Cochrane Database of Systematic Reviews (Reviews) || Adjuvant (post-surgery) chemotherapy for early...

Adjuvant (post-surgery) chemotherapy for early stage

epithelial ovarian cancer (Review)

Winter-Roach BA Kitchener HC Dickinson HO

This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2009 Issue 2

httpwwwthecochranelibrarycom

Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer (Review)

Copyright copy 2009 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

4OBJECTIVES

5METHODS

7RESULTS

Figure 1 14

15DISCUSSION

16AUTHORSrsquo CONCLUSIONS

17ACKNOWLEDGEMENTS

17REFERENCES

19CHARACTERISTICS OF STUDIES

25DATA AND ANALYSES

25WHATrsquoS NEW

25HISTORY

26CONTRIBUTIONS OF AUTHORS

26DECLARATIONS OF INTEREST

26DIFFERENCES BETWEEN PROTOCOL AND REVIEW

iAdjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer (Review)


[Intervention Review]

Adjuvant (post-surgery) chemotherapy for early stageepithelial ovarian cancer

Brett A Winter-Roach1 Henry C Kitchener2 Heather O Dickinson3

1Department of Obstetrics and Gynaecology Salford Royal NHS Foundation Trust Salford UK 2Academic Unit of Obstetrics and

Gynaecology University of Manchester St Maryrsquos Hospital Manchester UK 3Institute of Health and Society Newcastle University

Newcastle upon Tyne UK

Contact address Brett A Winter-Roach Department of Obstetrics and Gynaecology Salford Royal NHS Foundation Trust Stott Lane

Salford M6 8HD UK brettwinter-roachsrftnhsuk brettwinter_roachbtinternetcom (Editorial group Cochrane Gynaecolog-

ical Cancer Group)

Cochrane Database of Systematic Reviews Issue 2 2009 (Status in this issue Unchanged)


DOI 10100214651858CD004706pub2

This version first published online 21 January 2009 in Issue 1 2009

Last assessed as up-to-date 2 June 2008 (Help document - Dates and Statuses explained)

This record should be cited as Winter-Roach BA Kitchener HC Dickinson HO Adjuvant (post-surgery) chemotherapy

for early stage epithelial ovarian cancer Cochrane Database of Systematic Reviews 2009 Issue 1 Art No CD004706 DOI

10100214651858CD004706pub2

A B S T R A C T

Background

Epithelial ovarian cancer kills about 1700 in the UK each year Ten to fifteen percent of all cases are diagnosed early when there is still

a good chance of cure The treatment of early stage disease involves surgery to remove disease often followed by chemotherapy The

largest clinical trials of this adjuvant therapy show an overall survival (OS) advantage with adjuvant platinum based chemotherapy but

the precise role of this treatment in sub-groups of patients with differing prognoses needs to be defined

Objectives

To systematically review the evidence for adjuvant chemotherapy in early stage epithelial ovarian cancer to determine firstly whether there

is a survival advantage of this treatment over the policy of observation following surgery with chemotherapy reserved for treatment of

disease recurrence and secondly to determine if clinical sub-groups of differing prognosis based on histological sub-type or completeness

of surgical staging have more or less to gain from chemotherapy following initial surgery

Search strategy

An electronic search was performed using the Cochrane Gynaecological Cancer Specialised Register Cochrane Central Register of

Controlled Trials (CENTRAL Issue 2 2008) MEDLINE (1966 to 2008) EMBASE (1980 to 2008) and CancerLit The search

strategy was developed using free text and medical subject headings (MESH) This yielded a large number of article titles which were

sifted down by two review authors to a limited number of articles the full text versions of which were independently reviewed to select

out clinical trials of direct and specific relevance to the review question Hand searches of the clinical literature were conducted where

appropriate to identify additional full-text papers or abstracts of other directly relevant clinical trials

Selection criteria

The review authors selected those clinical trials that met the inclusion criteria set out based on the populations interventions

comparisons and outcome measures as detailed in the full text review

Data collection and analysis

1Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer (Review)


Two review authors independently extracted data and assessed trial quality Disagreements were resolved by discussion or a third reviewer

Random effects meta-analyses and sub-group analyses were conducted

Main results

Five randomised controlled trials (RCTs) enrolling 1277 women with 46 to 110 months follow-up met our inclusion criteria These

trials had low risk of bias Meta-analysis of three trials with adequate data assessing 1008 women indicated that women who received

adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (hazard ratio (HR) 071 95 CI 053

to 093) Likewise meta-analysis of four trials with adequate data assessing 1170 women indicated that women who received adjuvant

chemotherapy had better progression-free survival (PFS) than those who did not (HR 067 95 CI 053 to 084) The trials included

in these meta-analyses gave consistent estimates of the effects of chemotherapy

Sub-group analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant

chemotherapy (HR for OS 122 95 CI 063 to 237) whereas those who had sub-optimal staging did (HR for OS 063 95 CI

046 to 085) One trial showed a benefit from adjuvant chemotherapy among women at high risk (HR for OS 048 95 CI 032 to

072) but not among those at low risk (HR for OS 095 95 CI 054 to 166) However these sub-group findings could be due to

chance

Authorsrsquo conclusions

Adjuvant platinum based chemotherapy is effective in prolonging the survival of the majority of patients who are assessed as having

early stage epithelial ovarian cancer However even given the limits of sub-group analyses there is strong evidence that optimal surgical

staging identifies patients who have either little or nothing to gain from adjuvant chemotherapy Taken together with the lack of a

survival advantage seen in patients with ldquolow-riskrdquo cancers in the ICON1 trial it appears safe to withhold adjuvant chemotherapy from

optimally staged patients with well differentiated tumours

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

Post-surgery (adjuvant) chemotherapy for early stage epithelial ovarian cancer

Chemotherapy with platinum containing drugs given after surgery to remove ovarian cancers that have not spread beyond the pelvis

saves lives but is probably unnecessary when the tumour is proven to have not spread outside of the ovary particularly if the specific

cell type is not aggressive

B A C K G R O U N D

Description of the condition

Ovarian cancer is the sixth most common cancer among women (

Ferlay 2002) Worldwide there are more than 200000 new cases of

ovarian cancer each year accounting for around 4 of all cancers

diagnosed in women A womanrsquos risk of developing cancer of the

ovaries by age 75 varies between countries ranging from 05 to

16 corresponding to an age-standardised rate of 5 to 14 cases

per year in 100000 women (Parkin 2002) In Europe ovarian

cancer is the leading cause of gynaecological cancer death just over

a third of women are alive five years after diagnosis (Sant 2003)

largely because most women with ovarian cancer are diagnosed

when the cancer is already at an advanced stage and surgical cure

is usually impossible (Jemal 2008)

Over 85 of ovarian cancers develop in the surface (epithelial)

cells of the ovary There are different types based on microscopic

features (histopathological types) of which the more common are

serous endometrioid and mucinous Poor prognosis clear cell can-

cers are fortunately less common and the malignant Brenner type

is rare Malignant tumours are characterised by their grade this

describes the microscopic pattern of growth (architecture) and cel-

lular features (cytology) and varies from well differentiated (grade

G1) to moderately and poorly differentiated (G2 and G3 respec-

tively) Well-differentiated tumours are of better prognosis than

G2 or G3 tumours FIGO staging is used to describe the spread

of the disease FIGO Stage I disease is confined to one or both

ovaries and FIGO stage II disease is limited in spread to the true

pelvis FIGO stage I is sub-divided into three stages Ia-Ic In stage

Ia disease is confined to one ovary with no involvement of the



ovarian surface with no tumour cells in the fluid of the abdominal

cavity (negative peritoneal washings) stage Ib indicates similarly

encapsulated disease in both ovaries but with no evidence of other

spread stage Ic indicates ovarian cyst rupture or ascites containing

malignant cells (Shepherd 1989) FIGO Stage II is similarly di-

vided into three sub-stages Stage IIa indicates spread to the uterus

or fallopian tubes stage IIb indicates spread to other pelvic struc-

tures stage IIc is as for IIa or IIb but also indicates ovarian surface

involvement or positive ascites or peritoneal washings (See Table

1 for full details of FIGO staging) Fewer than 30 of women

present with stage I or II ovarian cancer (Jemal 2008)

Table 1 Staging of Ovarian Cancer

Stage Description

Ia Disease confined to one ovary with no capsular involvement Peritoneal washings cytology negative

Ib Disease confined to both ovaries with no capsular involvementPeritoneal washings cytology negative

Ic Disease confined to the ovary ovaries but ovarian capsulae involved or cyst rupture

IIa Extension to uterus or fallopian tubes

IIb Extension to other pelvic tissues

IIc As for IIa or IIb but one or both ovaries have ruptured capsule or surface tumour malignant ascites or positive peritoneal

washings

IIIa Histologically confirmed microscopic seeding of abdominal peritoneal surfaces and negative retroperitoneal lymph nodes

IIIb Histologically confirmed implants of abdominal peritoneal surfaces less than 2cm and negative retroperitoneal lymph nodes

IIIc Histologically confirmed implants of abdominal peritoneal surfaces greater than 2cm or positive retroperitoneal lymph nodes

IV Distant metastases (including liver parenchyma positive pleural fluid cytology)

Women with ovarian cancer should be offered surgery both to

remove the disease and to provide accurate staging which is a

key factor in assessing the impact of different treatments in this

patient group The pattern of spread of ovarian cancer is such

that small deposits of tumour rsquohiddenrsquo in the upper abdomen and

retro-peritoneum can be readily missed It has been shown that a

significant percentage of patients will be under-staged if the initial

staging surgery is sub-optimal Accurate staging helps provide bet-

ter prediction of outcome in individual cases is an independent

prognostic factor for survival in stage I disease (Zanetta 1998) and

influences ongoing management

Recent reports have confirmed a very good prognosis for women

with stage Ia disease treated with conservation of the contralateral

ovary in order to preserve their fertility (Morice 2001 Schilder

2002) A proportion of patients with stage I disease will be cured

by their surgery and it may be that the chance of survival is im-

proved if the surgery is undertaken by trained a gynaecological

oncologist (Mayer 1992) There is evidence from a randomised

controlled trial (RCT) that systematic pelvic and para-aortic lym-

phadenectomy will identify more women with lymph node metas-

tases than sampling of suspicious nodes However no survival dif-

ference was seen in this trial though it was underpowered to ex-

amine this outcome (Maggioni 2006) There is however a high

incidence of recurrent disease which can be as high as 30 in cer-

tain sub-groups of women with stage I disease The challenge is

to determine which patients are high risk and would benefit most

from additional treatment



Uncontrolled retrospective studies have identified prognostic fac-

tors of importance for this disease A multivariate analysis of 1545

patients with stage I epithelial ovarian cancer has confirmed tu-

mour grade to be the single most important determinant of survival

(Vergote 2001) In addition capsular involvement or cyst rupture

(FIGO stage Ic) were associated with poorer outcome The cur-

rent staging for ovarian cancer does not recognise the prognostic

importance of tumour grade Another issue relates to the class of

ovarian cancers of low malignant potential which are also called

borderline tumours These neoplasms tend to run a benign course

though again adverse prognostic factors are recognised based on

histological features These concerns have prompted calls for a re-

vision of FIGO staging to incorporate the borderline tumours and

endorse the importance of tumour grade (Green 2003)

Description of the intervention

Adjuvant treatment is any treatment given after surgical removal

of all visible disease Given the significant risk of recurrence in

sub-groups of patients with completely resected early stage dis-

ease adjuvant treatment is usually considered The rationale for

this treatment is to eradicate any microscopic deposits of tumour

that may remain after surgery and thus prevent or delay the recur-

rence of disease Several underpowered clinical trials have exam-

ined the merits of adjuvant chemotherapy compared to adjuvant

radiotherapy in selected subgroups ( Chiara 1994 Hreshchyshyn

1980 Klaassen 1988 Sigurdsson 1982)

A Cochrane review and meta-analysis of individual patient data (

AOCTG 1999) confirmed modest two- and five-year survival ad-

vantages in women with advanced stage epithelial ovarian can-

cer who were given platinum based combination chemotherapy

compared to those given combination therapy lacking platinum

(hazard ratio (HR) 088 95 CI 079 to 098 AOCTG 1999)

ICON2 1998 subsequently confirmed equivalent efficacy of single

agent carboplatin compared with a combination regimen of cyclo-

phosphamide doxorubicin and cisplatin (CAP) Given the higher

toxicity of the CAP regimen single agent carboplatin was recom-

mended as the standard initial treatment of advanced stage epithe-

lial ovarian cancer (ICON2 1998) ICON3 2002 and McGuire

1996 have examined the place of paclitaxel in the first line che-

motherapeutic management of advanced epithelial ovarian cancer

There is no dispute that the standard first-line management of ad-

vanced epithelial ovarian cancer should be platinum based though

the combination with paclitaxel is often recommended Based on

the results seen in advanced disease platinum based chemother-

apy was adopted for use in early stage disease

Previous practice has been to offer patients with stage Ic disease

adjuvant chemotherapy while those with well-differentiated Ia and

Ib disease have not been offered this treatment In contrast there

has not been international consensus on the use of chemotherapy

in patients who had moderately-poorly differentiated FIGO stage

Ia or Ib disease

Why it is important to do this review

An appreciation of the safety of withholding chemotherapy from

certain low-risk sub-groups of patients with early-stage epithelial

ovarian cancer has made it possible for trials of adjuvant chemo-

therapy versus observation with treatment on recurrence Initial

trials of this kind have been too small to demonstrate any treatment

effect (Bolis 1995 Trope 2000 Young 1990) but more recent col-

laborative trials have greatly improved the evidence regarding the

efficacy of chemotherapy (ACTION 2003 ICON1 2003)

Nevertheless the precise role of chemotherapy in early stage disease

continues to be the subject of some discussion Some clinicians

may be reluctant to recommend platinum based chemotherapy to

certain patients who are unlikely to develop recurrent disease The

authors have already systematically reviewed the broader topic of

adjuvant therapy including radiotherapy in early stage epithelial

ovarian cancer (Winter-Roach 2003) Since then other system-

atic reviews have been published (Elit 2004Trope 2007) Trope

produced a systematic review of RCTs of adjuvant radiotherapy

and chemotherapy in a similar way to Winter-Roach 2003 but

in addition included a post-hoc sub-group analysis of adequately

versus inadequately surgical staged patient groups Trope 2007

also commented in some detail on the strength and weaknesses of

the evidence base informing the use of adjuvant platinum based

chemotherapy

There remain unanswered questions about the subject of adjuvant

chemotherapy Specifically clinicians and their patients need to

know which if any patient subgroups can be safely managed with-

out adjuvant chemotherapy Alternatively is there any evidence

that particular groups of patients have more to gain from having

adjuvant chemotherapy This review aims to collate all the rele-

vant published data in the area to determine the overall benefit

of adjuvant chemotherapy in early stage (FIGO stages I and II)

epithelial ovarian cancer and to give further guidance on which

patients should receive chemotherapy

O B J E C T I V E S

Primary objective

To assess the efficacy of adjuvant chemotherapy in early stage ovar-

ian cancer in terms of OS and disease free survival (DFS)

Secondary objectives

To determine if there are some patients with early stage disease

who are more or less likely to benefit form this treatment (ie

accurate versus sub-optimal staging stage Ia to II differentiation

status)



M E T H O D S

Criteria for considering studies for this review

Types of studies

RCTs

Types of participants

Women with stage I and II epithelial ovarian cancer staged at

laparotomy

Types of interventions

Adjuvant chemotherapy versus no adjuvant chemotherapy or

placebo

The term adjuvant used here describes treatment given within

three months following surgery which removed all visible disease

Types of outcome measures

Primary outcomes

Overall Survival (OS) (survival until death from any cause)

Secondary outcomes

(1) Disease-specific survival (DSS) (defined as survival until death

from ovarian cancer or complications of treatment with deaths

from other causes censored)

(2) Progression-free survival (PFS)

(3) Adverse events extracted and grouped as

(a) haematological (leucopenia anaemia thrombocytopenia neu-

tropenia haemorrhage)

(b) gastrointestinal (nausea vomiting anorexia diarrhoea liver

proctitis)

(c) genitourinary

(d) skin (stomatitis mucositis alopecia allergy)

(e) neurological (peripheral and central)

(f ) pulmonary

Search methods for identification of studies

Electronic searches

An electronic search was performed using the Cochrane Gynaeco-

logical Cancer Specialised Register Cochrane Central Register of

Controlled Trials (CENTRAL Issue 2 2008) MEDLINE (1966

to 2008) EMBASE (1980 to 2008) and CancerLit with the search

strategy in Appendix 1 adapted for the other databases No lan-

guage restriction was applied

Searching other resources

The bibliographies of all relevant papers selected through this strat-

egy were searched Relevant articles were identified on PubMed

and using the rsquorelated articlesrsquo feature a further search was carried

out for newly published articles Meta-register was searched for

on-going trials PDQ was searched for open and closed trials

Personal communication with corresponding authors and clinical

experts was established where possible to enquire about other

published or unpublished relevant studies


Selection of studies

All titles and abstracts retrieved by electronic searching were down-

loaded to a reference management database (Endnote) duplicates

were removed and the remaining references were examined by

two review authors (BWR And HK) independently Those studies

which clearly did meet the inclusion criteria were included and

copies of the full text of potentially relevant references were ob-

tained The eligibility of retrieved papers was assessed indepen-

dently by two review authors (BWR and HK) Disagreements

were resolved by discussion between two review authors (BWR

and HK)

Data extraction and management

For included studies data on characteristics of patients the num-

ber recruited to each arm the completeness of surgical staging

the proportion of the different tumour stages and grades the bal-

ance of prognostic factors achieved and interventions the dose

and duration of chemotherapy given in the treatment arm study

quality duration of follow-up outcomes and deviations from pro-

tocol were extracted independently by two review authors (BWR

and HK) onto a predesigned data extraction forms A record as

also made of any reported adverse effects reported in the trials

Disagreements were resolved by discussion between the review au-

thors(BWR HK HD)

Assessment of risk of bias in included studies

Risk of bias was evaluated using the following criteria

Randomisation

The randomisation of participants to intervention groups was

coded as

bull adequate eg a computer-generated random sequence

or a table of random numbers

bull quasi-randomised eg date of birth clinic id-number

or surname

bull unclear eg not reported



Allocation concealment

bull adequate (eg by telephone randomisation or use of

consecutively numbered sealed opaque envelopes) (A)

bull unclear eg not reported (B)

bull inadequate (eg open random number lists or quasi

randomisation such as alternate days oddeven date of

birth or hospital number) (C)

Prognostic balance between the treatment arms

This was coded as

bull adequate (if the key prognostic determinants were

evenly represented between trial arms)

bull inadequate

bull unclear

Blinding

Blinding of and outcome assessors was coded as

bull yes

bull no

bull unclear

Loss to follow-up

We recorded the proportion of participants whose outcomes were

not reported at the end of the study we noted if loss to follow-up

was not reported

Loss to follow-up was coded as

bull adequate if fewer than 20 of patients were lost to

follow-up and reasons for loss to follow-up were similar

in both treatment arms

bull unclear if loss to follow-up was not reported

bull inadequate if more than 20 of patients were lost to

follow-up or reasons for loss to follow-up differed be-

tween treatment arms

Intention to treat analysis

This was be coded as

bull adequate if participants were analysed in groups to

which they were assigned

bull inadequate if participants were not analysed in groups

to which they were assigned

bull unclear if method of analysis was not reported

Measures of treatment effect

For time-to-event data (OS DSS and PFS) we abstracted the log

(hazard ratio (HR)) and its variance from trial reports If these

were not presented we attempted to abstract the data required to

estimate them using Parmarrsquos methods (Parmar 1998) eg number

of events in each arm and log-rank p-value comparing the relevant

outcomes in each arm or relevant data from Kaplan-Meier sur-

vival curves If it was not possible to estimate the HR we planned

to abstract the number of patients in each treatment arm who ex-

perienced the outcome of interest and the number of participants

assessed in order to estimate a relative risk (RR)

The number needed to treat (NNT) was estimated by first per-

forming a meta-analysis of the risk difference (RD) and then tak-

ing the inverse of the pooled RD

For dichotomous outcomes (eg adverse events) we abstracted

the number of patients in each treatment arm who were assessed

at endpoint and the number who experienced the outcome of

interest in order to estimate a RR

Dealing with missing data

If primary outcome data were not reported authors of trial reports

were contacted If missing outcome data were imputed data were

abstracted on the outcomes only among participants who were

assessed at endpoint

Assessment of heterogeneity

Heterogeneity between studies was assessed by visual inspection

of Forest plots by estimation of the percentage heterogeneity be-

tween trials which cannot be ascribed to sampling variation (

Higgins 2003) and by a formal statistical test of the significance of

the heterogeneity (Deeks 2001) If there was evidence of substan-

tial heterogeneity the possible reasons for this were investigated

and reported

Assessment of reporting biases

Funnel plots corresponding to meta-analysis of the primary out-

come were examined to assess the potential for publication bias

If these plots suggested that treatment effects were not sampled

from a symmetric distribution as assumed by the random effects

model (REM) a further meta-analyses using fixed effects models

was performed

Data synthesis

Results of studies were pooled in a meta-analysis when sufficient

clinically similar studies were available

bull For time-to-event data HRs were pooled using the

generic inverse variance facility of RevMan 5

bull For any dichotomous outcomes (eg adverse events and

numbers of patients who relapsed or died if it was not

possible to treat these outcomes as time-to-event data)

RRs were pooled

REM models were used for all meta-analyses (DerSimonian 1986)

If it was inappropriate to pool the data because of clinical hetero-

geneity a meta-analysis excluding outlying studies was performed



Subgroup analysis and investigation of heterogeneity

Sub-group analyses were performed grouping trials by (i) type

of chemotherapy used and (ii) optimalsub-optimal surgical stag-

ing where optimal staging was defined as peritoneal staging plus

retroperitoneal node assessment Table 1 However since the only

trials with data of satisfactory quality evaluated platinum-based

chemotherapy sub-group analysis by type of chemotherapy was

not performed

We had planned to perform additional subgroup analyses to ex-

amine the influence of prognostic factors (eg clear-cell histolog-

ical subtype degree of tumour differentiation) and dose of che-

motherapy However this was not possible since data were not

consistently reported by these sub-groups in the included trials

and we were unable to obtain individual patient data

After publication of an abstract reporting the effect of adjuvant

chemotherapy compared to no adjuvant chemotherapy in sub-

groups of high risk and intermediatelow risk patients in the

ICON1 2003 trial we decided to present these sub-group data in

the review

Sensitivity analysis

No sensitivity analyses were performed since there were no trials

which failed to report adequate (i) concealment of allocation (ii)

blinding of the outcome assessor

After identification of both 5-year and 10-year follow-up of the

ICON1 2003 trial it was decided to use the 5-year data from this

trial in the primary meta-analysis since this was more consistent

with the duration of follow-up of the other included trials How-

ever the 10-year data were used in sensitivity analyses

R E S U L T S

Description of studies

See Characteristics of included studies Characteristics of excluded

studies

Identification of included studies

The search strategy identified 2133 total number of reference hits

The title and abstract screening of these references identified 17

trials as potentially eligible for this review (Table 2) The full text

screening of these 17 trials excluded 12 for the reasons described in

the table of Characteristics of excluded studies The remaining five

RCTs (ACTION 2003 Bolis 1995 ICON1 2003 Trope 2000

Young 1990) met our inclusion criteria and are described in the

table of Characteristics of included studies

Table 2 Randomised trials of adjuvant treatment Description and Quality assessment

Study ID Recruitment

period

Staging Comparison Randomisa-

tion

Intention to

treat

Prognostic

balance

5 year follow-

up

Smith 1969-74 No CT vsRT Unspecified No Incomplete

Dembo 1971-75 No RT vs

RT+CT

Stratified No Median 52

months

Hreschyshyn 1971-78 No CT vs RT vs

NA

Unspecified No No

Sigurdson 1975-78 No NT vs CT

RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes

Sevelda 1980-85 Yes complete

in 605

NA vs RT vs

(RT+CT)

Unspecified No Median 42

months

Klassen 1975-84 No CT vs RT vs

IPR

Central

telephone

Yes Median 8

years



Table 2 Randomised trials of adjuvant treatment Description and Quality assessment (Continued)

Sell 1981-87 Complete RT vs

(RT+CT)

Block

randomisation

Yes 4 years

Young 1976 Complete CT vs NA or

IPR

Central com-

puter stratified

Yes gt6 years

Vergote 1982-88 Complete CT vs IPR Central com-

puter stratified

Yes Median 62

months

Chiara 1985-89 Complete in

87

CT vs RT Central com-

puterised

Yes

Bolis 1983-90 Complete CT vs NA or

IPR

Central

random gener-

ated numbers

Yes Yes

Trope 1992-97 Complete CT vs NA Central com-

puterised

Yes Median 46

months

Kojs 1990-96 Complete CT vs RT Method not

explicit

Yes Yes

ICON1 1990-2001 incomplete CT vs NA Central com-

puterised

Yes Median 51

months

ACTION 1990-2000 Complete CT vs NA Central com-

puterised

Yes Median 66

months

These five included trials enrolling a total of 1277 participants

compared immediate adjuvant chemotherapy with no immediate

adjuvant chemotherapy (Table 3)

Table 3 Trials of Adjuvant chemotherapy versus No Further Treatment

Study ID Patients Intervention 5 Year survival Statistic Adverse effects Comments

ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003

Not reported Survival improve-

ment with adju-

vant therapy



Table 3 Trials of Adjuvant chemotherapy versus No Further Treatment (Continued)

ACTION 448FIGO Ia-Ib

grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002

Not reported Sub-gruop analy-

sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences

Bolis 85 FIGO (1976) I

A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms

Young 1990 published the first prospective RCT of adjuvant che-

motherapy in early stage ovarian cancer to include a control group

that had no immediate post-surgical treatment with chemother-

apy being reserved for treatment of disease recurrence This Amer-

ican trial published in 1990 was a joint effort of the Gynecologic

Oncology Group and the Ovarian Cancer Study Group and ran-

domised patients with FIGO 1976 stage Ia and Ib well-differen-

tiated or moderately-differentiated tumours to receive either Mel-

phalan 02mgKg or no chemotherapy These patients were sur-

gically staged via a midline laparotomy to allow thorough assess-

ment of the abdomen and pelvis A total abdominal hysterectomy

bilateral salpingo-oohporectomy and infracolic omentectomy was

performed and biopsies were taken of any peritoneal deposits

Random biopsies of the pelvic and abdominal peritoneum and

retroperitoneal lymph node assessment were also performed This

surgical staging routine is most likely to identify occult metastatic

disease if present and therefore is optimal This trial was flawed by



the inclusion of 27 patients with the Borderline Ovarian Tumour

histological sub-type though they were evenly distributed between

the 2 arms of the trial

The trial enrolled 92 women randomising 48 to the chemother-

apy arm and 44 to the observation-only arm After randomisa-

tion 11 women (5 in the chemotherapy arm and 6 in the obser-

vation-only arm) were deemed ineligible and so 81 women (43

in the chemotherapy arm and 38 in the observation-only arm)

were available for analysis OS and DFS were reported Six women

died two in the chemotherapy arm and four in the observation-

only arm Likewise six women had disease recurrence two in the

chemotherapy arm and four in the observation-only arm The au-

thors reported no significant differences between treatment arms

in either OS or DFS Surviving women were followed up for a

median of 6 years

HRs were not reported but Kaplan-Meier plots and log-rank p-

values were presented for both OS and DFS based on analysis

of all eligible patients regardless of the treatment they received

Minimum and maximum duration of follow-up were estimated

from censoring marks on the Kaplan-Meier plots

Adverse events were reported in the adjuvant chemotherapy arm

but not assessed in the no adjuvant chemotherapy arm

Bolis 1995 is an Italian multicentre RCT that recruited women

with FIGO stage I epithelial ovarian cancer into two trial proto-

cols In Trial 1 patients with Stage Ia and Ib G2 and G3 were ran-

domised to receive either cisplatin (50mgm2) for six cycles or to

have no further therapy The authors have specified the inclusion

of retroperitoneal (pelvic and paraaortic) nodal sampling in the

protocol of this trial and therefore staging is considered optimal In

Trial 2 Cisplatin was compared to intra-peritoneal radio-isotope

in a higher risk group of patients this trial was not considered in

our review because it did not meet our inclusion criteria

The trial enrolled 85 women randomising 41 to the chemotherapy

arm and 44 to the observation-only arm After randomisation two

women (both in the observation-only arm) were deemed ineligible

and so 83 women (41 in the chemotherapy arm and 42 in the

observation-only arm) were available for analysis OS and PFS were

reported Seventeen women died nine in the chemotherapy arm

and eight in the observation-only arm Twenty-one women had

disease recurrence seven in the chemotherapy arm and fourteen

in the observation-only arm The authors reported no significant

differences between treatment arms in either OS or PFS The five-

year DFS was 83 for women receiving cisplatin and 64 for the

control group the five-year OS was 87 and 81 in the cisplatin

and control groups respectively Women were followed up for a

median of 69 months

HRs for OS and PFS and their 95 confidence intervals (CI)

were reported adjusted for tumour grade These were based on

analysis of all eligible patients according to the treatment allocated

by randomisation


but not in the no adjuvant chemotherapy arm

Trope 2000 was a Scandinavian multicentre RCT in women with

high-risk Stage I epithelial ovarian cancer which compared ad-

juvant carboplatin chemotherapy versus observation with treat-

ment on clinical recurrence The entry criteria for this trial were

FIGO stage I non-clear cell carcinoma G2 to G3 after a stipulated

staging laparotomy via a midline incision with a total abdominal

hysterectomy bilateral salpingo-oophorectomy and an infracolic

omentectomy Peritoneal washings were obtained and a thorough

assessment of peritoneal surfaces with biopsy of any suspicious

peritoneal or retroperitoneal lesions was performed A systematic

retroperitoneal lymphadenectomy was not stipulated in the sur-

gical staging protocol although this was recommended as being

optimal

This trial had two aims firstly to determine if there was a sur-

vival advantage for patients having adjuvant chemotherapy and

secondly to test whether DNA ploidy was an independent prog-

nostic factor in high-risk (non-clear cell) stage I epithelial ovarian

cancer

The treatment protocol was with carboplatin intravenously dosed

at AUC7 according to Calvertrsquos formula (Calvert 1989) for six

courses

The trial enrolled 175 women After randomisation 13 women

were deemed ineligible and so 162 women (81 in each arm) were

available for analysis DSS (ie survival of women who did not

die of ovarian cancer or complications of treatment) and DFS

were reported Eighteen women died of ovarian cancer nine in

both arms Thirty-nine women had disease progression 20 in

the chemotherapy arm and 19 in the observation-only arm The

authors reported no significant differences between treatment arms

in either DSS or PFS Women were followed up for a median of

46 months

Unadjusted HRs for DSS and PFS and their 95 CIs were re-

ported Multivariate Cox regression confirmed DNA ploidy tu-

mour grade and FIGO substage as independent prognostic deter-

minants of DSS

Adverse events were not reported

ICON1 2003 trial was a pragmatic trial of adjuvant platinum

based chemotherapy in early stage epithelial ovarian cancer which

recruited patients from 5 countries United Kingdom Ireland

Brazil Italy and Switzerland Computerised randomisation was

done from offices in Milan and London It was run alongside an-

other collaborative trial ACTION and reported simultaneously

with it It was pragmatic about the entry criteria as well as the treat-

ment protocol Clinicians were asked to recruit patients with his-

tologically confirmed invasive epithelial cancer in whom there was



some uncertainty of the need for adjuvant chemotherapy Most

patients were FIGO stage I although some patients had stage II

disease Recommended surgical staging was less stringent in this

trial than in the ACTION trial with the minimum requirement

being for patients to have had removal of all visible tumour with

a total abdominal hysterectomy and bilateral salpingo-oophorec-

tomy where appropriate and omentectomy The minimal recom-

mendation for rsquoperitoneal surgical stagingrsquo means that the patients

were sub-optimally staged in ICON1

The majority of patients in the treatment group (87) had carbo-

platin (AUC5) 11 had cisplatin in combinations and a smaller

percentage had other platinum based regimens

The trial enrolled 477 women randomising 241 to the chemo-

therapy arm and 236 to the observation-only arm Despite pro-

tocol violations all analyses were on an intention-to-treat (ITT)

basis OS and recurrence-free survival (RFS) after five-year follow-

up were reported

One hundred and three women died 42 in the chemotherapy

arm and 61 in the observation-only arm One hundred and seven

women had disease recurrence 47 in the chemotherapy arm and

60 in the observation-only arm The authors reported a statistically

significant benefit of chemotherapy in terms of both OS and RFS

Surviving women were followed up for a median of 51 months

Unadjusted HRs for OS and PFS and their 95 CIs were reported

(066 95 CI 045 to 097 and 065 95 CI 046 to 091

respectively) Five-year survival was 79 among patients who had

chemotherapy compared to 70 among those who did not



Longer-term follow-up of this trial reported in an abstract by

Swart 2007 confirmed these results After median follow-up of

92 years 144 women had died and 168 had disease recurrence


(074 95 CI 053 to 102 and 070 95 CI 052 to 095

respectively) Ten-year survival was 72 among patients who had

chemotherapy compared to 64 among those who did not This

abstract also reported the effect of adjuvant chemotherapy sub-

grouped by level of risk

In a subgroup analysis of these ten-year data patients were di-

chotomized into lowmedium risk (Ia G1 and G2 Ib or Ic G1)

and high risk (Ia G3 Ib or Ic G2 or G3 any clear cell) Among the

high risk patients those who received adjuvant chemotherapy had

significantly better OS and recurrence-free survival than those who

did not receive chemotherapy (HR 048 95 CI 032 to 072

and HR 052 95 CI 033 to 082 respectively) whereas among

lowmedium risk patients there was no significant difference in

survival outcomes between treatment arms (HR 096 95 CI

054 to 166) and HR 096 95 CI 050 to 138 respectively)

ACTION 2003 was run at the same time as the ICON1 2003

trial by the European Organisation for Research and Treatment of

Cancer (EORTC) collaborators and recruited 448 patients This

was a multicentre trial with centralized computer randomisation

in Brussels Nine countries provided patients between November

1990 and January 2000 Entry criteria were more stringent than

in the ICON1 2003 trial The trial was open to patients with stage

Ia and Ib G2 and G3 (moderately and poorly differentiated tu-

mours) all stage Ic and stage Ia Surgical staging was also specified

and optimal staging to include pelvic and para-aortic retroperi-

toneal node dissection was strongly recommended A pre-planned

examination of the impact of surgical staging on survival outcome

required careful documentation of surgical staging for each case

which was categorized as being inadequate minimal modified or

optimal

The allowed chemotherapy regimens were single agent or combi-

nations based on either cisplatin at 75 mgm2 or carboplatin at

350 mgm2 Of the assessable patients who were randomised to

receive chemotherapy 47 had cisplatin in combination with cy-

clophosphamide and 33 had single-agent carboplatin Patients

in the control group had no adjuvant treatment They were fol-

lowed-up and chemotherapy was reserved for cases of disease re-

currence

The trial enrolled 448 women randomising 224 to each arm De-

spite protocol violations all analyses were on an intention-to-treat

(ITT) basis OS and RFS were reported Seventy-eight women

died 33 in the chemotherapy arm and 45 in the observation-only

arm One hundred women had disease recurrence 40 in the che-

motherapy arm and 60 in the observation-only arm The authors

reported a statistically significant benefit of chemotherapy in terms

of recurrence-free survival and a benefit in terms of OS which was

not statistically significant Women were followed up for a median

of 55 years

Unadjusted HRs for OS and RFS and their 95 CIs were re-

ported (069 95 CI 044 to 108 and 063 95 CI 043 to

092 respectively) Five-year survival was 76 among patients who

had chemotherapy compared to 68 among those who did not

Multivariate Cox regression confirmed that staging adequacy and

tumour grade were statistically significant prognostic factors for

both OS and RFS


In a pre-planned sub-group analysis staging adequacy was di-

chotomized into optimal and sub-optimal groups Among the 295

sub-optimally staged patients those who received adjuvant che-

motherapy had significantly better OS and RFS than those who

did not receive chemotherapy whereas among the 151 optimally

staged patients there was no significant difference in survival out-

comes between treatment armsSummary of included trials



Four of the included trials used cisplatin-based chemotherapy (

ACTION 2003 Bolis 1995 ICON1 2003 Trope 2000) while

one used melphalan (Young 1990) The trials had some important

differences related to inclusion criteria treatment arm protocols

trial size and results statistic The three earlier trials (Bolis 1995

Trope 2000 Young 1990) all recruited a small numbers of par-

ticipants and so may have lacked the statistical power to detect

a treatment effect even if one were present In contrast the two

later trials (ICON1 2003 ACTION 2003) were each much larger

than preceding trials and since they were run in parallel and re-

ported in a joint analysis the rsquocombined trialrsquo had sufficient power

to demonstrate a treatment effect Furthermore while the Bolis

1995 trial protocol specified examination of the retroperitoneal

nodal groups at laparotomy in addition to peritoneal staging the

protocol for ICON1 2003 made no such stipulation As such the

patients in the former trial are regarded to have been optimally

staged while staging for the ICON1 2003 patients was sub-opti-

mal

An important difference between ACTION 2003 and the other

trials was the predetermined intention of the trialists to exam-

ine in a sub-group the effect of staging adequacy in either trial

arm Roughly one third of the patients recruited to this trial had

more thorough surgical staging (described as optimal as opposed

to adequate) The adequacy of staging in the other trials has not

been specified but is assumed to be adequate rather than optimal

This is an important difference because it is recognised that more

thorough surgical staging (specifically retroperitoneal lymph node

dissection) will result in a more accurate identification of patients

with occult advanced disease

Risk of bias in included studies

The five included trials were of uniformly good quality (see

Characteristics of included studies)

All included trials reported adequate randomisation and adequate

concealment of allocation Consequently a balance of prognostic

factors was reported by ACTION 2003 ICON1 2003 Trope

2000 and Young 1990 however Bolis 1995 reported that women

in the cisplatin arm were more likely to have poorly differentiated

(G3) tumours and less likely to have clear cell histotype

One trial (ICON1 2003) reported that the trial was open inves-

tigators patients and trial centre staff were not blinded to treat-

ment allocation after randomisation None of the other four trials

reported blinding of outcome assessors

ICON1 2003 reported no loss to follow-up after five years one

trial (ACTION 2003) reported 2 loss to follow-up after five

years Trope 2000 reported 7 of women were deemed ineligible

after randomisation but that no further participants were lost to

follow-up the remaining two trials reported 2 (Bolis 1995) and

12 (Young 1990) of women were deemed ineligible after ran-

domisation but they did not report whether any subsequent loss

to follow-up occurred

All trials used an ITT analysis

Effects of interventions

Four trials (ACTION 2003 Bolis 1995 ICON1 2003 Young

1990) reported OS One trial (Bolis 1995) reported PFS two trials

reported RFS (ACTION 2003 ICON1 2003) two trials reported

DFS (Trope 2000 Young 1990) For the purposes of meta-analysis

we assumed that these endpoints referred to the same outcome

measured in the same way although this may not necessarily be

true (Altman 1995) One trial (Trope 2000) reported DSS defined

as survival until death from ovarian cancer or from complications

of treatment for the disease with deaths from other causes being

censored

We excluded the trial of Young 1990 from all meta-analyses since

the data reported in the published report were not internally con-

sistent table 3 in the trial paper reported one disease recurrence in

the chemotherapy group whereas figure 1 in the trial paper showed

two disease recurrences in this group The table 3 reported deaths

at 35 and 38 months in the chemotherapy group whereas figure

2 showed deaths at 35 and 38 months in this group This trial

evaluated melphalan whereas all other included trials evaluated

platinum-based chemotherapy

The four trials (ACTION 2003 Bolis 1995 ICON1 2003 Trope

2000) that were included in meta-analyses had similar median

durations of follow-up 66 69 51 and 46 months respectively One

trial (ICON1 2003) additionally reported the effect of adjuvant

chemotherapy after 10 years follow-up (see abstract Swart 2007)

this report sub-grouped women by level of risk

Overall Survival (comparison 1 outcome 1)

Meta-analysis of three trials assessing 1008 women showed signif-

icantly better OS among women receiving adjuvant chemother-

apy than among women who did not (HR 071 95 CI 053 to

093) with no heterogeneity between trials (I2 = 0) This corre-

sponded to an NNT of 17 95CI 9 to 100 The trials contribut-

ing greatest weight to the analysis were ICON1 2003 (53) and

ACTION 2003 (39) (Analysis 11)

Sensitivity analysis using the 10-year rather than the 5-year results

for the trial of ICON1 2003 yielded similar results (HR 075

95 CI 058 to 097)

Overall Survival sub-grouped by adequacy of surgical

staging (comparison 1 outcome 2)

Meta-analysis of three trials ACTION 2003 Bolis 1995 ICON1

2003 was performed sub-grouping by optimalsub-optimal sur-

gical staging and excluding two women in the ACTION 2003

trial whose staging status was unknown Among optimally staged

women this showed no significant difference in OS between those

who did and did not receive adjuvant chemotherapy (HR 122

95 CI 063 to 237) among sub-optimally staged women those

receiving adjuvant chemotherapy had significantly better OS than

those who did not (HR 063 95 CI 046 to 085) (Analysis 12



Overall Survival sub-grouped by level of risk

(comparison 1 outcome 3)

Among women at low and medium risk ICON1 2003 showed no

significant difference in OS between those who did and did not

receive adjuvant chemotherapy (HR 095 95 CI 054 to 166)

among women at high risk those receiving adjuvant chemotherapy

had significantly better OS than those who did not (HR 048 95

CI 032 to 072) The numbers of women in the low to medium

and high risk groups were not reported (Analysis 13)

Progression-free survival (comparison 1 outcome 4)

Meta-analysis of four trials assessing 1170 women showed signif-

icantly better PFS among women receiving chemotherapy than

among women who did not (HR 067 95 CI 053 to 084)

with no heterogeneity between trials (I2 = 0) This corresponded

to an NNT of 12 95 CI 7 to 33 (Analysis 14)


for the trial of ICON1 2003 again yielded similar results (HR

069 95 CI 056 to 085)

Progression-free survival sub-grouped by adequacy of

surgical staging (comparison 1 outcome 5)

Meta-analysis of these trials was performed sub-grouping by opti-

malsub-optimal surgical staging and excluding two women in the

ACTION 2003 trial whose staging status was unknown Among

optimally staged women this showed no significant difference in

PFS between those who did and did not receive adjuvant chemo-

therapy (HR 067 95 CI 036 to 122) among sub-optimally

staged women those receiving adjuvant chemotherapy had signif-

icantly better PFS than those who did not ( HR 064 95 CI

050 to 082) (Analysis 15)

Progression-free survival sub-grouped by level of risk



significant difference in PFS between those who did and did not



had significantly better PFS than those who did not (HR 052

95 CI 033 to 082) We were unable to reproduce in RevMan

the 95 CI reported by Swart 2007 since the latter CI was not

symmetric on a log scale (Analysis 16)

Disease-specific survival (comparison 1 outcome 7)

Trope 2000 assessing 162 women reported no significant differ-

ence in DSS between those who did and did not receive adjuvant

chemotherapy (HR 094 95 CI 037 to 237) (Analysis 17)

Deaths form ovarian cancer (comparison 1 outcome

8)

Meta-analysis of three trials (ACTION 2003 Bolis 1995 Trope

2000) assessing 693 women reported no significant difference in

DSS between those who did and did not receive adjuvant chemo-

therapy (RR 076 95 CI 052 to 111) with no heterogeneity

between trials (I2 = 0) (Analysis 18)

Adverse events

We were unable to compare the risk of adverse events in women

who did and did not receive adjuvant chemotherapy since none

of the trials reported adverse events among women who did not

receive adjuvant chemotherapy

Assessment of reporting bias

A funnel plot was not produced for OS as only three trials were

included in meta-analysis of this outcome A funnel plot corre-

sponding to PFS showed no evidence of bias among small studies

(Figure 1)



Figure 1 Fig 01 Funnel plotStandard error of estimated treatment effect vs estimated treatment effect



Sensitivity analyses

Sensitivity analyses excluding poor quality trials were not per-

formed since all trials reported adequate concealment of allocation

and no trials reported blinding of outcome assessors

D I S C U S S I O NSummary of main results

Five randomised controlled trials (ACTION 2003 Bolis 1995

ICON1 2003 Trope 2000 Young 1990) were identified and met

the inclusion criteria for this systematic review of which four trials

evaluating platinum based chemotherapy (ACTION 2003 Bolis

1995 ICON1 2003 Trope 2000) were of sufficient quality to

contribute to a meta-analysis In all 1170 patients contributed

data to this

Among women with early stage epithelial ovarian cancer those

receiving adjuvant chemotherapy had better OS (HR 071 95

CI 053 to 093) and PFS (HR 067 95 CI 053 to 084) than

those who did not receive adjuvant chemotherapy This indicates

that at 5 years follow up almost 30 more patients were alive

as a result of receiving adjuvant chemotherapy However between

9 and 100 women would have to be treated with adjuvant che-

motherapy to prevent one death and between 7 and 33 women

would have to be treated with adjuvant chemotherapy to prevent

one case of disease recurrence

However adjuvant chemotherapy appeared to benefit only specific

sub-groups of patients It was associated with improved OS or PFS

among the 772 (66) patients who were not optimally staged

but not among others Evidence from one trial (ICON1 2003)

showed that adjuvant chemotherapy was associated with improved

PFS or OS among high risk patients but not among others

Overall completeness and applicability ofevidence

The large number of patients pooled in this meta-analysis gives

clear and consistent evidence of the overall benefit of adjuvant che-

motherapy for women with early stage ovarian cancer especially

among the two thirds of the patients (all patients in ICON1 2003

and two thirds of those in ACTION 2003 - a total of 772) who

were sub-optimally staged This sub-group is probably represen-

tative of the majority of patients treated world-wide for early stage

epithelial ovarian cancer

It seems unlikely that the apparent lack of benefit of adjuvant

chemotherapy among women who were optimally staged could

be due to lack of statistical power in this smaller group of 234

women While there was some indication that these women might

have better PFS if they had adjuvant chemotherapy there was no

evidence that their OS improved with adjuvant chemotherapy

The apparent limitation of the benefits of chemotherapy to sub-

optimally staged patients suggests that the real value of adjuvant

chemotherapy is in the treatment of occult advanced stage disease

However some benefit for chemotherapy in optimally staged dis-

ease cannot be excluded For this reason the authors support the

continued practice of offering adjuvant chemotherapy to women

staged optimally who have high risk histology

However it is possible that the apparent limitation of the benefits

of treatment to sub-groups of women with sub-optimal staging

andor high risk are a chance finding It has been shown that

if an overall treatment effect is statistically significant at the five

percent level (as immediate adjuvant chemotherapy is in our meta-

analyses) and the patients are divided at random into two similarly

sized sub-groups then there is a one in three chance that the

treatment effect will be large and statistically significant in one

group but irrelevant and non-significant in the other (Peto 1982)

Quality of the evidence

The trials which have contributed to the meta-analysis are method-

ologically strong

Inadequate concealment of allocation and lack of blinding are of-

ten associated with an exaggeration of the effects of treatment (

Moher 1998 Schulz 1995) Although all trials included in the

meta-analysis reported adequate randomisation and concealment

of allocation lack of blinding could have resulted in an over-es-

timate of the effects of chemotherapy No efforts were described

to prevent either the patients the clinicians treating them or the

clinicians assessing their outcomes from knowing which treatment

the patients had received Blinding of the patients and the clini-

cians treating them would have required giving sham chemother-

apy to patients who were not randomised to receive chemotherapy

which would have been impractical and unethical It may have

been possible though expensive and impractical to assess patients

during their follow-up by people not involved in their prior care

but this would probably have been unacceptable to patients and

their clinicians Regarding the outcomes assessed it is difficult to

see how death could be subject to biased reporting However clin-

icians may be more or less vigilant in detecting disease recurrence

if they are aware of the patientrsquos previous treatments

The five included trials were similar enough in entry and exclusion

criteria to recruit patients who were broadly similar This lack

of clinical heterogeneity was confirmed by the lack of statistical

heterogeneity in the meta-analyses

Unfortunately none of the trials assessed impact of adjuvant che-

motherapy on the quality of life of the patients

Adverse events were poorly reported and did not use consistent

definitions (NCI CTCAE v30 2006) Only three of the trials

reported adverse events (Bolis 1995 ICON1 2003 Young 1990)

in women receiving adjuvant chemotherapy none of the trials

reported adverse events in women who did not receive adjuvant

chemotherapy

Potential biases in the review process



A funnel plot showed no evidence of publication bias however

this was based on only four trials so we cannot exclude the pos-

sibility that small trials that showed no benefit of chemotherapy

have not been published Certainly there were several trials (Bolis

1995 Young 1990 Trope 2000) which showed no clear benefit for

adjuvant chemotherapy before the publication of ICON1 2003

and ACTION 2003

The assignment of Trope 2000 and Bolis 1995 to optimal staging

and of ICON1 2003 to sub-optimal staging was post hoc and

subjective and similarly the highlow risk sub-group analysis of

ICON1 2003 was post-hoc and not specified in the protocol

Agreements and disagreements with otherstudies or reviews

The main questions that arise and have been the focus of other

reviews are

bull Should chemotherapy be given to all women following

surgery for early stage ovarian cancer

bull What about patients who have had optimal staging

bull What about high risk histotypes

bull Is re-staging surgery a good idea

bull How effective is salvage therapy

Three previous systematic reviews have compared the effects of

adjuvant chemotherapy with no chemotherapy for women with

early stage ovarian cancer (Trimbos 2003 Trope 2007 Winter-

Roach 2003) Two other systematic reviews of therapy in ovarian

cancer have also looked at this topic (Hoberg 2001 Lyngstadaas

2005) These reviews identified the five studies which were in-

cluded in our review and conducted meta-analyses of OS and PFS

which yielded similar results to those which we obtained despite

using slightly different methods Only the review of Trope 2007

performed sub-group analyses by adequacy of surgical staging and

again obtained similar results to ours

Trope 2007 noted the different inclusion criteria of ICON1 2003

and ACTION 2003 (more low-risk disease and sub-optimal stag-

ing in ICON1 2003) and specifically concluded that since only a

small proportion of patients in the combined analysis of these trials

were optimally staged the evidence in support of adjuvant chemo-

therapy in adequately staged epithelial ovarian cancer is lacking

Trope 2007 concluded that Stage Ia G1 tumours did not require

adjuvant chemotherapy The evidence provided from a sub-group

analysis of optimally staged patients as well as a comparison of sur-

vival rates of the optimally staged patients of the ACTION 2003

trial with another optimally staged subgroup in a later trial (three

versus six cycles ie Bell 2006) was taken to infer a lack of benefit

for optimally staged patients from adjuvant chemotherapy That

author recommended selective restaging done either laparoscopi-

cally or by repeat laparotomy for patients who were sub-optimally

staged at the outset The information gained at restaging would

provide evidence to guide decisions on adjuvant chemotherapy

For sub-optimally staged patients who were not fit for such re-

staging adjuvant chemotherapy was recommended

The authors share the view expressed by Trope 2007 that the ev-

idence for adjuvant chemotherapy in optimally staged disease is

lacking That author would reserve adjuvant chemotherapy for se-

lective use in ldquoa small and highly selective group of very high risk

patientsrdquo The authors of the current review however believe that

the optimal retroperitoneal staging practiced by in a few centres

is not representative of the majority of patients treated for ldquoearly

stage ovarian cancerrdquo and therefore such a selective use of adjuvant

chemotherapy cannot be recommended A more pragmatic real

world interpretation of the evidence would be more conservative

making adjuvant chemotherapy the default position for the ma-

jority of patients with carefully selected patients being managed

expectantly with chemotherapy reserved for salvage therapy

Regression analyses of patients in trials have consistently identified

tumour grade as a significant prognostic determinant Bolis 1995

Trope 2000 Young 1990 Authors have not always agreed on the

importance of the current sub-stages in stage I disease but there are

now data from this and previous meta-analyses that begin to bring

together these factors into a pragmatic approach to patient care

The long term follow-up data from the ICON1 2003 trial would

additionally suggest that patients with poor prognosis tumours as

defined by the FIGO sub-stage and histological sub-type are more

likely to benefit from chemotherapy

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

Implications for practice

Since the finding of early stage disease is often unexpected and

therefore often managed by general gynaecologists without sub-

specialist training it is not surprising that comprehensive staging

is infrequently achieved On this basis it may be safe practice to

recommend adjuvant chemotherapy for the majority of cases of

apparent early stage ovarian cancer However if staging is compre-

hensive it should be possible to identify patients in whom it is

safe if not better to withhold chemotherapy unless and until it is

needed to treat recurrent disease

A conservative position would be to recommend adjuvant che-

motherapy to all patients with apparent early stage disease unless

they have had comprehensive staging and the histology is not high

grade Patients with well or moderately differentiated encapsulated

tumours confined to one ovary who are optimally staged should

be advised that there is evidence to suggest they will gain limited

if any survival benefit from adjuvant chemotherapy

Implications for research

There are deficiencies in the evidence which can and should be

addressed in the context of a collaborative trials



The ACTION 2003 investigators have proposed a trial in which

patients who are sub-optimally staged are randomised either to

have a staging laparotomy or to have adjuvant chemotherapy The

authors propose a trial in apparent early ovarian cancer with two

levels of randomisation the first step would randomise to either

optimal staging or peritoneal staging All patients with high grade

tumours would be recommended adjuvant chemotherapy In the

second step patients with rsquolow riskrsquo histology in the peritoneal

staging arm would be randomly assigned to either adjuvant che-

motherapy or observation and those optimally staged would be

observed Such a trial would evaluate firstly whether there is a

survival advantage to retroperitoneal node sampling in early stage

ovarian cancer and secondly whether a group of patients with early

stage epithelial ovarian cancer can safely be managed without ad-

juvant chemotherapy

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

We thank the staff of the Cochrane Gynaecological Cancer Re-

view Group in particular Chris Williams Gail Quinn Clare Jess

and Anne Oestmann for their helpful advice and administrative

support We thank Andy Bryant Newcastle University for helpful

comments on the review

R E F E R E N C E S

References to studies included in this review

ACTION 2003 published data only

Trimbos JB Vergote I Bolis G Vermorken JB Mangioni C

Madronal C et alEORTC-ACTION collaborators European Or-

ganisation for Research and Treatment of Cancer-Adjuvant Chemo-

Therapy in Ovarian Neoplasm Impact of adjuvant chemotherapy

and surgical staging in early-stage ovarian carcinoma Journal of the

National Cancer Institute 200395(2)113ndash25

Bolis 1995 published data only

Bolis G Colombo N Pecorelli S Torri V Marsoni S Bonazzi C

et alAdjuvant treatment for early epithelial ovarian cancer results

of two randomised clinical trials comparing cisplatin to no further

treatment or chromic phosphate (32P) GICOG Gruppo Inter-

regionale Collaborativo in Ginecologia Oncologica Annals of On-

cology 19956(9)887ndash93

ICON1 2003 published data only

Colombo N Guthrie D Chiari S Parmar M Qian W Swart AM

et alInternational Collaborative Ovarian Neoplasm trial 1 a ran-

domized trial of adjuvant chemotherapy in women with early-stage

ovarian cancer Journal of the National Cancer Institute 200395(2)

125ndash32

Swart AC on behalf of ICON collaborators Long-term follow-up of

women enrolled in a randomized trial of adjuvant chemotherpay for

early stage ovarian cancer (ICON1) Journal of Clcinical Oncology

200725(18S)5509

Trope 2000 published data only

Trope C Kaern J Hogberg T Abeler V Hagen B Kristensen G

et alRandomized study on adjuvant chemotherapy in stage I high-

risk ovarian cancer with evaluation of DNA-ploidy as prognostic

instrument Annals of Oncology 200011(3)281ndash8

Young 1990 published data only

Young RC Walton LA Ellenberg SS Homesley HD Wilbanks GD

Decker DG et alAdjuvant therapy in stage I and stage II epithelial

ovarian cancer Results of two prospective randomized trials New

England Journal of Medicine 1990322(15)1021ndash7

References to studies excluded from this review

Chiara 1994 published data only

Chiara S Conte P Franzone P Orsatti M Bruzzone M Rubagotti A

et alHigh-risk early-stage ovarian cancer Randomized clinical trial

comparing cisplatin plus cyclophosphamide versus whole abdominal

radiotherapy American Journal of Clinical Oncology 199417(1)72ndash

6

Hreshchyshyn 1980 published data only

Hreshchyshyn MM Park RC Blessing JA Norris HJ Levy D La-

gasse LD The role of adjuvant therapy in Stage I ovarian cancer

American Journal of Obstetrics and Gynecology 1980138(2)139ndash45

Klaassen 1988 published data only

Klaassen D Shelley W Starreveld A Kirk M Boyes D Gerulath A

et alEarly stage ovarian cancer a randomized clinical trial compar-



ing whole abdominal radiotherapy melphalan and intraperitoneal

chromic phosphate a National Cancer Institute of Canada Clinical

Trials Group report Journal of Clinical Oncology 19886(8)1254ndash

63

Kojs 2001 published data only

Kojs Z Glinski B Reinfuss M Pudelek J Urbanski K Kowalska T et

alResults of a randomized prospective trial comparing postoperative

abdominopelvic radiotherapy with postoperative chemotherapy in

early ovarian cancer Cancer Radiotherapie 20015(1)5ndash11

Maggioni 2006 published data only

Maggioni A Benedetti Panici P DellrsquoAnna T Landoni F Lissoni

A Pellegrino A et alRandomised study of systematic lymphadenec-

tomy in patients with epithelial ovarian cancer macroscopically con-

fined to the pelvis British Journal of Cancer 200695(6)699ndash704

Sell 1990 published data only

Sell A Bertelsen K Andersen JE Stroyer I Panduro J Bentzen SM

et alRandomized study of whole-abdomen irradiation versus pelvic

irradiation plus cyclophosphamide in treatment of early ovarian can-

cer Gynecologic Oncology 199037(3)367ndash73

Sevelda 1987 published data only

Sevelda P Gitsch E Dittrich C Haider F Czerwenka K Schemper

M et alTherapeutic and prognostic results of a prospective mul-

ticenter ovarian cancer study of FIGO stages I and II Geburtshilfe

Frauenheilkd 198747(3)179ndash85

Sigurdsson 1982 published data only

Sigurdsson K Johnsson JE Trope C Carcinoma of the ovary stages I

and II A prospective randomized study of the effects of postoperative

chemotherapy and radiotherapy Annales Chirurgiae et Gynaecologiae

198271(6)321ndash9

Smith 1975 published data only

Smith JP Rutledge FN Delclos L Mayer AR Chambers SK Graves

E et alResults of chemotherapy as an adjunct to surgery in patients

with localized ovarian cancer Seminars in Oncology 19752(3)277ndash

81

Vergote 1992 published data only

Vergote IB Vergote-De Vos LN Abeler VM Aas M Lindegaard

MW Kjorstad KE et alRandomized trial comparing cisplatin with

radioactive phosphorus or whole-abdomen irradiation as adjuvant

treatment of ovarian cancer Cancer 199269(3)741ndash9


Young RC Three cycles versus six cycles of adjuvant paclitaxel

(Taxol)carboplatin in early stage ovarian cancer Seminars in Oncol-

ogy 200027(3 Suppl 7)8ndash10


Young RC Brady MF Nieberg RK Long HJ Mayer AR Lentz SS et

alAdjuvant treatment for early ovarian cancer a randomized phase

III trial of intraperitoneal 32P or intravenous cyclophosphamide and

cisplatin--a gynecologic oncology group study Journal of Clinical

Oncology 200321(23)4350ndash5

Additional references

Altman 1995

Altman DG De Stavola BL Love SB Stepniewska KA Review of

survival analyses published in cancer journals British Journal of Can-

cer 199572511ndash8

AOCTG 1999

Advanced Ovarian Cancer Trialists Group Chemotherapy for ad-

vanced ovarian cancer Cochrane Database of Systematic Reviews 1999

Issue 1 [DOI 10100214651858CD001418]

Bell 2006

Bell J Brady MF Young RC Walker JL Look KY Rose GS et

alRandomised phase III trial of three versus six cycles of adjuvant

carboplatin and paclitaxel in early stage epithelial ovarian carcinoma

a Gynecologic Oncology Group study Gynecologic Oncology 2006

102(3)432ndash9

Calvert 1989

Calvert AH Newell DR Gumbrell LA OrsquoReilly S Burnell M Box-

all FE et alCarboplatin dosage prospective evaluation of a simple

formula based on renal function Journal of Clinical Oncology 1989

13(8)2147ndash8

Deeks 2001

Deeks JJ Altman DG Bradburn MJ Statistical methods for exam-

ining heterogeneity and combining results from several studies in

meta-analysis In Egger M Davey Smith G Altman DG editor

(s) Systematic Reviews in Health Care Meta-Analysis in Context 2nd

Edition BMJ Publication Group 2001

DerSimonian 1986

DerSimonian R Laird N Meta-analysis in clinical trials Controlled

Clinical Trials 19867177ndash88

Elit 2004

Elit L Chambers A Fyles A Covens A Carey M Fung MF System-

atic review of adjuvant care for women with Stage I ovarian carci-

noma Cancer 2004101(9)1926ndash35

Ferlay 2002

Ferlay J Bray F Pisani P Parkin DM GLOBOCAN 2002 Cancer

Incidence Mortality and Prevalence Worldwide IARC CancerBase

No 5 version 20 Lyon IARCPress 2004

Green 2003

Green JA Early ovarian cancer--time for a rethink on stage Gyneco-

logic Oncology 200390235ndash7

Higgins 2003

Higgins JPT Thompson SG Deeks JJ Altman DG Measuring in-

consistency in meta-analyses BMJ 2003327557ndash560

Hoberg 2001

Houmlgberg T Glimelius B Nygren P SBU-group Swedish Council

of Technology Assessment in Health Care A systematic overview of

chemotherapy effects in ovarian cancer Acta Oncologica 200140(2-

3)340ndash60

ICON2 1998

ICON collaborators ICON2 randomised trial of sin-

gle agent carboplatin against three-drug combination of CAP

(cyclophosphamide doxorubicin and cisplatin) in women with ovar-

ian cancer ICON International Collaborative Neoplasm Study

Lancet 19983521571ndash6

ICON3 2002

ICON Collaborators Paclitael plus carboplatin versus standard che-

motherapy with either single-agent carboplatin or cyclophospha-

mide doxorubicin and cisplatin in women with ovarian cancer the

ICON3 trial Lancet 2002360505ndash15



Jemal 2008

Jemal A Siegel R Ward E Hao Y Xu J Murray T et alCancer

Statistics 2008 CA A Cancer Journal for Clinicians 20085871ndash96

Lyngstadaas 2005

Lyngstadaas A Ekanger R Hagen B Himmelmann A Iversen OE

Iversen T et alPrimary treatment of ovarian cancer Tidsskr Nor

Laegeforen 2005125(3)278ndash81

Mayer 1992

Mayer AR Chambers SK Graves E Holm C Tseng PC Nelson BE

et alOvarian cancer staging does it require a gynecologic oncologist

Gynecologic Oncology 199247223ndash7

McGuire 1996

McGuire WP Hoskins WJ Brady MF Kucera PR Partridge EE

Look KY et alCyclophosphamide and cisplatin compared with pa-

clitaxel and cisplatin in patients with stage III and stage IV ovarian

cancer New England Journal of Medicine 1996334(1)1ndash6

Moher 1998

Moher D Pham D Jones A Cook DJ Jadad AR Moher M et

alDoes quality of reports of randomised trials affect estimates of

intervention efficacy reported in meta-analyses Lancet 1998352

609ndash13

Morice 2001

Morice P Wicart-Poque F Rey A El-Hassan J Pautier P Lhomme C

et alResults of conservative treatment in epithelial ovarian carcinoma

Cancer 2001922412ndash8

NCI CTCAE v30 2006

National Cancer Institute National Cancer Institute Common Ter-

minology Criteria for Adverse Events version 30 (NCI CTCAE

v30) httpctepcancergovreportingctc_v30html

Parkin 2002

Parkin DM Whelan SL Ferlay J Teppo L Thomas DB Cancer In-

cidence in five continents Vol VIII Lyon IARC Scientific Publica-

tion 2002 [ No 155]

Parmar 1998

Parmar MK Torri V Stewart L Extracting summary statistics to per-

form meta-analyses of the published literature for survival endpoints

Statistics in Medicine 1998172815ndash34

Peto 1982

Peto R Statistical aspects of cancer trials In Halnan KE editor(s)

Treatment of cancer London Chapman and Hall 1982

Sant 2003

Sant M Aareleid T Berrino F Bielska Lasota M Carli PM Faivre

J et alEUROCARE-3 survival of cancer patients diagnosed 1990-

94- results and commentary Annals of Oncology 200314v61ndashv118

[ Supplement 5]

Schilder 2002

Schilder JM Thompson AM DePriest PD Ueland FR Cibull ML

Kryscio RJ et alOutcome of reproductive age women with stage IA

or IC invasive epithelial ovarian cancer treated with fertility-sparing

therapy Gynecologic Oncology 200287(1)1ndash7

Schulz 1995

Schulz KF Chalmers I Hayes RJ Altman D Empirical evidence of

bias Dimensions of methodological quality associated with estimates

of treatment effects in controlled trials JAMA 1995273408ndash12

Shepherd 1989

Shepherd JH Revised FIGO staging for gynaecological cancer

British Journal of Obstetrics and Gynaecology 198996889ndash92

Swart 2007


women enrolled in a randomized trial of adjuvant chemotherapy in

early stage ovarian cancer (ICON1) Journal of Clinical Oncology

Chicago ASCO Annual Meeting Proceedings 2007 Vol 25

Trimbos 2003

Trimbos JB Parmar M Vergote I Guthrie D Bolis G Colombo

N et alInternational Collaborative Ovarian Neoplasm trial 1 and

Adjuvant ChemoTherapy In Ovarian Neoplasm trial two parallel

randomized phase III trials of adjuvant chemotherapy in patients

with early-stage ovarian carcinoma Journal of the National Cancer

Institute 200395(2)105ndash12

Trope 2007

Trope C Kaern J Adjuvant chemotherapy for early-stage ovarian

cancer review of the literature Journal of Clinical Oncology 2007

25(20)2909ndash20

Vergote 2001

Vergote I De Brabanter J Fyles A Bertelsen K Einhorn N Selvelda

P et alPrognostic importance of degree of differentiation and cyst

rupture in stage 1 invasive epithelial carcinoma Lancet 2001357

176ndash82

Zanetta 1998

Zanetta G Rota S Chiari S Bonazzi C Bratina G Torri V et alThe

accuracy of staging an important prognostic determinator in stage I

ovarian carcinoma A multivariate analysis Annals of Oncology 1998

9(10)1097ndash101

References to other published versions of this review

Winter-Roach 2003

Winter-Roach B Hooper L Kitchener H Systematic review of adju-

vant therapy for early stage (epithelial) ovarian cancer International

Journal of Gynecological Cancer 200313(4)395ndash404lowast 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]

ACTION 2003

Methods Multicentre RCT

Participants 448 FIGO Ia-Ib G23FIGO Ic-IIaFIGO I-IIa clear cell

Interventions Immediate platinum based chemotherapy vs treatment on progression Cisplatin dose=

75mgm2]Carboplatin dose= 350mgm2

Outcomes DFS and OS

Adverse events not reported

Median follow-up 55 yrs

Notes Sub group analysis examined impact of staging adequacy

Risk of bias

Item Authorsrsquo judgement Description

Adequate sequence generation Yes Based on minimisation

Allocation concealment Yes Minimisation performed by central co-ordinating centres

Blinding of outcome assessors No No blinding

Loss to follow-up Yes T 6224 (2)

C 3224 (1)

Intention-to-treat analysis Yes

Bolis 1995

Methods Randomised controlled trial

Participants 85 FIGO (1976) IA-IB Grade 2 and 3

Interventions Cisplatin 50mgm2X 6 cycles Q 287 vs Observation

Outcomes DFS 83 vs 64

OS 88 vs 82



Bolis 1995 (Continued)

Adverse events in adjuvant chemotherapy arm nausea and vomiting in more than 23 of patients

but in severe form in less than 10 of courses leukopenia and thrombocytopenia in 14 of patients

but gt= Grade 3 in only 1 of patients no episodes of febrile infection

Adverse events in no adjuvant chemotherapy arm not reported

Median follow-up 69 mths

Notes Patients with residual disease in both arms

Risk of bias


Adequate sequence generation Yes Based on tables of random numbers

Allocation concealment Yes Central randomisation by telephone call to co-ordinating centre

Blinding of outcome assessors Unclear Not reported

Loss to follow-up Yes Deemed ineligible after randomisation

T 041 (0)

C 244 (5)

Did not report whether any further loss to follow-up occurred


ICON1 2003


Participants 447 FIGO I-III

93 FIGO stage

Interventions Immediate Platinum based chemotherapy vs treatment on progression

Outcomes DFS and OS

Adverse events in adjuvant chemotherapy arm 63241 (26) experienced toxicity sufficient to

require modification of treatment


Median follow-up of surviving women 51 mths (Colombo2003)

Median follow-up 92 yrs (Swat 2007)

Notes Long term follow-up examined subgroup differences

Risk of bias



ICON1 2003 (Continued)



Allocation concealment Yes Minimisation performed by two co-ordinating centres



C 0236 (0)


Trope 2000


Participants 162 High risk

FIGO stage I

Interventions Carboplatin 6 cycles Q287 AUC=7 vs treatment at progression

Outcomes DFS and OS



Notes

Risk of bias





Loss to follow-up Yes 13175 (7) deemed ineligible after randomisation not reported by treat-

ment arm

No further loss to follow-up




Young 1990


Participants 92 FIGO stage I

Interventions Melphalan chemotherapy vs treatment on progression

Outcomes DFS and OS

Adverse events in adjuvant chemotherapy arm 79 had some degree of myelosuppression 7

patients (16) had severe myelosuppression 5 patients (12) had platelet count nadirs under

50000 per cubic mm 4 patients (9) had platelet count nadirs under 2000 per cubic mm no

infectious complications related to leukopenia no bleeding episodes related to thrombocytopenia

induced by chemotherapy 11 patients (26) reported mil-to-moderate gastric gastrointestinal side

effects No other adverse effects were reported One patient dies 6 years after completing treatment

with a diagnosis of aplastic anaemia no other myeloprolific disorders or second cancers were seen

after gt250 person-years follow-up


Median follow-up of surviving women 6 years

Notes Melphalan produced severe

myelosuppression

Risk of bias


Adequate sequence generation Yes Based on computer-generated random numbers



Loss to follow-up Unclear Deemed ineligible after randomisation

T 548 (10)

C 644 (14)





Characteristics of excluded studies [ordered by study ID]

Chiara 1994 This RCT compared whole abdominal radiotherapy (WAR) vs CAP chemotherapy

Hreshchyshyn 1980 This trial compared chemotherapy against radiotherapy and no-further treatment The method of randomised

was not specified and a prognostic balance was not achieved in the different arms of the trial

Klaassen 1988 This trial compared 3 different adjuvant treatments all given after pelvic radiotherapy Melphalan whole

abdominal radiotherapy and intraperitoneal radio-isotope therapy

Kojs 2001 This trial compared adjuvant whole abdominal radiotherapy with CAP (Cyclophosphamide Adriamycin and

Cisplatin)

Maggioni 2006 This was a trial comparing systematic lymphadenectomy with lymph node sampling in apparent early stage

ovarian cancer it was not a trial of adjuvant treatment

Sell 1990 In this trial whole abdominal radiotherapy was compared to a combination of pelvic radiotherapy and cyclo-

phosphamide Additionally the block randomisation method did not achieve prognostic balance between the

2 trial arms

Sevelda 1987 This was a trial of adjuvant radiotherapy versus adjuvant chemo-irradiation in early stage ovarian cancer

Sigurdsson 1982 In this trial Melphalan chemotherapy was compared to observation for mucinous stage Ia and Ib tumours

chemotherapy vs radiotherapy compared for non-mucinous stage Ia and Ib and radiotherapy vs chemo-

radiotherapy were compared in stage Ic-IIc There was a stratified quasi-randomisation which did not achieve

prognostic balance between the various trial arms

Smith 1975 This trial compared Melphalan chemotherapy versus whole abdominal radiotherapy The method of randomi-

sation was unspecified and more patients with stage 1 disease were in the chemotherapy arm

Vergote 1992 This was a methodologically good trial with central computerised randomisation It compared chemotherapy

with intraperitoneal radio-isotope therapy

Young 2000 The comparison was between 3 and 6 cycles of platinum based adjuvant chemotherapy

Young 2003 This was a trial comparing intraperitoneal radio-isotope therapy with cyclophosphamide and cisplatin che-

motherapy after surgery in early stage disease There was no control arm on observation only



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

Comparison 1 Adjuvant chemotherapy vs Observation

Outcome or subgroup titleNo of

studies

No of

participants Statistical method Effect size

1 Overall 5-yr survival 3 1008 Hazard ratio (Random 95 CI) 071 [053 093]

2 Overall 5-yr survival (sub-

grouped by surgical staging)

3 1006 Hazard ratio (Random 95 CI) 072 [053 097]

21 Optimal staging 2 234 Hazard ratio (Random 95 CI) 122 [063 237]

22 Non-optimal staging 2 772 Hazard ratio (Random 95 CI) 063 [046 085]

3 Overall 10-yr survival

(subgrouped by risk)

1 Hazard ratio (Random 95 CI) Totals not selected

31 Lowmedium risk 1 Hazard ratio (Random 95 CI) Not estimable

32 High risk 1 Hazard ratio (Random 95 CI) Not estimable

4 Progression-free 5-yr survival 4 1170 Hazard ratio (Random 95 CI) 067 [053 084]

5 Progession-free 5-yr survival

(sub-grouped by surgical

staging)




6 Progression-free 10-yr survival

(sub-grouped by risk)


61 Lowmedium 1 Hazard ratio (Random 95 CI) Not estimable

62 High 1 Hazard ratio (Random 95 CI) Not estimable

7 Disease-specific survival 1 162 Hazard ratio (Random 95 CI) 094 [037 237]

8 Death from ovarian cancer 3 693 Risk Ratio (M-H Random 95 CI) 076 [052 111]

W H A T rsquo S N E W

Last assessed as up-to-date 2 June 2008

5 June 2008 Amended Converted to new review format



H I S T O R Y

Protocol first published Issue 2 2004

Review first published Issue 1 2009

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

BWR wrote the protocol conducted the literature search identified the studies for inclusion abstracted data and together with co-

authors wrote the final review HK edited and advised with the protocol helped in the selection of studies and data abstraction and

edited earlier versions of the complete review HD contributed to data abstraction and writing the review and performed all statistical

analyses

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

None known

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

After publication of an abstract reporting the effect of adjuvant chemotherapy compared to no adjuvant chemotherapy in sub-groups

of high risk and intermediatelow risk patients in the ICON1 2003 trial we decided to present these sub-group data in the review

As this abstract reported 10-year follow-up of the ICON1 2003 trial we decided to use the 5-year data from this trial in the primary

meta-analysis since this was more consistent with the duration of follow-up of the other included trials but to use the 10-year data in

sensitivity analyses

Many of the planned sub-group and sensitivity analyses were not possible because relevant data were not reported in original papers

and we were unable to obtain these data from authors



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

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

4OBJECTIVES

5METHODS

7RESULTS

Figure 1 14

15DISCUSSION

16AUTHORSrsquo CONCLUSIONS

17ACKNOWLEDGEMENTS

17REFERENCES

19CHARACTERISTICS OF STUDIES

25DATA AND ANALYSES

25WHATrsquoS NEW

25HISTORY

26CONTRIBUTIONS OF AUTHORS

26DECLARATIONS OF INTEREST

26DIFFERENCES BETWEEN PROTOCOL AND REVIEW

iAdjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer (Review)










ical Cancer Group)



DOI 10100214651858CD004706pub2





10100214651858CD004706pub2

A B S T R A C T

Background





Objectives





Search strategy







Selection criteria








Main results











chance












B A C K G R O U N D











































Stage Description







washings



















































































Ia or Ib disease
























chemotherapy











O B J E C T I V E S

Primary objective







status)



M E T H O D S


Types of studies

RCTs



laparotomy



placebo




Primary outcomes


Secondary outcomes









proctitis)

(c) genitourinary



(f ) pulmonary


Electronic searches



























and HK)












thors(BWR HK HD)



Randomisation


coded as




or surname












This was coded as



bull inadequate

bull unclear

Blinding


bull yes

bull no

bull unclear

Loss to follow-up



was not reported














































and reported







was performed

Data synthesis








RRs were pooled













not performed











the review










R E S U L T S



studies












period


tion

Intention to

treat

Prognostic

balance

5 year follow-

up



RT+CT


months


NA

Unspecified No No


RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes


in 605

NA vs RT vs

(RT+CT)


months


IPR

Central

telephone

Yes Median 8

years





(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known



















ical Cancer Group)



DOI 10100214651858CD004706pub2





10100214651858CD004706pub2

A B S T R A C T

Background





Objectives





Search strategy







Selection criteria








Main results











chance












B A C K G R O U N D











































Stage Description







washings



















































































Ia or Ib disease
























chemotherapy











O B J E C T I V E S

Primary objective







status)



M E T H O D S


Types of studies

RCTs



laparotomy



placebo




Primary outcomes


Secondary outcomes









proctitis)

(c) genitourinary



(f ) pulmonary


Electronic searches



























and HK)












thors(BWR HK HD)



Randomisation


coded as




or surname












This was coded as



bull inadequate

bull unclear

Blinding


bull yes

bull no

bull unclear

Loss to follow-up



was not reported














































and reported







was performed

Data synthesis








RRs were pooled













not performed











the review










R E S U L T S



studies












period


tion

Intention to

treat

Prognostic

balance

5 year follow-

up



RT+CT


months


NA

Unspecified No No


RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes


in 605

NA vs RT vs

(RT+CT)


months


IPR

Central

telephone

Yes Median 8

years





(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known













Main results











chance












B A C K G R O U N D











































Stage Description







washings



















































































Ia or Ib disease
























chemotherapy











O B J E C T I V E S

Primary objective







status)



M E T H O D S


Types of studies

RCTs



laparotomy



placebo




Primary outcomes


Secondary outcomes









proctitis)

(c) genitourinary



(f ) pulmonary


Electronic searches



























and HK)












thors(BWR HK HD)



Randomisation


coded as




or surname












This was coded as



bull inadequate

bull unclear

Blinding


bull yes

bull no

bull unclear

Loss to follow-up



was not reported














































and reported







was performed

Data synthesis








RRs were pooled













not performed











the review










R E S U L T S



studies












period


tion

Intention to

treat

Prognostic

balance

5 year follow-

up



RT+CT


months


NA

Unspecified No No


RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes


in 605

NA vs RT vs

(RT+CT)


months


IPR

Central

telephone

Yes Median 8

years





(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known























Stage Description







washings



















































































Ia or Ib disease
























chemotherapy











O B J E C T I V E S

Primary objective







status)



M E T H O D S


Types of studies

RCTs



laparotomy



placebo




Primary outcomes


Secondary outcomes









proctitis)

(c) genitourinary



(f ) pulmonary


Electronic searches



























and HK)












thors(BWR HK HD)



Randomisation


coded as




or surname












This was coded as



bull inadequate

bull unclear

Blinding


bull yes

bull no

bull unclear

Loss to follow-up



was not reported














































and reported







was performed

Data synthesis








RRs were pooled













not performed











the review










R E S U L T S



studies












period


tion

Intention to

treat

Prognostic

balance

5 year follow-

up



RT+CT


months


NA

Unspecified No No


RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes


in 605

NA vs RT vs

(RT+CT)


months


IPR

Central

telephone

Yes Median 8

years





(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known




























































Ia or Ib disease
























chemotherapy











O B J E C T I V E S

Primary objective







status)



M E T H O D S


Types of studies

RCTs



laparotomy



placebo




Primary outcomes


Secondary outcomes









proctitis)

(c) genitourinary



(f ) pulmonary


Electronic searches



























and HK)












thors(BWR HK HD)



Randomisation


coded as




or surname












This was coded as



bull inadequate

bull unclear

Blinding


bull yes

bull no

bull unclear

Loss to follow-up



was not reported














































and reported







was performed

Data synthesis








RRs were pooled













not performed











the review










R E S U L T S



studies












period


tion

Intention to

treat

Prognostic

balance

5 year follow-

up



RT+CT


months


NA

Unspecified No No


RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes


in 605

NA vs RT vs

(RT+CT)


months


IPR

Central

telephone

Yes Median 8

years





(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known











M E T H O D S


Types of studies

RCTs



laparotomy



placebo




Primary outcomes


Secondary outcomes









proctitis)

(c) genitourinary



(f ) pulmonary


Electronic searches



























and HK)












thors(BWR HK HD)



Randomisation


coded as




or surname












This was coded as



bull inadequate

bull unclear

Blinding


bull yes

bull no

bull unclear

Loss to follow-up



was not reported














































and reported







was performed

Data synthesis








RRs were pooled













not performed











the review










R E S U L T S



studies












period


tion

Intention to

treat

Prognostic

balance

5 year follow-

up



RT+CT


months


NA

Unspecified No No


RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes


in 605

NA vs RT vs

(RT+CT)


months


IPR

Central

telephone

Yes Median 8

years





(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known



















This was coded as



bull inadequate

bull unclear

Blinding


bull yes

bull no

bull unclear

Loss to follow-up



was not reported














































and reported







was performed

Data synthesis








RRs were pooled













not performed











the review










R E S U L T S



studies












period


tion

Intention to

treat

Prognostic

balance

5 year follow-

up



RT+CT


months


NA

Unspecified No No


RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes


in 605

NA vs RT vs

(RT+CT)


months


IPR

Central

telephone

Yes Median 8

years





(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known


















not performed











the review










R E S U L T S



studies












period


tion

Intention to

treat

Prognostic

balance

5 year follow-

up



RT+CT


months


NA

Unspecified No No


RT vs CT or

(RT + CT)

Strati-

fied quasi ran-

domised

No Yes


in 605

NA vs RT vs

(RT+CT)


months


IPR

Central

telephone

Yes Median 8

years





(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known













(RT+CT)

Block

randomisation

Yes 4 years


IPR

Central com-

puter stratified

Yes gt6 years


puter stratified

Yes Median 62

months


87


puterised

Yes


IPR

Central

random gener-

ated numbers

Yes Yes


puterised

Yes Median 46

months


explicit

Yes Yes


puterised

Yes Median 51

months


puterised

Yes Median 66

months






ICON1 447FIGO I-III

93 FIGO stage

1

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

OS 79 ( adju-

vant arm) vs70

( no treatment)

Hazard ratios

OS 066

CI 045-097

P=003


ment with adju-

vant therapy





grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known













grade II-IIIFIGO

Ic-IIaFIGO I-IIa

clear cell

Immediate adju-

vant platinum

based chemother-

apy vs treatment

on progression

Cisplatin

dose=75mgm2

Carboplatin dose

=350mgm2

OS 85 (adju-

vant arm)vs 78

(no treatment)

Hazard ratios

OS 069

CI 044-108

P=010

RFS 063

CI 043-092

P=002


sis showed that

non-optimally

staged patients in

observation arm

have significantly

worse survival

Trope 162High risk

Stage I36 pa-

tients had low vol-

ume residual dis-

ease

Carboplatin 6 cyl-

ces Q287

AUC=7vs chemo

at progression

No difference be-

tween arms DFS

70 vs 71 OS

86 vs 85

Log rank test

DFS P=041

OS P=043

Hazard ratiosDFS

098 CI 052-

183DSS 094 CI

037-236

Not reported

Young 9248 treat-

ment44 observa-

tion

Melphalan vs no

further treat

DFS 91

vs 98OS 94

vs98

Log rank test

DFS P=041

OS P=043

Melphalan 16

had severe myelo-

suppres-

sion26 had GI

side effectsOne

death myelopro-

liferative disorder

aplastic anaemia 6

years after com-

pleting treatment

Under powered

trial to show any

real differences


A-I B Grade 2 and

3

Cisplatin

50mgm2 times 6 cy-

cles Q287 vs No

further treatment

DFS 83 vs

64OS 88 vs

82

Hazard ratios

DFS 050

CI 021-119

p=017

OS 120

CI 046-31

p=071

Nausea and vom-

iting in more than

two-thirds of pa-

tients in cisplatin

arm

Severe in less than

10Leucopenia

14Thrombocy-

topenia 8Neu-

rological toxicity

in 6Renal toxic-

ity 7

There were pa-

tients with resid-

ual disease in both

arms


































median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known

























median of 6 years































median of 69 months




by randomisation















optimal





cancer



courses










46 months




minants of DSS





























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known



























up were reported








(066 95 CI 045 to 097 and 065 95 CI 046 to 091









(074 95 CI 053 to 102 and 070 95 CI 052 to 095





























optimal








currence










of 55 years







both OS and RFS




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known




























mal












































censored


























95 CI 058 to 097)































069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known




























069 95 CI 056 to 085)



























8)






Adverse events









(Figure 1)

















data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known

























data to this


















































ologically strong































chemotherapy










and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known

















and ACTION 2003







reviews are

































































































juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known

























juvant chemotherapy







R E F E R E N C E S





















125ndash32




200725(18S)5509

















6













63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known














63

























198271(6)321ndash9





81

















Altman 1995



cer 199572511ndash8

AOCTG 1999



Issue 1 [DOI 10100214651858CD001418]

Bell 2006





102(3)432ndash9

Calvert 1989




13(8)2147ndash8

Deeks 2001






DerSimonian 1986



Elit 2004




Ferlay 2002




Green 2003



Higgins 2003



Hoberg 2001




3)340ndash60

ICON2 1998






ICON3 2002







Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known











Jemal 2008



Lyngstadaas 2005




Mayer 1992




McGuire 1996





Moher 1998




609ndash13

Morice 2001




NCI CTCAE v30 2006




Parkin 2002



tion 2002 [ No 155]

Parmar 1998




Peto 1982



Sant 2003




[ Supplement 5]

Schilder 2002





Schulz 1995




Shepherd 1989



Swart 2007





Trimbos 2003







Trope 2007



25(20)2909ndash20

Vergote 2001




176ndash82

Zanetta 1998




9(10)1097ndash101


Winter-Roach 2003








ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known













ACTION 2003





Outcomes DFS and OS




Risk of bias






C 3224 (1)


Bolis 1995





OS 88 vs 82










Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known


















Risk of bias






T 041 (0)

C 244 (5)



ICON1 2003



93 FIGO stage


Outcomes DFS and OS







Risk of bias









C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known

















C 0236 (0)


Trope 2000



FIGO stage I


Outcomes DFS and OS



Notes

Risk of bias






ment arm





Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known











Young 1990




Outcomes DFS and OS












myelosuppression

Risk of bias






T 548 (10)

C 644 (14)












Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known


















Cisplatin)





2 trial arms


















studies

No of
















staging)
















H I S T O R Y







analyses


None known














studies

No of
















staging)
















H I S T O R Y







analyses


None known











H I S T O R Y







analyses


None known











Cochrane Database of Systematic Reviews (Reviews) || Adjuvant (post-surgery) chemotherapy for early...

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Transcript of Cochrane Database of Systematic Reviews (Reviews) || Adjuvant (post-surgery) chemotherapy for early...