ARTICLES International Collaborative Ovarian Neoplasm Trial1 and Adjuvant ChemoTherapy In Ovarian Neoplasm Trial:Two Parallel Randomized Pha III Trials of Adjuvant Chemotherapy in Patients With Early-Stage Ovarian Carcinoma
International Collaborative Ovarian Neoplasm1(ICON1)and European Organisation for Rearch and Treatment of Cancer Collaborators–Adjuvant ChemoTherapy In Ovarian Neoplasm(EORTC–ACTION)1
Background:Adjuvant chemotherapy has been suggested as a possible strategy to improve survival in women with early-stage ovarian cancer;however,all randomized studies to date have been too small to answer this question reliably. Methods:We performed a preplanned combined analysis of two parallel randomized clinical trials(International Collaborative Ovarian Neoplasm1[ICON1]and Adjuvant ChemoTherapy In Ovarian Neoplasm[ACTION])in early-stage ovarian cancer that compared platinum-bad adju-vant chemotherapy with obrvation following surgery. Between November1990and January2000,925patients (477in ICON1and448in ACTION)who had surgery for early-stage ovarian cancer were randomly assigned to re-ceive platinum-bad adjuvant chemotherapy(n=465)or obrvation(n=460)until chemotherapy was indicated. Kaplan–Meier analysis was ud to compare overall and re-currence-free survival by treatment allocation.In subgro
up analys of pretreatment age,tumor stage,histologic cell type,and differentiation grade,the differences in relative size of effect were tested using a chi-square test for interac-tion or a chi-square test for trend.All tests of statistical significance were two-sided.Results:After a median follow-up of over4years,245patients had died or had a recurrence (ICON1:133,ACTION:112).Overall survival at5years was82%in the chemotherapy arm and74%in the obr-vation arm(difference=8%[95%confidence interval(CI)= 2%to12%];hazard ratio[HR]=0.67,95%CI=0.50to 0.90;P=.008).Recurrence-free survival at5years was also better in the adjuvant chemotherapy arm than it was in the obrvation arm(76%versus65%,difference=11% [95%CI=5%to16%];HR=0.64,95%CI=0.50to0.82; P=.001).Subgroup analys provided no evidence of a dif-ference in the size of effect of chemotherapy on survival in any pretreatment subcategory.Conclusions:Platinum-bad adjuvant chemotherapy improved overall survival and re-currence-free survival at5years in this combined group of patients with early-stage ovarian cancer defined by the in-clusion criteria of the ICON1and ACTION trials.[J Natl Cancer Inst2003;95:105–12]
The treatment for early-stage ovarian cancer is typically sur-gery alone,and in patients with well or moderately differentiated early-stage ovarian cancer confined to the pelvis(International Federation of Gynecology and Obstetrics[FIGO]stage I–IIa), surgical treatment alone may be curative.Overall,however,the
5-year survival rate for patients with early-stage ovarian cancer varies from50%to85%,depending on stage and grade of tumor (1).The disappointing results have t the stage for all kinds of adjuvant treatment,of which chemotherapy is the most popular (2).Whole abdominal radiation with intraperitoneal radioactive chromic phosphate(32P)has also been suggested as a possible adjuvant treatment(1),but there is no agreement about whether
any of the treatments are of real benefit to the patient(3).
Few randomized trials have attempted to investigate the ques-
tion of whether adjuvant treatment is of benefit to patients. Widely discusd randomized trials include an American study
(4)(of obrvation versus melphalan),which included only46 patients with just six events,an Italian study(2)(of obrvation versus cisplatin),which included83patients,and a recent Scan-dinavian study(5)(of obrvation versus carboplatin),which reported on162patients.In the Italian study,adjuvant cisplatin chemotherapy was associated with a statistically significant im-provement in dia-free survival(hazard ratio[HR]for dis-
ea-free survivalס0.35[95%confidence interval(CI)ס0.14
西进运动
to0.89])but not in overall survival(HRס1.15[95%CIס0.44
1Writing Committee:J.Baptist Trimbos,Mahesh Parmar,Ignace Vergote,
David Guthrie,Giorgio Bolis,Nicoletta Colombo,Jan B.Vermorken,Valter
Torri,Costantino Mangioni,Sergio Pecorelli,Andrea Lissoni,Ann Marie Swart. Affiliations of Writing Committee:J.B.Trimbos,Leiden University Medical Center,Leiden,The Netherlands;M.Parmar,D.Guthrie,A.M.Swart,Medical Rearch Council Clinical Trial Unit,London,U.K.;I.Vergote,University Hospital Gasthuisberg,Leuven,Belgium;G.Bolis,Istituto Mangiagalli/Istituto Nazionale per lo Studio e la Cura dei Tumori,Milan,Italy;N.Colombo,Euro-
pean Institute of Oncology,Milan;J.B.Vermorken,University Hospital Ant-werp,Antwerp,Belgium;V.Torri,Istituto Mario Negri,Milan;C.Mangioni,
A.Lissoni,Ospedale San Gerardo,Monza,Italy;S.Pecorelli,Universita di Brescia,Brescia,Italy.
Correspondence to:J.Baptist Trimbos,M.D.,Ph.D.,Department of Gyne-cology,Leiden University Medical Center,POB9600,2300RC,Leiden,The Netherlands(J.B.M.Z.Trimbos@lumc.nl)or Mahesh Parmar,Ph.D.,Medical Rearch Council Clinical Trials Unit Cancer Division,222Euston Rd.,London
NW12DA,U.K.(Mahesh.ac.uk).酱豆的做法
See“Appendix”for the full list of names and affiliations of the ICON1and EORTC–ACTION collaborators.
See“Notes”following“References.”
©Oxford University Press
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to2.98]).In the other two trials,no differences were found between the two trial arms.However,all three trials were small and lacked the statistical power to detect realistic differences.
The question of whether the u of adjuvant chemotherapy would prolong recurrence-free survival and improve overall sur-vival in patients with early-stage epithelial ovarian carcinoma was identified by veral European rearch groups as requiring investigation.The European Organisation of Rearch and Treatment of Cancer–Adjuvant ChemoTherapy In Ovarian Neo-plasm trial(EORTC–A
CTION)and the International Collabo-rative Ovarian Neoplasm(ICON1)trial were t up as parallel, complementary randomized trials designed to compare the effect of using immediate platinum-bad adjuvant chemotherapy with that of deferring adjuvant ,obrvation)until clini-cally indicated in patients with surgically rected early-stage ovarian cancer.The aim was to perform two trials that would each be large enough to answer the relevant questions but that could also be combined in a joint analysis.
S UBJECTS AND M ETHODS
Trial Designs
Although the EORTC–ACTION trial and the ICON1trial had similar designs with regard to randomly assigning patients to either adjuvant chemotherapy or no adjuvant chemotherapy (i.e.,obrvation)and to addressing the same question,there were differences between them.Detailed information on eligi-bility criteria for ICON1and ACTION is available in the com-panion papers(6,7);only brief details are given here.
In the ACTION trial,patients were considered eligible for entry into the trial if they had high-risk early-stage ovarian can-cer,defined as FIGO stage Ia and Ib with grade II or III tumor, all grades of FIGO s
tage Ic–IIa,and all clear-cell carcinomas (8,9).Strict guidelines for comprehensive surgical staging and tumor typing and grading were given in the study protocol.In the protocol,patients in the immediate chemotherapy arm had to receive at least four cours of a platinum-bad , single-agent carboplatin,single-agent cisplatin,combination carboplatin,or combination cisplatin.The preferred do and do modification in ca of morbidity were outlined in the study protocol.The chemotherapy regimen ud was to be de-cided by each individual institution at the beginning of the trial, and patients in the no-adjuvant-chemotherapy arm who had a recurrence were to receive the same regimen as patients in the immediate chemotherapy arm.Recurrence of dia had to be confirmed cytologically or histologically.
In the ICON1trial,by contrast,all patients with histologically confirmed ovarian carcinoma of epithelial origin were eligible for participation in the trial if,in the opinion of the responsible clinician,it was uncertain whether the patients would benefit from immediate adjuvant chemotherapy.Although patients of all stages were potentially eligible,most patients were either stage I or stage II.Guidelines for surgical staging including total hys-terectomy,bilateral salpingo-oophorectomy,and,if the omen-tum was involved,a total supracolonic omentectomy,or,if it was not macroscopically involved,removal of the distal2cm or infracolic omentectomy.Patients in the chemotherapy arm had to receive six cour
s of platinum-bad adjuvant chemotherapy, with the combination of cyclophosphamide+doxorubicin+cis-platin(CAP)or single-agent carboplatin being recommended, although other regimens that included platinum at predefined minimum dos were also allowed.Patients in the control arm
were able to receive chemotherapy at the time of recurrence or
after recurrence.Tumor recurrence was bad on clinical,radio-logic,or histologic diagnosis.
Statistical Analysis
In both studies,the primary endpoint was overall survival and
the condary endpoint was recurrence-free survival.Overall survival was defined as the time from randomization to the date
of death from any cau;patients who were alive at the time of analysis were censored at the time of last follow-up.Recurrence-
free survival was defined as the time from randomization to the
date of the first recurrence or death from any cau;patients who
were alive and without recurrence at the time of analysis were censored at the time of last follow-up.
自我鉴定学生The ACTION and ICON1datats were combined for this analysis.The trials were analyzed on an intention-to-treat basis.
All statistical tests were two-sided.The stratified(by trial)
log-rank test,which adjusted for possible differences between ACTION and ICON1,was ud for comparing overall survival
and recurrence-free survival in the two combined trial arms.
Log-rank statistics were ud to calculate hazard ratios,and the hazard ratios themlves were stratified by trial.Kaplan–Meier curves(10)of overall survival and recurrence-free survival
by treatment allocation were compared.Subgroup analys explored whether the effect of chemotherapy was different in different subgroups defined by pretreatment characteristics in-cluding age,tumor stage,histologic cell type,and cell differen-tiation.The differences in relative size of effect were tested
using a chi-square test(2)for interaction or,when appropriate,
a2test for trend(11).
A systematic review of the literature was undertaken to iden-
tify all randomized trials of the treatment of patients with early-stage ovarian cancer that included a comparison of platinum-bad adjuvant chemotherapy with no adjuvant chemotherapy. Literature arches included MEDLINE®and Cancerlit®,with
a modified version of the optimum strategy developed by the Cochrane Collaboration(12).Abstracts were reviewed to deter-
mine the treatment groups and methods of treatment allocation.
The derived log-rank of obrved minus expected number of events and the variance for individual trials(back-calculated
from the hazard ratios)were combined across all trials with the
fixed effect model to give a pooled hazard ratio.This pooled hazard ratio reprents the overall risk of an event on immediate adjuvant chemotherapy versus that of an event on no immediate adjuvant chemotherapy.The2test for heterogeneity(13)was
ud to test for statistical heterogeneity in all trials and to asss
the consistency of the effect across different subts of trials.
R ESULTS
Between November1990and January2000,448patients
were accrued to the ACTION trial,and between August1991
and January2000,477patients were accrued to the ICON1trial.
A total of925patients from124centers in13countries were randomly assigned to immediate platinum-bad adjuvant che-motherapy(465patients)or to ,no adjuvant chemotherapy)until chemotherapy was indicated(460patients). Table1gives the distribution of the various patient and tumor characteristics among the two trial arms for the total of925 patients;the two trial arms appeared well-balanced.
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With over4years median follow-up for survivors(59months for ACTION and51months for ICON1),a total of245patients have died or experienced recurrence of dia:112in ACTION (25%of the ACTION trial population)and133in ICON1(28% of the ICON1trial population).A total of181patients have died: 78in ACTION(17%)and103in ICON1(22%).Kaplan–Meier curves for overall survival and recurrence-free survival in the combined trial population are shown in Figs.1and2,respec-tively.For overall survival,HRס0.67(95%CIס0.50to0.90, Pס.008)in favor of adjuvant chemotherapy.The results translate into5-year overall survival figures of74%for women in the no-adjuvant-chemotherapy arm and82%for women in the adjuvant chemotherapy arm,a difference of8%(95%CIס2% to12%).For recurrence-free survival,HRס0.64(95%CIס0.50to0.82,Pס.001)in favor of adjuvant chemotherapy.The results translate into5-year recurrence-free survival fig-
ures of65%for women in the no-adjuvant-chemotherapy arm
and76%for women in the adjuvant chemotherapy arm,a dif-
ference of11%(95%CIס5%to16%).
Subgroup analys of the combined ICON1and ACTION
data within the subcategories of age,tumor stage,histologic cell
type,and cell differentiation(Fig.3)provide no evidence that
the effect of adjuvant chemotherapy was different within any of
the subgroups.A parate subgroup analysis of staging com-
pleteness was not done becau information about surgical stag-
ing was not collected in the ICON1trial(6).
The results of both trials individually are similar to one an-
other(6,7).There is an early and sustained paration of the
Kaplan–Meier curves for both overall survival and recurrence-
free survival in both trials,with evidence of a benefit from
adjuvant chemotherapy.The hazard ratios for overall survival
are also similar:0.66(95%CIס0.45to0.97)and0.69(95%CI ס0.44to1.08)for ICON1and ACTION,respectively,as are the hazard ratios for recurrence-free survival,0.65(95%CIס
0.46to0.91)and0.63(95%CIס0.44to0.92)for ICON1and
ACTION,respectively.
In a systematic review of the literature,we identified eight
randomized trials of early-stage ovarian cancer that include a
comparison of adjuvant chemotherapy with no further treatment.
Four of the trials ud melphalan or other nonplatinum-bad
chemotherapy as adjuvant chemotherapy(4,14–16),and they
are,therefore,of limited relevance to current clinical practice.
Four other,more recent studies(including ACTION and
施展
ICON1)ud platinum-bad adjuvant chemotherapy(2,5–7);
the results of the trials are summarized in Table2.With data
from the four trials combined,of which the ACTION and
ICON1trials provide84%of deaths and80%of the recurrences
and/or deaths,the hazard ratio for overall survival among pa-
tients in the adjuvant chemotherapy arms compared with that
among patients in the no-adjuvant-chemotherapy arms is0.72
(95%CIס0.55to0.94,Pס.017),and the hazard ratio for
recurrence-free survival is0.66(95%CIס0.53to0.83,
P<.001),with no evidence of heterogeneity between the trials
(Fig.4).
D ISCUSSION
The findings indicate that platinum-bad adjuvant chemo-
therapy improves overall survival and recurrence-free survival
in the spectrum of patients studied in the ICON1and EORTC–
ACTION trials.There were different eligibility criteria in the
two trials,with a more precily defined patient population in the ACTION trial than in the ICON1trial.The ICON1trial did not collect data on surgical staging details;thus,the results from that trial cannot contribute to the discussion on staging.
The main strength of this combined analysis is the number of patients included and the consistency of the results across the two trials.Subgroup analysis revealed no differences between the various subgroups with regard to the beneficial treatment effect of chemotherapy;however,a conclusion on this point is hampered by the small number of patients in each subgroup.The results of this analysis provide evidence that platinum-bad adjuvant chemotherapy can improve the survival of women with early-stage ovarian cancer as defined in the ACTION and ICON1trials.The better toxicity profile
of single-agent carbo-
Table1.Patient characteristics in the combined European Organisation for Rearch and Treatment of Cancer–Adjuvant ChemoTherapy In Ovarian Neoplasm(EORTC–ACTION)/International Collaborative Ovarian
Neoplasm1(ICON1)trials*
Adjuvant chemotherapy (Nס465)
No adjuvant chemotherapy (Nס460)
Age(y),n(%)†
<55233(50)233(51) 55–65126(27)147(32) >65105(23)80(17) Missing10 Median age,y5555 Tumor stage‡,n(%)†
I9(2)4(<1) Ia168(36)173(38) Ib46(10)43(9) Ic208(45)205(45) II31(7)29(6) III2(<1)4(1) Missing12 Histologic cell type,n(%)†
Serous161(36)139(31) Mucinous90(20)90(20) Endometrioid94(21)129(29) Clear-cell68(15)62(13) Undifferentiated9(2)7(2) Other/mixed23(5)19(4) Missing2014 Tumor grade,n(%)†
I97(22)100(23) II210(47)203(46) III139(32)141(32) Missing1916 Adjuvant chemotherapy regimen,n(%)†
Single–agent carboplatin242(57)
Combination cisplatin115(27)
Allocated treatment not received25(6)
Combination carboplatin23(6)
Single–agent cisplatin12(3)
CAP8(2)
Missing40
*A total of925patients were enrolled in the combined trials of EORTC–ACTION and ICON1.Missingסi
nformation on patient was missing.CAPסcyclophosphamide+doxorubicin+cisplatin.Percentages may not add up to 100%becau of rounding.
†Percentages were calculated excluding missing values from denominator.‡Two patients who were randomly assigned as stage Ia and II,respectively, were found to have been stage III,and one patient randomly assigned as stage III was found to have been stage IV.Staging and grading were in accordance with International Federation of Gynecology and Obstetrics(FIGO)and World Health Organization(WHO)guidelines(8,9). at Chine Academy of Medical Sciences on July 26, fordjournals Downloaded from
platin alone suggests that it may be the treatment of choice for early-stage ovarian cancer.Other regimens,including taxanes,have not been studied in this patient population;therefore,ex-trapolation to different chemotherapy regimens from trials of later dia may not be appropriate (22–25).However,clinical trials,especially in rarer dias such as early-stage ovarian cancer,cannot provide answers to all of the questions regarding the optimal chemotherapy treatment for in-dividual patients.Some clinicians may interpret the results of the trials as a basis for considering the routine offering
of Fig.1.Kaplan–Meier curves for over-
all survival in patients with early-
stage ovarian carcinoma.Adjuvant
chemotherapy patients (n ס465)
(solid line )were tho patients who
received immediate adjuvant chemo-
therapy.No-adjuvant-chemotherapy
patients (n ס460)(dotted line )were
tho patients who were obrved
until adjuvant chemotherapy was in-
dicated.The hazard ratio is 0.67
(95%CI ס0.50to 0.90,P ס.008
using the log-rank test)in favor of
adjuvant chemotherapy.Five-year
survival figures were 74%for women
in the no-adjuvant-chemotherapy
group and 82%for women in the ad-
juvant chemotherapy group,a differ-
ence of 8%(95%CI ס2%to
12%).
Fig.2.Kaplan–Meier curves for re-
currence-free survival in patients
with early-stage ovarian carcinoma.
Adjuvant chemotherapy patients
(n ס465)(solid line )were tho pa-
tients who received immediate adju-
vant chemotherapy.No-adjuvant-
chemotherapy patients (n ס460)
(dotted line )were tho patients who
were obrved until adjuvant chemo-
therapy was indicated.The hazard ra-
tio is 0.64(95%CI ס0.50to 0.82,
P ס.001using the log-rank test)in
favor of adjuvant chemotherapy.
Five-year survival figures were 65%
for women in the no-adjuvant-
chemotherapy group and 76%for
women in the adjuvant chemotherapy
group,a difference of 11%(95%CI
ס5%to 16%).
at Chine Academy of Medical Sciences on July 26, 2011
platinum-bad adjuvant chemotherapy to a majority of patients
with early-stage ovarian cancer.Others might highlight the fact that,of the 925patients,only one-sixth were known to be op-timally staged—that is,there was evidence that all of the dia
was surgically removed.In the optimally staged patients,the clinician may consider the argument for using adjuvant chemo-therapy as not strong (7,17).It has been shown that incompletely staged early-stage ovarian carcinoma harbors occult stage III dia in approximately one-fifth to one-fourth of patients (18–21).This unappreciated residual dia could be postulated as an explanation for the beneficial effect of adjuvant chemo-therapy.Whichever point of view is taken,the trials show that adjuvant chemotherapy can have a distinct role in the treatment of women with early-stage ovarian cancer.A PPENDIX
ICON1Trial Collaborators and Affiliations
U.K.:Addenbrooke’s Hospital,Cambridge:H.M.Earl,N.M.Bleehen,R.J.Osborne;Belfast City Hospital,Belfast:R.J.Atkinson;Birmingham &Midland Hospital for Women,Birmingham:K.K.Chan;Cha
ring Cross Hospital,London:G.Rustin;Cheltenham General Hospital,Cheltenham:R.Coun-
ll,J.R.Owen;Churchill Hospital,Oxford:N.P.Rowell,C.J.Alcock,T.Ganesan;Birmingham City Hospital,Birmingham:D.M.Luesley;Clatterbridge Hospital,Wirral:J.A.Green;Der-byshire Royal Infirmary,Derbyshire:D.Guthrie;Dudley Road Hospital,Birmingham:G.R.Blackledge,R.Callender,D.
M.interaction or trend between
the subgroups age,tumor
stage,histologic cell type,and
cell differentiation versus treat-
ment effect (adjuvant chemo-
therapy better versus no-
adjuvant-chemotherapy better)
for overall survival.For each
datat,the hazard ratio (HR)arp病毒
for overall survival is plotted
as a solid square,and the
area of the square is propor-
tional to the variance of the
estimated effect.The length
of the horizontal line through
the square indicates the 99%
confidence interval (CI),and
the inner tick marks indicate
the 95%CI.The arrow at the
end of the horizontal line in-
dicates that the CI is larger
than the scale of the figure.
猪肉炒什么菜好吃
The differences in relative
size of effect were tested us-
ing a chi-square test (2)for
interaction,or when appropri-
ate,a 2test for trend.
Table 2.Meta-analysis of four randomized trials comparing no adjuvant chemotherapy with platinum-bad adjuvant chemotherapy in early ovarian cancer*
Trial Entry criteria Intervention Median follow-up,mo Survival No.of events/No.of patients†
HR (95%CI)P value‡Adjuvant chemotherapy No adjuvant
chemotherapy Bolis et al.(2)FIGO stage Ia and Ib,grade 2or 3Cisplatin 71RF 7/4114/420.48(0.24to 1.14).095
O 9/418/42 1.15(0.44to 2.98).773
Trope et al.(5)FIGO stage I,non-clear-cell aneuploid grade 1;FIGO stage I,non-clear-cell,grade 2or 3;
FIGO stage I,clear-cell
开业活动策划方案Carboplatin 46RF 20/8119/810.98(0.52to 1.83).9
O 9/819/810.94(0.37to 2.36).9
Trimbos et al.,ACTION (7)FIGO stage Ia,Ib,grade 2or 3;FIGO stage Ic,IIa,all grades;
clear-cell Platinum 59RF 46/22466/2240.63(0.43to 0.92).02O 33/2245/2240.69(0.44to 1.08).104
ICON1Collaborators,ICON1(6)FIGO stage I and II;clinician uncertain if patient would benefit from treatment
Platinum 51RF 55/24178/2360.65(0.46to 0.91).01O 42/24161/2360.66(0.45to 0.97).03*RF סrecurrence free;O סoverall;FIGO סInternational Federation of Gynecology and Obstetrics (9);HR סhazard ratio;CI סconfidence interval.†No.of events סnumber of deaths plus the number of patients with dia recurrence.No.of patients סnumber of patients entered into the trial.‡P values were calculated using the log-rank test.
at Chine Academy of Medical Sciences on July 26, 2011
Luesley,H.M.Earl,C.J.Poole;George Eliot Hospital,Nunea-ton:V.G.Kenyon;Guy’s Hospital,London:P.G.Harper;Ham-mersmith Hospital,London:H.Thomas;Jery General Hospi-tal,St.Helier:S.Hima;Kent &Canterbury Hospital,Canterbury:R.S.Coltart;Leeds General Infirmary,Leeds:K.R.Peel;Manor Hospital,Walsall:A.D.Chetiyawardana;Mid-dlex Hospital,London:J.A.Ledermann,R.L.Souhami;Mount Vernon Hospital,London:D.C.Fermont,G.Rustin;North Staffordshire Royal Infirmary,Stoke on Trent:C.W.E.Redman,J.E.Scoble;Northern General Hospital,Sheffield:M.E.L.Paterson;Poole General Hospital,Poole:R.J.Osborne;Queen Elizabeth Hospital,Birmingham:A.D.Chetiyawardana,I.N.Fernando,J.J.Mould,C.J.Poole;Royal Devon &Exeter Hospital,Exeter:A.Hong;Royal South Hants Hospital,South-ampton:V.Hall,C.J.Williams,T.J.Iveson;Royal Susx County Hospital,Brighton:D.S.Murrell,G.Newman;Royal United Hospital,Bath:E.Gilby;Solihull Hospital,Solihull:C.J.F.Rowbotham,D.W.Sturdee;South Cleveland Hospital,Middlesborough:D.J.Cruickshank;Southampton General Hos-pital,Southampton:C.J.William
s;Southend General Hospital,Southend:A.Lamont,C.W.L.Trask;St.George’s Hospital,Lincoln:E.C.Murray;Stobhill Hospital,Glasgow:J.A.Davis;Stoke City General Hospital,Stoke on Trent:A.W.Clubb;Tameside General Hospital,Ashton-under-Lyne:J.K.Roberts;Walsgrave Hospital,Coventry:C.J.R.Irwin,D.A.Jones,A.D.Stockdale;Western General Hospital,Edinburgh:J.F.Smyth;Weston Park Hospital,Sheffield:R.E.Coleman,M.J.Whipp;Whittington Hospital,London:J.A.Ledermann.Italy:Casa di Cura Malzoni,Avellino:C.Malzoni;Ospedale degli Infermi,Biella:V.Vavalà;Ospedale Caduti Bollatesi,Bollate,Milan:E.Piatto;Policlinico S.Orsola-Malpighi,Bologna:A.Martoni;Ospedale SS.Trinità,Borgomanero,Novara:P.G.Fornara;UnitàSanitaria Locale Brindisi/1,Brindisi:M.C.Chetrì;Os-pedale Civile Sirai,Carbonia,Cagliari:G.Chessa;Ospedale Ramazzini,Carpi,Modena:F.Artioli;Ospedale S.Bambino,Catania:S.Cavallaro Nigro;Ospedale Generale Valduce,Como:C.Belloni;Ospedale Civile,Conegliano,Veneto,Tre-viso:E.Candiotto;Ospedale di Circolo,Desio,Milan:G.Or-fanotti;Azienda Ospedaliera Universitàdi Ferrara,Ferrara:A.Bianchi;Ospedale S.Cuore di Gesù,Gallipoli,Lecce:G.Mele;Ospedale Civile,Genova Sampierdarena:G.Marrè,Brunenghi;Ospedale Civile Miricordia,Grosto:R.Algeri;Ospedale Generale S.Salvatore,L’Aquila:M.Moscarini;Os-pedale Civile Renzetti,Lanciano,Chieti:G.Belfiore;Ospedale S.Maria Goretti,Latina:M.D’Aprile;Ospedale Alessandro
Manzoni,Lecco:N.Natale;Ospedale Maggiore,Lodi,Milan:M.Luerti;Ospedale Mandic/UnitàSocio Sanitaria Locale 14,Merate,Como:A.Vecchione;Clinica Mangiagalli-Universitàdegli studi di Milano,Milan:R.Maggi;Istituto Europeo di Oncologia,Milan:L.Bocciolone;Ospedale San Gerardo dei Tintori,Monza,Milan:C.Bonazzi,A.A.Lissoni,S.M.Rota;Azienda Ospedaliera San Luigi,Orbassano,Torino:L.Dogliotti;Ospedale Buccheri La Ferla Fatebenefratelli,Palermo:G.Vegna;Ospedale V.Cervello,Palermo:D.Gueli Alletti;Policlinico S.Pietro,Ponte S.Pietro,Bergamo:A.Epis;Osped-ale Generale S.Camillo,Rieti:V.Scotto di Palumbo;
Universitàanalysis of four randomized
trials (2,5–7)comparing no
adjuvant chemotherapy with
adjuvant chemotherapy in
early-stage ovarian cancer for
overall survival (A )and re-
currence free survival (B ).
The position of each square
indicates the hazard ratio,and
the area of the square is pro-
portional to the variance of
珍惜图片the estimated effect.The
length of the horizontal line
through the square indicates
the 99%confidence interval
(CI),and the inner tick marks
indicate the 95%CI.The ar-
row at the end of the horizon-
tal line indicates that the 99%
CI is larger than the scale of
the figure.The diamond in-
dicates the hazard ratio
(middle of the diamond)and
the 95%CI (extremes of the
diamond)for the combined
data from the four random-
ized trials.Linear trends and
heterogeneity of the hazard
ratios were assd by a chi-
square test for trend (2)and
a 2for heterogeneity (Het
2),respectively.Degrees of
freedom for each 2test are
given in parenthes.The hazard ratio for overall survival is 0.722(95%CI ס0.552to 0.942),2(1)ס5.740,P ס.017;Het 2(1)ס1.474,P ס.688,and for recurrence-free survival is 0.664(95%CI ס0.530to 0.831),2
(1)ס12.756,P <.001,Het 2
(1)ס2.101,P ס.552,both in favor of adjuvant chemotherapy.O–E
סnumber of events obrved minus number of events expected under the null hypothesis.Variance סvariance of 1/logarithm of the hazard ratio. at Chine Academy of Medical Sciences on July 26, fordjournals Downloaded from
