS16

Brok 2008

Brok J Thorlund K Gluud C Wetterslev J Trial sequential

analysis reveals insufficient information size and potentially false

positive results in many meta-analyses Journal of Clinical

Epidemiology 200861(8)763ndash9

Bruix 2001

Bruix J Sherman M Llovet JM Beaugrand M Lencioni R

Burroughs AK et alClinical management of hepatocellular

carcinoma Conclusions of the Barcelona-2000 EASL conference

European Association for the Study of the Liver Journal of


Buumlchner-Steudel 2002

Buumlchner-Steudel P Patzies A Behl S Fleig WE Transcatheter

arterial chemoembolization for hepatocellular carcinoma CochraneDatabase of Systematic Reviews 2002 Issue 2 [DOI 101002

14651858CD003629pub2]

Cammagrave 2002

Cammagrave C Schepis F Orlando A Albanese M Shahied L Trevisani

F et alTransarterial chemoembolization for unresectable

hepatocellular carcinoma meta-analysis of randomized controlled

trials Radiology 2002224(1)47ndash54

Chlebowski 1984

Chlebowski RT Tong M Weissman J Block JB Ramming KP

Weiner JM et alHepatocellular carcinoma Diagnostic and

prognostic features in North American patients Cancer 198453

(12)2701ndash6

Choi 1990

Choi TK Edward CS Fan ST Francis PT Wong J Results of

surgical resection for hepatocellular carcinoma Hepato-gastroenterology 199037(2)172ndash5

Davila 2004

Davila JA Morgan RO Shaib Y McGlynn KA El-Serag HB

Hepatitis C infection and the increasing incidence of hepatocellular

carcinoma a population-based study Gastroenterology 2004127

(5)1372ndash80

DeAngelis 2009

DeAngelis CD Fontanarosa PB Retraction Cheng B-Q et al

Chemoembolization combined with radiofrequency ablation for


randomized controlled trial JAMA 2008299(14)1669-1677

JAMA 2009 Vol 301 issue 181931 [PUBMED 19380477]

Deeks 2003

Deeks JJ Dinnes J DrsquoAmico R Sowden AJ Sakarovitch C Song F

et alEvaluating non-randomised intervention studies Health

Technology Assessment 20037(27)iiindash173

Deeks 2009

Deeks JJ Higgins JPT Altman DG (editors) Chapter 9 Analysing

data and undertaking meta-analyses In Higgins JPT Green S

(editors) Cochrane Handbook for Systematic Reviews of

Interventions Version 502 (updated September 2009) The



Cochrane Collaboration 2009 Available from wwwcochrane-

handbookorg

DerSimonian 1986

DerSimonian R Laird N Meta-analysis in clinical trials ControlledClinical Trials 19867(3)177ndash88

Egger 1997

Egger M Davey SG Schneider M Minder C Bias in meta-analysis

detected by a simple graphical test BMJ (Clinical Research Ed)1997315(7109)629ndash34

Eisenhauer 2009

Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D

Ford R et alNew response evaluation criteria in solid tumours

revised RECIST guideline (version 11) European Journal of Cancer200945(2)228ndash47

El-Serag 1999

El-Serag HB Mason AC Rising incidence of hepatocellular

carcinoma in the United States New England Journal of Medicine1999340(10)745ndash50

El-Serag 2003

El-Serag HB Davila JA Petersen NJ McGlynn KA The

continuing increase in the incidence of hepatocellular carcinoma in

the United States an update Annals of Internal Medicine 2003139

(10)817ndash23

El-Serag 2007

El-Serag HB Rudolph KL Hepatocellular carcinoma

epidemiology and molecular carcinogenesis Gastroenterology 2007

132(7)2557ndash76

Emerson 1990

Emerson JD Burdick E Hoaglin DC Mosteller F Chalmers TC

An empirical study of the possible relation of treatment differences

to quality scores in controlled randomized clinical trials Controlled

Clinical Trials 199011(5)339ndash52

Forner 2009

Forner A Ayuso C Varela M Rimola J Hessheimer AJ de Lope

CR et alEvaluation of tumor response after locoregional therapies

in hepatocellular carcinoma are response evaluation criteria in solid

tumors reliable Cancer 2009115(3)616ndash23

Gluud 2010

Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B

Colli A et alCochrane Hepato-Biliary Group About The

Cochrane Collaboration (Cochrane Review Groups (CRGs))

2010 Issue 10 Art No LIVER

Higgins 2002

Higgins JP Thompson SG Quantifying heterogeneity in a meta-

analysis Statistics in Medicine 200221(11)1539ndash58

Higgins 2009

Higgins JPT Green S (editors) Cochrane Handbook for

Systematic Reviews of Interventions Version 502 [updated

September 2009] The Cochrane Colloboration 2009 Available

from wwwcochrane-handbookorg

Higgins 2009a

Higgins JPT Altman DG (editors) Chapter 8 Assessing risk of

bias in included studies In Higgins JPT Green S (editors)

Cochrane Handbook for Systematic Reviews of Interventions

Version 502 (updated September 2009) The Cochrane

Collaboration 2009 Available from wwwcochrane-handbookorg

Hughes 1992

Hughes MD Freedman LS Pocock SJ The impact of stopping

rules on heterogeneity of results in overviews of clinical trials

Biometrics 199248(1)41ndash53

Hulot 2003

Hulot JS Cucherat M Charlesworth A Van Veldhuisen DJ

Corvol JC Mallet A et alPlanning and monitoring of placebo-

controlled survival trials comparison of the triangular test with

usual interim analyses methods British Journal of ClinicalPharmacology 200355(3)299ndash306

ICH-GCP 1997

International Conference on Harmonisation Expert Working

Group International conference on harmonisation of technical

requirements for registration of pharmaceuticals for human use ICHharmonised tripartite guideline Guideline for good clinical

practice1997 CFR amp ICH Guidelines Vol 1 PA 19063-2043

USA Barnett InternationalPAREXEL 1997

Jadad 1996

Jadad AR Moore RA Carroll D Jenkinson C Reynolds DJ

Gavaghan DJ et alAssessing the quality of reports of randomized

clinical trials is blinding necessary Controlled Clinical Trials199617(1)1ndash12

Juumlni 1999

Juumlni P Witschi A Bloch R Egger M The hazards of scoring the

quality of clinical trials for meta-analysis JAMA 1999282(11)

1054ndash60

Kjaergard 2001

Kjaergard LL Villumsen J Gluud C Reported methodologic

quality and discrepancies between large and small randomized trials

in meta-analyses Annals of Internal Medicine 2001135982ndash9

Llovet 2003a

Llovet JM Burroughs A Bruix J Hepatocellular carcinoma Lancet

20033621907ndash17

Llovet 2003b

Llovet JM Bruix J the Barcelona-Cliacutenic Cancer Group Systematic

review of randomised trials for unresectable hepatocellular

carcinoma chemoembolization improves survival Hepatology

200337429ndash42

McGlynn 2001

McGlynn KA Tsao L Hsing AW Devesa SS Fraumeni JFJr

International trends and patterns of primary liver cancer

International Journal of Cancer 200194(2)290ndash6

Moher 1998

Moher D Pham B Jones A Cook DJ Jadad AR Moher R et

alDoes quality of reports of randomised trials affect estimates of

intervention efficacy reported in meta-analyses Lancet 1998352

609ndash13

Montori 2005

Montori VM Devereaux PJ Adhikari NK Burns KE Eggert CH

Briel M et alRandomized trials stopped early for benefit a

systematic review JAMA 2005294(17)2203ndash9

Montori 2008

Montori V Devereaux PJ Schunemann H Meade MO Cook DJ

Guyatt G Randomized trials stopped early for benefit In Guyatt



G Rennie D Meade MO Cook DJ editor(s) Userrsquos guide to the

medical literature a manual for evidence-based clinical practice 2

New York The McGraw-Hill Companies 2008153ndash65

Nagorney 1989

Nagorney DM van Heerden JA Ilstrup DM Adson MA Primary

hepatic malignancy surgical management and determinants of

survival Surgery 1989106(4)740ndash8

Paquet 1991

Paquet KJ Koussouris P Mercado MA Kalk JF Muting D

Rambach W Limited hepatic resection for selected cirrhotic

patients with hepatocellular or cholangiocellular carcinoma a

prospective study British Journal of Surgery 199178(4)459ndash62

Parmar 1998

Parmar MK Torri V Stewart L Extracting summary statistics to

perform meta-analyses of the published literature for survival

endpoints Statistics in Medicine 199817(24)2815ndash34

Pogue 1998

Pogue J Yusuf S Overcoming the limitations of current meta-

analysis of randomised controlled trials Lancet 1998351(9095)

47ndash52

RevMan 2008

Review Manager (RevMan) [Computer program] Version 50

Copenhagen The Nordic Cochrane Centre The Cochrane

Collaboration 2008

Royle 2003

Royle P Milne R Literature searching for randomized controlled

trials used in Cochrane reviews rapid versus exhaustive searches

International Journal of Technology Assessment in Health Care 2003

19(4)591ndash603

Sangiovanni 2004

Sangiovanni A Del Ninno E Fasani P De Fazio C Ronchi G

Romeo R et alIncreased survival of cirrhotic patients with a

hepatocellular carcinoma detected during surveillance

Gastroenterology 2004126(4)1005ndash14

Schulz 1995

Schulz KF Chalmers I Hayes RJ Altman DG Empirical evidence

of bias Dimensions of methodological quality associated with

estimates of treatment effects in controlled trials JAMA 1995273

(5)408ndash12

Schulz 2005

Schulz KF Grimes DA Multiplicity in randomised trials II

subgroup and interim analyses Lancet 2005365(9471)1657ndash61

Therasse 2000

Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS

Rubinstein L et alNew guidelines to evaluate the response to

treatment in solid tumors European Organization for Research

and Treatment of Cancer National Cancer Institute of the United

States National Cancer Institute of Canada Journal of the NationalCancer Institute 200092(3)205ndash16 [PUBMED 10655437]

Thorlund 2009

Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP

Thabane L et alCan trial sequential monitoring boundaries reduce

spurious inferences from meta-analyses International Journal of


Tierney 2007

Tierney JF Stewart LA Ghersi D Burdett S Sydes MR Practical

methods for incorporating summary time-to-event data into meta-

analysis Trials 2007816

Wetterslev 2008

Wetterslev J Thorlund K Brok J Gluud C Trial sequential

analysis may establish when firm evidence is reached in cumulative

meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75

Wetterslev 2009

Wetterslev J Thorlund K Brok J Gluud C Estimating required

information size by quantifying diversity in random-effects model

meta-analyses BMC Medical Research Methodology 2009986

Wood 2008

Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et

alEmpirical evidence of bias in treatment effect estimates in

controlled trials with different interventions and outcomes meta-

epidemiological study BMJ (Clinical Research Ed) 2008336

(7644)601ndash5lowast Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Akamatsu 2004

Methods 1 Study design randomised clinical trial

2 Total study duration March 1997 to April 2001

Participants 1 Total number 42

2 Setting hospital

3 Diagnostic criteria

i) Arterial hyper-attenuation and portal hypo-attenuation on angiography

under CT

ii) Hypervascular nodule ie positively enhanced on hepatic arteriography

under CT

4 Eligibility criteria

i) A solitary HCC nodule

ii) No prior history of HCC treatment

5 Exclusion criteria

6 Mean age 655

7 Sex (MF) 2715

8 Country Japan

9 HCC characteristics

i) Aetiology

a) HBV 4

b) HCV 32

c) Alcohol not reported

d) Other not reported

ii) Liver histology

a) Chronic hepatitis 18

b) Cirrhosis 21

iii) Child-Pugh score

a) A NA

b) BC NA

iv) Okuda stage not reported

Interventions 1 Experimental TAE plus PTA regimen consisting of injection of lipiodol (8 ml)

followed by dispersion of gelatin sponges Next either injection of ethanol (50 ml) or

insertion of radio frequency ablation electrode (40 to 160 kW for 720 s for nodules 2

cm and 1440 s for nodules 3 cm in diameter)

2 Control PTA regimen consisting of either injection of ethanol (50 ml) or



Outcomes 1 All-cause mortality

Notes

Risk of bias



Akamatsu 2004 (Continued)

Item Authorsrsquo judgement Description

Adequate sequence generation Yes Quote ldquoA randomised sealed envelope

method was usedrdquo

Allocation concealment Unclear Quote ldquoA randomised sealed envelope


Blinding

Tumour response

No Outcome not assessed quantitatively

Blinding

All-cause mortality

No Participants and care givers not blinded due

to nature of intervention

Incomplete outcome data addressed

All outcomes

Yes No drop-outs

Free of selective reporting Yes Mortality and causes of mortality as well as

recurrence of HCC and complications are

reported

Free of other bias Yes No truncation no signs of academic or in-

dustry bias

Bruix 1998


2 Total study duration persons evaluated between January 1992 and April 1994


2 Setting hospital


i) Needle biopsy andorii) Increased alfa-foetoprotein


i) No previous treatment

ii) Tumour gt 4 cm andor multinodular


i) Age gt 75

ii) Uncontrolled liver disease decompensation (gastrointestinal bleeding

encephalopathy bacterial infection)

iii) Portal vein thrombosis

iv) Extrahepatic spread

v) Any contraindication for an arterial procedure such as impairment of

clotting tests (platelet count lt 50000mm3 or prothrombin activity lt 50)

vi) Renal failure

vii) Severe atheromatosis

viii) Advanced disease (Okuda stage III)



Bruix 1998 (Continued)

ix) Performance status gt 2

6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology

a) Chronic hepatitis not reported

b) Cirrhosis 80

iii) Child-Pugh score exact numbers not reported

iv) Okuda stage

a) I 54

b) II 26

Interventions 1 Experimental One TAE-session with consisting of embolisation with 1x1 mm

gelatin cubes combined with steel coil proximal occlusion in participants with

unilobar disease No chemotherapeutic agent was administered Some participants

were considered for additional sessions

2 Control no treatment


2 Tumour response

Notes

Risk of bias


Adequate sequence generation Yes Quote (from report) ldquoRandomization was

performed using a computer-generated al-

locationrdquo

Allocation concealment Yes Comment Most likely done due to re-

ported details in a later review by the same

investigators (Llovet 2003b P 431 and ta-

ble 3)

Blinding

Tumour response

No Not performed due to nature of interven-

tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs

Free of selective reporting Yes The authors of the trial report mortality

and causes of mortality as well as recurrence

of HCC and complications


dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes

Notes bull Participants underwent surgical resection of the liver

bull Group B and C apparently comparable

bull Paper has been requested from primary investigator for further assessment (and translation) No response at

the time of writing (31 August 2010)

Doffoeumll 2008


2 Total study duration May 1995 to June 2002


2 Setting hospital


i) Biopsy orii) Persistently elevated serum alpha-foetoprotein (gt 500 ngml) plus one

typical imaging finding (ultrasonography CT or MR)


i) Liver cirrhosis (histopathology clinical presentation or laboratory findings)


i) Age gt 75

ii) Advanced liver disease (Child-Pugh score C)

iii) Advanced HCC (Okuda stage III)

iv) Portal vein thrombosis (trunk and primary branches)

v) Arteriovenous shunting

vi) Extrahepatic metastases

vii) Renal failure (serum creatinine level gt 120 micromolL or creatinine clearance lt

80 mls)



Doffoeumll 2008 (Continued)

viii) Platelet count lt 50 x 109L

ix) Prothrombin activity lt 50

x) Cardiac ejection fraction lt 35

6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology


b) Cirrhosis not reported


a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35

Interventions 1 Experimental TACE plus tamoxifen regimen consisting of 1) injection of 50 mg

epirubicin mixed with 15 ml lipiodol followed by embolization with gel-foam cubes

Repetition of TACE every 2 months until tumour stabilization 2) a daily dose of 20

mg tamoxifen

2 Control A daily dose of 20 mg tamoxifen


2 Quality of life (Spitzer index)

Notes

Risk of bias


Adequate sequence generation Yes Quote (from correspondence) ldquoWe have

used a computer rdquo

Allocation concealment Yes Quote (from correspondence) ldquoAllocation

was done centrally at the FFCD centre (Di-

jon) using computerrdquo

Blinding

Tumour response

Unclear Outcome not assessed

Blinding

All-cause mortality


tion





All outcomes

Yes

Free of selective reporting Yes


dustry bias

GETCH 1995


2 Total study duration July 1990 to November 1992


2 Setting twenty-four centres in three countries (France Belgium Canada)


i) Histologiccytologic findings orii) Cirrhosis liver tumour and serum alfa-fetoprotein gt 250 ngml

4 Elegibility criteria

i) Not specified explicitly but probably all persons with diagnosed HCC

without any exclusion criteria

5 Exclution criteria

i) Indication for surgery

ii) previous treatment for HCC

iii) Severe hepatic disease (one of the following encephalopathy gastrointestinal

haemorrhage in the past month clinical ascites serum bilirubin gt 50 micromolL serum

albumin lt 30 gL)

iv) Vascular contraindications to chemoembolization (such as portal obstruction

of gt 3 segmental branches)

v) Contraindications to treatment with cisplatin

vi) Serum creatinine ge120 micromolL

vii) Extrahepatic metastasis

6 Mean age 64

7 Sex (MF) 924

8 Country France Belgium and Canada


1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87


a) A 87 (ie 100 of the cirrhotic participants)

b) B 0



GETCH 1995 (Continued)

iv) Okuda stage

a) I 86

b) II 10

Interventions 1 Experimental TACE with cisplatin (70 mg) emulsified in iodised oil (lipiodol)

followed by embolisation with gelatin sponge (Gelfoam) particles repeated every 2

months for a total of four courses



2 Tumour response

Notes

Risk of bias


Adequate sequence generation Yes Quote (from correspondence) ldquo() using

computerrdquo

Allocation concealment Yes Quote (from correspondence) ldquo() cen-

tralized by phone to the Biostat dptrdquo

Blinding

Tumour response

Yes Quote (from report) ldquoAll computed tomo-

graphic scans were reviewed by two radi-

ologists who were unaware of the patientrsquos

clinical data or treatment assignmentrdquo

Comment data assessors were blinded

Blinding

All-cause mortality


tion


All outcomes

Yes




Free of other bias No The trial was stopped early for lack of treat-

ment benefit (crossing the lower triangular

test border at the fifth interim inspection)

More participants in the control group had

multinodular and large tumours and seg-

mental obstruction which may have re-

sulted in significant baseline imbalance be-

tween the two groups



Li 1995

Methods Randomised to partial (radical or palliative) hepatectomy TACE versus partial (radical

or palliative) hepatectomy only

Participants 140 patients with hepatocellular carcinoma

Interventions 1 Experimental Partial (radical or palliative) hepatectomy + post-operative (3-4

weeks) TACE

2 Control Partial (radical or palliative) hepatectomy

Outcomes Cancer recurrence

Overall survival

Notes bull Trial described as randomised in abstract No further description in main text

bull No assessment of overall survival for all participants combined (70 vs 70) Survival

data are split up into radical resections and palliative hepatectomies respectively

bull Survival data only reported as survival percentages Data not suitable for inclusion

in meta-analysis of hazard ratios

bull Primary investigator has not been contacted due to difficulty of identification

Risk of bias


Adequate sequence generation Unclear No information

Allocation concealment Unclear No information

Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes

Unclear No tumour response adverse events or

quality of life described

Free of selective reporting Unclear No tumour response adverse events or


Li 2006

Methods Randomised trial

Participants 131 patients with hepatocellular carcinoma and portal vein tumour thrombosis

Interventions 1 Experimental Resection plus three courses of post-operative TACE starting after

4 weeks and with 2-weeks intervals

2 Control Resection only



Li 2006 (Continued)

Outcomes Disease-free survival

Notes bull No assessment of overall survival

bull Participants apparently overlapping with Li 2006

Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes

Unclear No assessment of overall survival tumour response adverse

events or quality of life

Free of selective reporting Unclear No assessment of overall survival tumour response adverse


Llovet [TACE] 2002


2 Total study duration July 1996 to July 2000


2 Setting three hospital centres in the Barcelona area


i) Needle biopsy orii) Two coincidental imaging techniques associated with increased alfa-

fetoprotein


i) Not explicitly stated but probably diagnosed HCC persons not fulfilling

exclusion criteria


i) Age gt 75


iii) Active gastrointestinal bleeding

iv) Encephalopathy

v) Refractory ascites

vi) Presence of vascular invasion (including segmental portal obstruction)

vii) Extrahepatic spread



Llovet [TACE] 2002 (Continued)

viii) Portosystemic shunt

ix) Hepatofugal blood flow

x) Any contradiction to arterial procedure such as impaired clotting tests

(platelet count lt 50x109L or prothrombin activity lt 50)

xi) Renal failure

xii) Severe atheromatosis

xiii) Any contraindication to doxorubicin (serum bilirubin gt 855 micromlL

leucocyte count lt 3x109L cardiac ejection fraction lt 50)

xiv) Endstage tumoral disease

6 Age 644

7 Sex (MF) 5520

8 Country Spain


i) Barcelona Clinic Liver Cancer (BCLC) staging classification

a) Intermediate (stage B) 62

b) Advanced (stage C) 13

ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1

iii) Liver histology



iv) Child-Pugh score

a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26

Interventions 1 Experimental One TACE-session at baseline with doxorubicin (bilirubin

adjusted) lipiodol and mechanical obstruction Repeated after 2 and 6 months and

then every 6 months



Notes The control group is identical to the control group in the Llovet [TAE] 2002 reference

Risk of bias


Adequate sequence generation Yes Quote (from report) ldquoRandomisation was

done with a computer-generated allocation

[]rdquo




Allocation concealment Yes Quote (from report) ldquoRandomisation was

done with [] sealed envelopes []rdquo

Comment It remains unclear whether en-

velopes were also sequentially numbered

and opaque

Blinding

Tumour response

Unclear Data assessors (eg radiologists) not re-

ported of being blinded

Blinding

All-cause mortality


tion


All outcomes

Yes

Free of selective reporting Yes Authors report all-cause mortality and ad-

verse events

Free of other bias No The authors report that the sponsors of the

study had no role in study design data col-

lect data analysis data interpretation or

writing of the manuscript However it re-

mains unclear whether the sponsor of the

chemotherapeutic agent had any role in the

decision of when to terminate the trial

Indeed the trial was stopped early for ap-

parent benefit (crossing the upper trian-

gular test border at the ninth interim in-

spection) after a total of 46 events (deaths)

had occurred (both arms combined) The

observed effect estimate at this time point

corresponded to a large relative risk reduc-

tion (RRR) of more than 50 No head-

to-head comparison of TACE versus TAE

was performed after stopping the TACE-

arm

Llovet [TAE] 2002







fetoprotein



Llovet [TAE] 2002 (Continued)



exclusion criteria


i) Age gt 75



iv) Encephalopathy








xi) Renal failureSevere atheromatosis

xii) Any contraindication to doxorubicin (serum bilirubin gt 855 micromlL


xiii) Endstage tumoral disease

6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2




iv) Child-Pugh class

a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26

Interventions 1 Experimental One TAE-session at baseline with gelfoam fragments repeated

after 2 and 6 months and then every 6 months



Notes The control group is identical to the control group in the Llovet [TACE] 2002 reference




Risk of bias




[]rdquo

Allocation concealment Unclear Quote (from report) ldquoRandomisation was




and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events






chemotherapy (doxorubicin) had any role

in the decision of when to terminate the

trial

The trial was designed for interim inspec-

tions using triangular test It was stopped

prematurely while still accumulating data

within the triangular borders (rsquounder-run-

ningrsquo) due to the results of the other ac-

tive (TACE) arm (Llovet [TACE] 2002) At

this time point a total of 50 events (deaths)

had occurred (both arms combined) Ac-

cordingly the null hypothesis could nei-

ther be accepted nor rejected Neverthe-

less the authors reported a HR but it re-

mains unclear whether or not this value was

adjusted for rsquounder-runningrsquo No head-to-

head comparison of TAE versus TACE was




performed after stopping the TACE-arm

Lo 2002


2 Total study duration Screening of eligible persons started in March 1996 Time

of data analyses not reported


2 Setting hospital


i) Histologycytology orii) Persistently elevated serum alfa-fetoprotein levels (gt 400 ngml) with typical

imaging findings



exclusion criteria


i) Poor hepatic function (encephalopathy ascites not controlled by diuretics

history of variceal bleeding within last three months a serum total bilirubin level gt 50

micromolL serum albumin level lt 28 gL prothrombin time gt 4 s over the control)

ii) Serum creatinine level gt 180 micromolL

iii) History of previous treatment for the tumour or acute tumour rupture

iv) Presence of extrahepatic metastasis

v) Vascular contraindications to chemoembolization (hepatic artery

thrombosis main portal vein thrombosis or arteriovenous shunting)

vi) Poor performance status (Eastern Cooperative Oncology Group

performance status rating grade 4)

6 Age 625

7 Sex (MF) 709

8 Country China (Hong Kong)


i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)

Interventions 1 Experimental TACE with cisplatin (median 10 mg) lipiodol and gelatin-

sponge pellets repeated every 2 to 3 months



2 Tumour response

Notes

Risk of bias


Adequate sequence generation Unclear Quote (from report) ldquoRandomization []

was performed [] by drawing consecu-

tively numbered sealed envelopesrdquo

Comment No description of method used

for sequence generation No additional in-

formation provided by corresponding au-

thor on request

Allocation concealment Yes Quote (from report) ldquoRandomization []



Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes


tumour response and adverse events


dustry bias

Pelletier 1990


2 Total study duration February 1985 to February 1988


2 Setting Multicentre trial involving ten different hospitals




Pelletier 1990 (Continued)

i) Histology orii) Serum alfa-fetoprotein gt 500 ngml and a diagnosis of a liver tumour on

radiological examinations


i) Not stated explicitly but probably diagnosed HCC persons not fulfilling

exclusion criteria


i) Resectable HCC

ii) Spontaneous encephalopathy


iv) Previous portocaval anastomosis

6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9

Interventions 1 Experimental TACE with doxorubicin (50 mg) followed by embolisation with

gelatin sponge (Gelfoam) powder repeated after 2 6 and 12 months



2 Tumour response

Notes Patient inclusion was 41 of all HCC persons observed during the inclusion period

Risk of bias


Adequate sequence generation Yes Quote (from correspondence) ldquoTo gener-

ate the allocation sequence we used a ran-

dom number tablerdquo




Allocation concealment Yes Quote (from report) ldquoEach patient was

randomly assigned to one of two groups us-

ing the sealed envelope techniquerdquo

Comment Principal investigator has con-

firmed that envelopes were also sequentially

numbered and opaque

Blinding

Tumour response

No No description of data assessors (eg radi-

ologists) being blinded

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998


2 Total study duration April 1991 to May 1995


2 Setting Multicentre trial involving eight hospital centres


i) Histologycytology


i) Not explicitly stated but probably unresectable HCC not fulfilling exclusion

criteria



ii) Previous treatment of hepatocellular carcinoma (except surgery)

iii) Portal vein occlusion (main trunk or one of the two branches)

iv) Extrahepatic metastasis

v) History of other cancer

vi) Age plusmn80 years

vii) Severe hepatic disease (encephalopathy bilirubin plusmn30 mgL clinical ascites

needing treatment prothrombin activity 30 of normal)

viii) Okuda stage 3

ix) WHO performance status stage 3 or 4

x) Serum creatinine plusmn120 mmolL

xi) Refusal to participate




6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21

Interventions 1 Experimental TACE plus tamoxifen regimen consisting of 1) TACE with

cisplatin (2 mgkg) lipiodol purified egg lecithin Gelfoam particles plus 2) tamoxifen

(20 mg twice daily) TACE repeated every 3 months during the first year thereafter

every 4 months

2 Control Tamoxifen (20 mg twice daily) and no treatment


Notes

Risk of bias



carried out [] using a computer-generated

listrdquo

Allocation concealment Yes Quote (from report) ldquo[] by telephonerdquo

Blinding

Tumour response

No Outcome not assessed

Blinding

All-cause mortality

No Not performed


All outcomes

Yes




Free of selective reporting Yes Authors report all-cause mortality tumour

response and adverse events

Free of other bias No A sample size of 80 persons was calculated

but the study was stopped after 73 persons

due to low accrual rate

No signs of academic or industry bias

Xiao 2003



Interventions 1 Experimental Pre-operative TACE plus resection

2 Control Resection

Outcomes Extent of apoptosis using histology


Risk of bias


Adequate sequence generation Unclear No description

Allocation concealment Unclear No description

Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





HCC = hepatocellular carcinoma

TACE = transarterial chemoembolisation

TAE = transarterial embolisation

s = seconds



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Bhattacharya 1995 Intervention groups not eligible for inclusion

Chen 2005 TAETACE was not performed

Cheng 2008 The trial fulfilled inclusion criteria but has been excluded from further analyses due to a later retraction based

on ldquoconcerns about the integrity of the data and the veracity of the reportrdquo (DeAngelis 2009)

Jin 2003 Groups are not comparable

Koda 2001 Althoug described as using a ldquorandomised sealed envelope methodrdquo an unreported number of PEI participants

also received TACE Given the small samples size(s) bias is introduced and data are significantly distorted

Quote (from report) ldquoIn the PEI alone group TACE was performed when five or more recurrent tumors were

detected and PEI could not be performedrdquo (P 1518 1st column line 37)

Li 2002 Trial compares hyperthermal iodized oil embolisation versus chemoembolisation

Liang 2007 Groups are not comparable

Lin 1988 IInformation from the lead author demonstrates that the principal investigator was identical to the co-ordinator

who conducted the randomisation Accordingly we assess the randomisation as being conducted with inadequate

allocation concealment

Liu 2006 TAETACE was not performed

Lu 2004 Groups are not comparable

Lu 2006 TAETACE was not performed

Lygidakis 1996 Intervention groups not eligible for inclusion

Madden 1993 Intervention groups not eligible for inclusion

Raoul 1997 Intervention groups are not comparable

Rougier 1993 Single cohort study

Shibata 2009 Inadequate randomisation (allocation according to day of the week)

Shuqun 2004 Intervention groups are not comparable

Taniai 2006 Intervention groups not comparable

Wang 1993 Intervention groups not comparable



(Continued)

Wang 1994 Single cohort study with irrelevant active treatment

Wang 2005 A questionnaire survey no randomisation no investigation of overall survival

Wu 1995 Groups not considered comparable due to TACE-induced delay in the experimental group

Wu 1998 Groups are not comparable

Zhou 2006 TAETACe was not performed

Zhou 2007 TAETACE was not performed

Zhu 1998 TAETACE was not performed

Characteristics of studies awaiting assessment [ordered by study ID]

Aikata 2006

Methods Participants described as ldquodivided randomly into two groupsrdquo without further details on generation of allocation

sequence and allocation concealment

Cisplatin was used as agent in TACE

Participants Forty-four participants with 44 hypervascular nodules smaller than 30 mm in diameter

Interventions Compares TACE + RFA (21) versus RFA (23)

Outcomes Total number of RFA electrode insertions and treatment sessions local tumour response survival and adverse events

Notes Study exist in abstract form only

The number of electrode insertions as well as treatment sessions needed to achieve complete necrosis of the lesions

were significantly fewer in the TACE + RFA group compared with the RFA alone group

Insufficient details on survival statistics but log-rank p-value 09495 reported Number of participants experiencing

event not reported Accordingly appropriate summary data for survival cannot be calculated to be used in meta-

analysis

There was no significant difference regarding objective tumour response

First author has been contacted by e-mail for further details regarding allocation generation and allocation conceal-

ment number of events and hazard ratio

Bolondi 1996

Methods Participants described as ldquorandomly assignedrdquo without further details on generation of allocation sequence and


Participants Multicenter trial with 150 participants with small (lt 5cm) unifocal unresectable hepatocellular carcinoma



Bolondi 1996 (Continued)

Interventions Compares TACE + PEI (66) versus PEI (84) In the first group TACE was performed before PEI

Outcomes AFP levels objective tumour response and survival

Notes Study exist in abstract form only Data are described as preliminary

Insufficient details on survival statistics no p-value reported Sufficient summary data cannot be calculated from the

available data


ment number of events and hazard ratio No reply in the time or writing

Dalla Palma 1997

Methods Multi-arm study with four groups including TACE group and no treatment group

Participants Participants described as undergoing ldquorandomised protocolsrdquo in the English abstract Italian text describes the use of

a ldquolista di randomizzazionerdquo which could or could not be a random table

Interventions TACE versus no treatment Numbers

Outcomes Survival

Notes Text only in Italian with English abstract

Exact number of participants to be determined

Survival data summarised with Kaplan-Meier plot Apparently no exact log-rank p-value HR etc

Author has been contacted by e-mail March 2009 about details regarding exact number of participants generation

of allocation sequence allocation concealment and relevant summary data The author was also asked about the

survival data by Bolondi et al which is cited in the paper (Fig 6) No reply by April 2009

Ferrari 2004

Methods Described as ldquorandomisedrdquo without any further details

Participants Cirrhotic participants were included in a four arm trial including TACE PEI and PEI alone

Interventions TACE + PEI (19) versus PEI (20)

Outcomes Extent of tumour necrosis

Notes Significant survival advantage in favour of TACE + PEI (log-rank P 0002)

However the two groups differ significantly regarding baseline Child-Pugh scores 16 out of 19 participants are class

A in the TACE + PEI group compared to 8 out 20 participants in PEI group Hence substantial selection bias

favouring the survival of TACE + PEI group since Child-Pugh score is a strong predictor



Li 2007

Methods

Participants

Interventions

Outcomes

Notes A full paper could not be retrieved for more detailed assessment However the title of the paper does not indicate a

design involving more than one group of participants

Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008

Methods Trial with no description of randomisation in the abstract

Participants 78 participants with HCC

Interventions Four groups comparison including TACE+ RFA and RFA alone

Outcomes

Notes A full paper is going to be retrieved for further assessment Corresponding author has been contacted by e-mail for

paper request No response in the time of writing (April 2009)



D A T A A N D A N A L Y S E S

Comparison 1 TACE or TAE versus control

Outcome or subgroup titleNo of

studies

No of

participants Statistical method Effect size

1 All-cause mortality (subgroup

risk of selection bias)

9 Hazard Ratio (Random 95 CI) 081 [064 102]

11 Trials with low risk of

selection bias


12 Trials with high risk of

selection bias



TAE or TACE)


21 TACE 6 Hazard Ratio (Random 95 CI) 079 [058 106]

22 TAE 3 Hazard Ratio (Random 95 CI) 094 [062 142]


TAE or TACE with low risk of

selection bias)





co-interventions)


41 Without co-intervention 6 Hazard Ratio (Random 95 CI) 075 [053 107]

42 With co-intervention 3 Hazard Ratio (Random 95 CI) 093 [069 126]


low risk of selection

bias trial truncation and

co-interventions)


51 Low risk of selection

bias no truncation no

co-intervention



bias truncation andor with

co-intervention



median survival in control

group))


61 Control group median

survival lt 12 months



survival gt12 months



trial truncation)


71 Non-truncated trials 5 Hazard Ratio (Random 95 CI) 089 [061 128]

72 Truncated trials 4 Hazard Ratio (Random 95 CI) 072 [053 097]



Analysis 11 Comparison 1 TACE or TAE versus control Outcome 1 All-cause mortality (subgroup risk of

selection bias)

Review Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma


Outcome 1 All-cause mortality (subgroup risk of selection bias)

Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio

(SE) IVRandom95 CI IVRandom95 CI

1 Trials with low risk of selection bias

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]

Heterogeneity Tau2 = 001 Chi2 = 682 df = 6 (P = 034) I2 =12

Test for overall effect Z = 109 (P = 027)

2 Trials with high risk of selection bias

Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5

Favours experimental Favours control



Analysis 12 Comparison 1 TACE or TAE versus control Outcome 2 All-cause mortality (subgroup TAE or

TACE)



Outcome 2 All-cause mortality (subgroup TAE or TACE)



1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5





TACE with low risk of selection bias)



Outcome 3 All-cause mortality (subgroup TAE or TACE with low risk of selection bias)



1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5




Analysis 14 Comparison 1 TACE or TAE versus control Outcome 4 All-cause mortality (subgroup co-

interventions)



Outcome 4 All-cause mortality (subgroup co-interventions)



1 Without co-intervention

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]



2 With co-intervention

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5




Analysis 15 Comparison 1 TACE or TAE versus control Outcome 5 All-cause mortality (subgroup low

risk of selection bias trial truncation and co-interventions)



Outcome 5 All-cause mortality (subgroup low risk of selection bias trial truncation and co-interventions)



1 Low risk of selection bias no truncation no co-intervention

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]



2 Low risk of selection bias truncation andor with co-intervention

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5




Analysis 16 Comparison 1 TACE or TAE versus control Outcome 6 All-cause mortality (subgroup

median survival in control group))



Outcome 6 All-cause mortality (subgroup median survival in control group))



1 Control group median survival lt 12 months

Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]



2 Control group median survival gt12 months

Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100




Analysis 17 Comparison 1 TACE or TAE versus control Outcome 7 All-cause mortality (subgroup trial

truncation)



Outcome 7 All-cause mortality (subgroup trial truncation)



1 Non-truncated trials

Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S

Appendix 1 Search Strategies

Name of database Time span Search strategy Search hits

The Cochrane Hepato-Biliary

Group Controlled Trials Regis-

ter

September 2010 (((transcatheter OR transar-

terial) AND (emboli OR

chemoemboli)) OR TAE OR

TACE) AND (rsquohepatocellular

carcinomarsquo OR HCC OR

hepatoma)

78

The Cochrane Central Regis-

ter of Controlled Trials (CEN-

TRAL) in The Cochrane Li-

brary

Issue 4 2010 1 MeSH descriptor Emboliza-

tion Therapeutic explode all

trees

2 ((transcatheter or transarte-

rial) and (emboli or chemoem-

boli)) or TAE or TACE

3 (1 OR 2)

4 MeSH descriptor Carci-

noma Hepatocellular explode

all trees

5 hepatocellular carcinoma

OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211

MEDLINE (Ovid SP) 1950 to September 2010 1 exp Embolization Thera-

peutic

2 (((transcatheter or transarte-


boli)) or TAE or TACE)mp

[mp=title original title ab-

stract name of substance word

subject heading word]

3 1 or 2

4 exp Carcinoma Hepatocel-

lular

5 (hepatocellular carcinoma

or HCC or hepatoma)mp




6 4 or 5

7 6 and 3

8 (random or blind or

placebo or meta-analysis)mp


319



(Continued)



9 8 and 7

EMBASE (Ovid SP) 1980 to September 2010 1 exp Artificial Embolism



boli)) or TAE or TACE)

mp [mp=title abstract subject

headings heading word drug

trade name original title de-

vice manufacturer drug manu-

facturer name]

3 1 or 2

4 exp Liver Cell Carcinoma

5 (hepatocellular carci-

noma or HCC or hepatoma)





facturer name]

6 4 or 5

7 6 and 3

8 (random or blind

or placebo or meta-analysis)





facturer name]

9 8 and 7

456

Science

Citation Index Expanded (http

appsisiknowledgecom)

1900 to September 2010 5 4 AND 3

4 TS=(random or blind or

placebo or meta-analysis)

3 2 AND 1

2 TS=(hepatocellular carci-

noma OR HCC OR hep-

atoma)

1 TS=(((transcatheter or

transarterial) and (emboli or

chemoemboli)) or TAE or

TACE)

622

LILACS From 1980 to September 2010 ldquocarcinoma hepatocelu-

larrdquo AND (ldquoembolizaciogravenrdquo OR

ldquoquimioembolizaciogravenrdquo)

15



H I S T O R Y

Protocol first published Issue 2 2004

Review first published Issue 3 2011

C O N T R I B U T I O N S O F A U T H O R S

Roberto S Oliveri drafted an update of the protocol originally prepared by Petra Buumlchner-Steudel et al (Buumlchner-Steudel 2002)

screened literature extracted relevant data assessed risk of bias of trials contacted investigators calculated point estimates performed

meta-analyses and drafted and approved the final manuscript Joslashrn Wetterslev performed TSA and reviewed and approved the final

manuscript Christian Gluud screened the literature extracted relevant data assessed risk of bias of trials and reviewed and approved

the final manuscript

D E C L A R A T I O N S O F I N T E R E S T

Christian Gluud is Co-ordinating Editor of The Cochrane Hepato-Biliary Group

S O U R C E S O F S U P P O R T

Internal sources

bull The Copenhagen Trial Unit Rigshospitalet Copenhagen University Hospital Denmark

External sources

bull No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

TAE or TACE versus other intervention were excluded from the review and will be assessed in future in a separate review Surgical co-

interventions were excluded



T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

3OBJECTIVES

3METHODS

Figure 1 5

Figure 2 6

Figure 3 8

8RESULTS

Figure 4 9

Figure 5 11

14DISCUSSION

16AUTHORSrsquo CONCLUSIONS

16ACKNOWLEDGEMENTS

16REFERENCES

21CHARACTERISTICS OF STUDIES

45DATA AND ANALYSES

Analysis 11 Comparison 1 TACE or TAE versus control Outcome 1 All-cause mortality (subgroup risk of selection

bias) 46

Analysis 12 Comparison 1 TACE or TAE versus control Outcome 2 All-cause mortality (subgroup TAE or TACE) 47

Analysis 13 Comparison 1 TACE or TAE versus control Outcome 3 All-cause mortality (subgroup TAE or TACE with

low risk of selection bias) 48

Analysis 14 Comparison 1 TACE or TAE versus control Outcome 4 All-cause mortality (subgroup co-interventions) 49

Analysis 15 Comparison 1 TACE or TAE versus control Outcome 5 All-cause mortality (subgroup low risk of selection

bias trial truncation and co-interventions) 50

Analysis 16 Comparison 1 TACE or TAE versus control Outcome 6 All-cause mortality (subgroup median survival in

control group)) 51

Analysis 17 Comparison 1 TACE or TAE versus control Outcome 7 All-cause mortality (subgroup trial truncation) 52

52APPENDICES

54HISTORY

55CONTRIBUTIONS OF AUTHORS

55DECLARATIONS OF INTEREST

55SOURCES OF SUPPORT

55DIFFERENCES BETWEEN PROTOCOL AND REVIEW

iTransarterial (chemo)embolisation for unresectable hepatocellular carcinoma (Review)















A B S T R A C T

Background



Objectives


Search strategy


Selection criteria










Main results




























B A C K G R O U N D






















1991)























O B J E C T I V E S







M E T H O D S


Types of studies





were not included

















Primary outcome


Secondary outcomes



individual trials














discussion
















All-cause mortality
















































Tumour response




Quality of life


































not for harms
















trial











stated








recorded or not











Publication bias






R E S U L T S












































Akamatsu 2004)











(Llovet [TAE] 2002)




were blinded





All-cause mortality











to 102 P = 007)






























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources




















A B S T R A C T

Background



Objectives


Search strategy


Selection criteria










Main results




























B A C K G R O U N D






















1991)























O B J E C T I V E S







M E T H O D S


Types of studies





were not included

















Primary outcome


Secondary outcomes



individual trials














discussion
















All-cause mortality
















































Tumour response




Quality of life


































not for harms
















trial











stated








recorded or not











Publication bias






R E S U L T S












































Akamatsu 2004)











(Llovet [TAE] 2002)




were blinded





All-cause mortality











to 102 P = 007)






























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources







Main results




























B A C K G R O U N D






















1991)























O B J E C T I V E S







M E T H O D S


Types of studies





were not included

















Primary outcome


Secondary outcomes



individual trials














discussion
















All-cause mortality
















































Tumour response




Quality of life


































not for harms
















trial











stated








recorded or not











Publication bias






R E S U L T S












































Akamatsu 2004)











(Llovet [TAE] 2002)




were blinded





All-cause mortality











to 102 P = 007)






























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources



























O B J E C T I V E S







M E T H O D S


Types of studies





were not included

















Primary outcome


Secondary outcomes



individual trials














discussion
















All-cause mortality
















































Tumour response




Quality of life


































not for harms
















trial











stated








recorded or not











Publication bias






R E S U L T S












































Akamatsu 2004)











(Llovet [TAE] 2002)




were blinded





All-cause mortality











to 102 P = 007)






























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources




















All-cause mortality
















































Tumour response




Quality of life


































not for harms
















trial











stated








recorded or not











Publication bias






R E S U L T S












































Akamatsu 2004)











(Llovet [TAE] 2002)




were blinded





All-cause mortality











to 102 P = 007)






























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources

























not for harms
















trial











stated








recorded or not











Publication bias






R E S U L T S












































Akamatsu 2004)











(Llovet [TAE] 2002)




were blinded





All-cause mortality











to 102 P = 007)






























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








R E S U L T S












































Akamatsu 2004)











(Llovet [TAE] 2002)




were blinded





All-cause mortality











to 102 P = 007)






























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources





























Akamatsu 2004)











(Llovet [TAE] 2002)




were blinded





All-cause mortality











to 102 P = 007)






























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources























038)


























P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources














P = 068)










included studies)

Tumour response










1 Complete response


both echography and













control group



levels separately


was classified as

1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase



1 gt50 decrease

2 25-50 decrease


increase (stable)

4 ge25 increase








months

TACE group (N = 43)

Decreased gt50 16

Decreased 25-50 37

Stable disease 37

Increased ge25 9


Decreased gt50 5

Decreased 25-50 8

Stable disease 37

Increased ge25 50









TAE group (N = 40)

Complete response 0

Partial response 55

Stable disease 35





tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources









tumour response









Progression 10


Not reported



as

1 Complete response


tumour lesions)




not defined


45 participants


Complete response 0


pants


reported

Tamoxifen group

Complete response 0


pants


reported



as


neoplastic disease)




increase of lt25)




months






as


neoplastic disease)




increase of lt25)




months












classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources













classified as

1 Complete response















to baseline)



sponses







TACE group (N = 28)

Complete response 0

Major response 39

Minor response 21

Stabilization 25

Progression 14


Complete response 0

Major response 6

Minor response 11

Stabilization 33

Progression 50






Quality of life



(Doffoeumll 2008)

Adverse events












tiveness

D I S C U S S I O N

























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources
























2003 Li 2006)




2009)





















































































80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources










80 power (β = 020)












2003)



















































R E F E R E N C E S







24(6)625ndash9
















(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources









(5)305ndash7































235ndash40



































116(2)203ndash7























(4)401ndash3











200192(6)1516ndash24












49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources
















49ndash51





















1611ndash9




































53(68)258ndash61








[PUBMED 7531022]












































199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources




















199625S118




















20005(6)380ndash5






Altman 2003



(7382)219

Bassler 2007




Bassler 2008




Bosch 2004



1)S5ndashS16

Brok 2008





Bruix 2001









14651858CD003629pub2]

Cammagrave 2002





Chlebowski 1984




(12)2701ndash6

Choi 1990



Davila 2004




(5)1372ndash80

DeAngelis 2009






Deeks 2003




Deeks 2009








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








handbookorg

DerSimonian 1986


Egger 1997



Eisenhauer 2009




El-Serag 1999



El-Serag 2003




(10)817ndash23

El-Serag 2007



132(7)2557ndash76

Emerson 1990





Forner 2009





Gluud 2010





Higgins 2002



Higgins 2009





Higgins 2009a






Hughes 1992




Hulot 2003





ICH-GCP 1997






Jadad 1996




Juumlni 1999



1054ndash60

Kjaergard 2001




Llovet 2003a


20033621907ndash17

Llovet 2003b




200337429ndash42

McGlynn 2001




Moher 1998




609ndash13

Montori 2005




Montori 2008








Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources










Nagorney 1989




Paquet 1991





Parmar 1998




Pogue 1998



47ndash52

RevMan 2008



Collaboration 2008

Royle 2003




19(4)591ndash603

Sangiovanni 2004





Schulz 1995




(5)408ndash12

Schulz 2005



Therasse 2000






Thorlund 2009





Tierney 2007




Wetterslev 2008




Wetterslev 2009




Wood 2008










Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources









Akamatsu 2004




2 Setting hospital



under CT


under CT





6 Mean age 655

7 Sex (MF) 2715

8 Country Japan


i) Aetiology

a) HBV 4

b) HCV 32



ii) Liver histology


b) Cirrhosis 21


a) A NA

b) BC NA










Notes

Risk of bias









Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources













Blinding

Tumour response


Blinding

All-cause mortality




All outcomes

Yes No drop-outs



reported


dustry bias

Bruix 1998




2 Setting hospital







i) Age gt 75







vi) Renal failure







6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources









6 Age 63

7 Se (MF) 6020

8 Country Spain


i) Aetiology

a) HBV 3

b) HCV 60

c) Alcohol 3

d) Other 14

ii) Liver histology


b) Cirrhosis 80


iv) Okuda stage

a) I 54

b) II 26







2 Tumour response

Notes

Risk of bias




locationrdquo




ble 3)

Blinding

Tumour response


tion

Blinding

All-cause mortality


tion





All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources









All outcomes

Yes No drop-outs





dustry bias

Cheng 2004

Methods

Participants

Interventions

Outcomes





Doffoeumll 2008




2 Setting hospital







i) Age gt 75







80 mls)







6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources











6 Mean age 644

7 Sex (MF) 10716

8 Country France


i) Aetiology

a) HBV 6

b) HCV 13

c) Alcohol 93

d) Other 10

ii) Liver histology




a) A 86

b) B 35

iv) Okuda stage

a) I 88

b) II 35




mg tamoxifen




Notes

Risk of bias







Blinding

Tumour response


Blinding

All-cause mortality


tion





All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources









All outcomes

Yes



dustry bias

GETCH 1995















albumin lt 30 gL)






6 Mean age 64

7 Sex (MF) 924



1 i) Aetiology

a) HBV 5

b) HCV 8

c) Alcohol 65

d) Other 9

ii) Liver histology


b) Cirrhosis 87



b) B 0




iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








iv) Okuda stage

a) I 86

b) II 10






2 Tumour response

Notes

Risk of bias



computerrdquo



Blinding

Tumour response






Blinding

All-cause mortality


tion


All outcomes

Yes














Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources







Li 1995





weeks) TACE



Overall survival







Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Li 2006








Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources







Li 2006 (Continued)




Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes





Llovet [TACE] 2002







fetoprotein



exclusion criteria


i) Age gt 75



iv) Encephalopathy











xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources












xi) Renal failure





6 Age 644

7 Sex (MF) 5520

8 Country Spain





ii) Aetiology

a) HBV 5

b) HCV 65

c) Alcohol 4

d) Other 1





a) A 52

b) B 23

v) Okuda stage

a) I 49

b) II 26



then every 6 months




Risk of bias




[]rdquo








and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources












and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events


















arm

Llovet [TAE] 2002







fetoprotein






exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources










exclusion criteria


i) Age gt 75



iv) Encephalopathy












6 Age 65

7 Sex (MF) 5319

8 Country Spain





ii) Aetiology

a) HBV 3

b) HCV 62

c) Alcohol 5

d) Other 2





a) A 48

b) B 24

v) Okuda stage

a) I 46

b) II 26









Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








Risk of bias




[]rdquo





and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes


verse events








trial



















Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources









Lo 2002





2 Setting hospital



imaging findings



exclusion criteria












6 Age 625

7 Sex (MF) 709



i) Aetiology

a) HBV 63

b) HCV not reported


d) Other 16

ii) Liver histology




a) A not reported

b) B not reported

iv) Okuda stage

a) I 37

b) II 42



Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources







Lo 2002 (Continued)





2 Tumour response

Notes

Risk of bias








thor on request




Blinding

Tumour response


tion

Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1990













exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources












exclusion criteria


i) Resectable HCC




6 Age 64

7 Sex (MF) 375

8 Country France


i) Aetiology

a) HBV 3

b) HCV not reported

c) Alcohol 29

d) Other 6

ii) Liver histology


b) Cirrhosis 37


a) A not reported

b) B Note reported

iv) Okuda stage

a) I 11

b) II 22

c) III 9





2 Tumour response


Risk of bias













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources













numbered and opaque

Blinding

Tumour response



Blinding

All-cause mortality


tion


All outcomes

Yes




dustry bias

Pelletier 1998









criteria










viii) Okuda stage 3







6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








6 Age 66

7 Sex (MF) 6211

8 Country France


i) Aetiology

a) HBV 11

b) HCV 10

c) HBV+HCV 2

d) Alcohol 39

e) Other 3

ii) Liver histology


b) Cirrhosis 65


a) A 56

b) B 17

iv) Okuda stage

a) I 44

b) II 21




every 4 months



Notes

Risk of bias




listrdquo


Blinding

Tumour response


Blinding

All-cause mortality

No Not performed


All outcomes

Yes










Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources














Xiao 2003




2 Control Resection



Risk of bias




Blinding

Tumour response

No

Blinding

All-cause mortality

No


All outcomes








s = seconds
































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources




































(Continued)









Aikata 2006












analysis




Bolondi 1996











available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources












available data



Dalla Palma 1997





Outcomes Survival







Ferrari 2004











Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources







Li 2007

Methods

Participants

Interventions

Outcomes



Wang 2000

Methods

Participants

Interventions

Outcomes



Yang 2008




Outcomes








studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources










studies

No of






selection bias



selection bias



TAE or TACE)






selection bias)





co-interventions)







co-interventions)




co-intervention




co-intervention




group))









trial truncation)







selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








selection bias)







Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 817 088 [ 071 110 ]




Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Subtotal (95 CI) 183 053 [ 034 083 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5





TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








TACE)






1 TACE

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 776 079 [ 058 106 ]



2 TAE

Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Subtotal (95 CI) 224 094 [ 062 142 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5











1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources














1 TACE

Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 771 087 [ 067 114 ]



2 TAE

Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Subtotal (95 CI) 229 087 [ 047 161 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5





interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








interventions)







Bruix 1998 00926 (02582) 138 110 [ 066 182 ]

GETCH 1995 -03425 (02303) 159 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 63 057 [ 024 134 ]

Lo 2002 -06931 (0245) 147 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 93 148 [ 076 291 ]

Subtotal (95 CI) 656 075 [ 053 107 ]




Akamatsu 2004 00554 (07584) 24 106 [ 024 467 ]

Doffol 2008 -00726 (01972) 188 093 [ 063 137 ]

Pelletier 1998 -00834 (02659) 133 092 [ 055 155 ]

Subtotal (95 CI) 344 093 [ 069 126 ]



Total (95 CI) 1000 081 [ 064 103 ]



02 05 1 2 5












Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources















Bruix 1998 00926 (02582) 165 110 [ 066 182 ]

Pelletier 1990 03946 (0343) 100 148 [ 076 291 ]

Subtotal (95 CI) 265 122 [ 082 183 ]




Doffol 2008 -00726 (01972) 257 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 201 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 56 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 64 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 157 092 [ 055 155 ]

Subtotal (95 CI) 735 079 [ 063 100 ]



Total (95 CI) 1000 088 [ 071 110 ]



02 05 1 2 5












Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources















Doffol 2008 -00726 (01972) 195 093 [ 063 137 ]

GETCH 1995 -03425 (02303) 166 071 [ 045 112 ]

Lo 2002 -06931 (0245) 154 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 99 148 [ 076 291 ]

Subtotal (95 CI) 613 081 [ 055 119 ]




Akamatsu 2004 -02614 (0577) 42 077 [ 025 239 ]

Bruix 1998 00926 (02582) 145 110 [ 066 182 ]

Llovet [TACE] 2002 -0755 (04661) 61 047 [ 019 117 ]

Pelletier 1998 -00834 (02659) 140 092 [ 055 155 ]

Subtotal (95 CI) 387 090 [ 065 124 ]



Total (95 CI) 1000 082 [ 064 105 ]



001 01 1 10 100





truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources








truncation)







Akamatsu 2004 -02614 (0577) 38 077 [ 025 239 ]

Bruix 1998 00926 (02582) 136 110 [ 066 182 ]

Doffol 2008 -00726 (01972) 186 093 [ 063 137 ]

Lo 2002 -06931 (0245) 145 050 [ 031 081 ]

Pelletier 1990 03946 (0343) 91 148 [ 076 291 ]

Subtotal (95 CI) 596 089 [ 061 128 ]



2 Truncated trials

GETCH 1995 -03425 (02303) 157 071 [ 045 112 ]

Llovet [TACE] 2002 -0755 (04661) 55 047 [ 019 117 ]

Llovet [TAE] 2002 -05621 (04367) 62 057 [ 024 134 ]

Pelletier 1998 -00834 (02659) 131 092 [ 055 155 ]

Subtotal (95 CI) 404 072 [ 053 097 ]



Total (95 CI) 1000 081 [ 064 102 ]



02 05 1 2 5




A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources







A P P E N D I C E S





ter






hepatoma)

78




brary



trees




3 (1 OR 2)



all trees


OR HCC OR hepatoma

6 (4 OR 5)

7 (3 AND 6)

211


peutic







3 1 or 2


lular






6 4 or 5

7 6 and 3




319



(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources







(Continued)



9 8 and 7









facturer name]

3 1 or 2








facturer name]

6 4 or 5

7 6 and 3

8 (random or blind






facturer name]

9 8 and 7

456

Science






3 2 AND 1


noma OR HCC OR hep-

atoma)




TACE)

622




15



H I S T O R Y












Internal sources


External sources







H I S T O R Y












Internal sources


External sources







Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma

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Transcript of Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma