International Collaborative Ovarian Neoplasm 1 (ICON1), European Organisation for Research and Treatment of Cancer CollaboratorsAdjuvant ChemoTherapy In Ovarian Neoplasm (EORTCACTION)1
Affiliations of Writing Committee: J. B. Trimbos, Leiden University Medical Center, Leiden, The Netherlands; M. Parmar, D. Guthrie, A. M. Swart, Medical Research 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, European Institute of Oncology, Milan; J. B. Vermorken, University Hospital Antwerp, 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 Gynecology, Leiden University Medical Center, POB 9600, 2300 RC, Leiden, The Netherlands (J.B.M.Z.Trimbos{at}lumc.nl) or Mahesh Parmar, Ph.D., Medical Research Council Clinical Trials Unit Cancer Division, 222 Euston Rd., London NW1 2DA, U.K. (Mahesh.Parmar{at}ctu.mrc.ac.uk).
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ABSTRACT |
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INTRODUCTION |
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Few randomized trials have attempted to investigate the question of whether adjuvant treatment is of benefit to patients. Widely discussed randomized trials include an American study (4) (of observation versus melphalan), which included only 46 patients with just six events, an Italian study (2) (of observation versus cisplatin), which included 83 patients, and a recent Scandinavian study (5) (of observation versus carboplatin), which reported on 162 patients. In the Italian study, adjuvant cisplatin chemotherapy was associated with a statistically significant improvement in disease-free survival (hazard ratio [HR] for disease-free survival = 0.35 [95% confidence interval (CI) = 0.14 to 0.89]) but not in overall survival (HR = 1.15 [95% CI = 0.44 to 2.98]). 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 use of adjuvant chemotherapy would prolong recurrence-free survival and improve overall survival in patients with early-stage epithelial ovarian carcinoma was identified by several European research groups as requiring investigation. The European Organisation of Research and Treatment of CancerAdjuvant ChemoTherapy In Ovarian Neoplasm trial (EORTCACTION) and the International Collaborative Ovarian Neoplasm (ICON1) trial were set up as parallel, complementary randomized trials designed to compare the effect of using immediate platinum-based adjuvant chemotherapy with that of deferring adjuvant treatment (i.e., observation) until clinically indicated in patients with surgically resected 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.
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SUBJECTS AND METHODS |
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Although the EORTCACTION trial and the ICON1 trial had similar designs with regard to randomly assigning patients to either adjuvant chemotherapy or no adjuvant chemotherapy (i.e., observation) and to addressing the same question, there were differences between them. Detailed information on eligibility criteria for ICON1 and ACTION is available in the companion 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 cancer, defined as FIGO stage Ia and Ib with grade II or III tumor, all grades of FIGO stage IcIIa, 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 courses of a platinum-based regimen, i.e., single-agent carboplatin, single-agent cisplatin, combination carboplatin, or combination cisplatin. The preferred dose and dose modification in case of morbidity were outlined in the study protocol. The chemotherapy regimen used was to be decided 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 disease had to be confirmed cytologically or histologically.
In the ICON1 trial, 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 hysterectomy, bilateral salpingo-oophorectomy, and, if the omentum was involved, a total supracolonic omentectomy, or, if it was not macroscopically involved, removal of the distal 2 cm or infracolic omentectomy. Patients in the chemotherapy arm had to receive six courses of platinum-based adjuvant chemotherapy, with the combination of cyclophosphamide + doxorubicin + cisplatin (CAP) or single-agent carboplatin being recommended, although other regimens that included platinum at predefined minimum doses were also allowed. Patients in the control arm were able to receive chemotherapy at the time of recurrence or after recurrence. Tumor recurrence was based on clinical, radiologic, or histologic diagnosis.
Statistical Analysis
In both studies, the primary endpoint was overall survival and the secondary endpoint was recurrence-free survival. Overall survival was defined as the time from randomization to the date of death from any cause; 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 cause; patients who were alive and without recurrence at the time of analysis were censored at the time of last follow-up.
The ACTION and ICON1 datasets 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 used for comparing overall survival and recurrence-free survival in the two combined trial arms. Log-rank statistics were used to calculate hazard ratios, and the hazard ratios themselves were stratified by trial. KaplanMeier curves (10) of overall survival and recurrence-free survival by treatment allocation were compared. Subgroup analyses explored whether the effect of chemotherapy was different in different subgroups defined by pretreatment characteristics including age, tumor stage, histologic cell type, and cell differentiation. The differences in relative size of effect were tested using a chi-square test (2) for interaction or, when appropriate, a
2 test for trend (11).
A systematic review of the literature was undertaken to identify all randomized trials of the treatment of patients with early-stage ovarian cancer that included a comparison of platinum-based adjuvant chemotherapy with no adjuvant chemotherapy. Literature searches included MEDLINETM and CancerlitTM, with a modified version of the optimum strategy developed by the Cochrane Collaboration (12). Abstracts were reviewed to determine the treatment groups and methods of treatment allocation. The derived log-rank of observed 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 represents the overall risk of an event on immediate adjuvant chemotherapy versus that of an event on no immediate adjuvant chemotherapy. The 2 test for heterogeneity (13) was used to test for statistical heterogeneity in all trials and to assess the consistency of the effect across different subsets of trials.
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RESULTS |
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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 these trials used melphalan or other nonplatinum-based chemotherapy as adjuvant chemotherapy (4, 1416), and they are, therefore, of limited relevance to current clinical practice. Four other, more recent studies (including ACTION and ICON1) used platinum-based adjuvant chemotherapy (2, 57); the results of these trials are summarized in Table 2. With data from the four trials combined, of which the ACTION and ICON1 trials provide 84% of deaths and 80% of the recurrences and/or deaths, the hazard ratio for overall survival among patients in the adjuvant chemotherapy arms compared with that among patients in the no-adjuvant-chemotherapy arms is 0.72 (95% CI = 0.55 to 0.94, P = .017), and the hazard ratio for recurrence-free survival is 0.66 (95% CI = 0.53 to 0.83, P<.001), with no evidence of heterogeneity between the trials (Fig. 4
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DISCUSSION |
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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-based adjuvant chemotherapy can improve the survival of women with early-stage ovarian cancer as defined in the ACTION and ICON1 trials. The better toxicity profile of single-agent carboplatin 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, extrapolation to different chemotherapy regimens from trials of later disease may not be appropriate (2225).
However, clinical trials, especially in rarer diseases such as early-stage ovarian cancer, cannot provide answers to all of the questions regarding the optimal chemotherapy treatment for individual patients. Some clinicians may interpret the results of these trials as a basis for considering the routine offering of platinum-based adjuvant chemotherapy to a majority of patients with early-stage ovarian cancer. Others might highlight the fact that, of the 925 patients, only one-sixth were known to be optimally stagedthat is, there was evidence that all of the disease was surgically removed. In these optimally staged patients, the clinician may consider the argument for using adjuvant chemotherapy as not strong (7, 17). It has been shown that incompletely staged early-stage ovarian carcinoma harbors occult stage III disease in approximately one-fifth to one-fourth of patients (1821). This unappreciated residual disease could be postulated as an explanation for the beneficial effect of adjuvant chemotherapy. Whichever point of view is taken, these trials show that adjuvant chemotherapy can have a distinct role in the treatment of women with early-stage ovarian cancer.
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APPENDIX |
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U.K.: Addenbrookes 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; Charing Cross Hospital, London: G. Rustin; Cheltenham General Hospital, Cheltenham: R. Counsell, 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; Derbyshire Royal Infirmary, Derbyshire: D. Guthrie; Dudley Road Hospital, Birmingham: G. R. Blackledge, R. Callender, D. M. Luesley, H. M. Earl, C. J. Poole; George Eliot Hospital, Nuneaton: V. G. Kenyon; Guys Hospital, London: P. G. Harper; Hammersmith Hospital, London: H. Thomas; Jersey General Hospital, St. Helier: S. Hima; Kent & Canterbury Hospital, Canterbury: R. S. Coltart; Leeds General Infirmary, Leeds: K. R. Peel; Manor Hospital, Walsall: A. D. Chetiyawardana; Middlesex 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, Southampton: V. Hall, C. J. Williams, T. J. Iveson; Royal Sussex 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 Hospital, Southampton: C. J. Williams; Southend General Hospital, Southend: A. Lamont, C. W. L. Trask; St. Georges 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; Unità Sanitaria Locale Brindisi/1, Brindisi: M. C. Chetrì; Ospedale 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, Treviso: E. Candiotto; Ospedale di Circolo, Desio, Milan: G. Orfanotti; Azienda Ospedaliera Università di Ferrara, Ferrara: A. Bianchi; Ospedale S. Cuore di Gesù, Gallipoli, Lecce: G. Mele; Ospedale Civile, Genova Sampierdarena: G. Marré, Brunenghi; Ospedale Civile Misericordia, Grosseto: R. Algeri; Ospedale Generale S. Salvatore, LAquila: M. Moscarini; Ospedale Civile Renzetti, Lanciano, Chieti: G. Belfiore; Ospedale S. Maria Goretti, Latina: M. DAprile; Ospedale Alessandro Manzoni, Lecco: N. Natale; Ospedale Maggiore, Lodi, Milan: M. Luerti; Ospedale Mandic/Unità Socio Sanitaria Locale 14, Merate, Como: A. Vecchione; Clinica Mangiagalli-Università degli 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; Ospedale Generale S. Camillo, Rieti: V. Scotto di Palumbo; Università La Sapienza, Rome: L. Marzetti; Ospedale Civile, Rovereto, Trento: G. Gorga; Ospedale S. Leonardo, Salerno: S. Cariello; Ospedale Civile Agnelli, Savigliano, Cuneo: L. Galletto; Ospedale Civile, Sesto San Giovanni, Milan: A. Raina; Ospedale Unità Sanitaria Locale Roma 26, Tivoli, Rome: F. Corrado; Ospedale S. Anna-Div A, Torino: E. Guercio; Ospedale S. Anna-Div B, Torino: R. Jura; Ospedale S. Giovanni Azienda Sanitaria, Torino: C. Bumma; Università Dipartimento Discipline Ginecologiche-Ostetriche, Torino: M. Massobrio; Ospedale Civile Consortile, Treviglio, Bergamo: R. Grassi; Ospedale di Circolo, Varese: M. Grampa; Azienda Ospedaliera, Verona: G. Cetto; Ospedale Civile S. Bortolo, Vicenza; V. Fosser. Republic of Ireland: South Infirmary-Victoria Hospital, Cork: A. Curtain. Brazil: Fêmina S.A., Porto Alegre: E. Palmeiro. Switzerland: Kantonsspital, Basel: A. Dieterle; Inselspital Onkologie, Bern: T. Hardegger; Centre Hospitalier Universitaire Vaudois, Lausanne: J. F. Delaloye; Ospedale Civico, Lugano: M. Rabaglio, C. Sessa; Ospedale Beata Vergine, Mendrisio: A. Goldhirsch, M. P. Saletti; Ospedale San Giovanni, Bellinzona: M. Wörtelboer; Frauenfeld, St. Gallen: C. Furrer; Hopital Cantonal Universitaire, Geneva: A. Hügli, H. Bonnefoi; Kantonsspital, St. Gallen: B. Thürlimann. Data Management: ICON office Mario Negri Institute, Italy: Monica Flann, Alessandro Buda, Irene Floriani, Angelo Tinazzi. Medical Research Council (MRC) Clinical Trials Unit, U.K.: Nicholas Chadwick, Josie Sandercock, Ben Tham, Sarah Wheeler. Statistical analysis: ICON office in Italy: Angelo Tinazzi, Valter Torri. MRC in the U.K.: Wendi Qian, Mahesh Parmar.
EORTCACTION Trial Collaborators and Affiliations
Institut dOncologica Corachan, Barcelona, Spain: C. Madronal; Centro di Referimento Oncologico, Italy: S. Tumolo; Velindre Hospital, U.K.: M. Adams; Ziekenhuis de Heel, The Netherlands: A. v. Bochove; Daniel den Hoedkliniek, The Netherlands: M. E. L. van der Burg; Hospital Clinico Universitario de Valencia, Spain: A. Cervantes; Centre Henri Becquerce, France: B. Chevalier; Instituto Europeo di Oncologia, Italy: N. Colombo; Kaiser Franz Josef Spital, Austria: C. Dittrich; Eemland Ziekenhuis, The Netherlands: J. Duk; Medical University of Gdansk, Poland: J. Emerich; Universita di Brescia, Italy: C. Favalli; Clinica Universita Torino, Italy: A. Ferrero; Ospedale di Circulo e Fondazione Macchi, Varese, Italy: M. Franchi; Policlinico A. Gemelli-Università del Sacro Cuore, Italy: S. Greggi; Centre Leon Berard, France: J. P. Guastalla; Hospital General de Asturias, Spain: A. J. Lacave; Rigshospitalet, Denmark: B. Lund; Università di Padova, Italy: T. Maggino; Istituto Scientifico H. S. Raffaele, Italy: G. Mangili; Azienda Ospedaliera di Parma, Italy: M. Melpignano; Centre Antoine Lacassagne, France: M. Namer; Instituto Regina Elena, Italy: M. Nardi; Instituto Portugues de OncologiaCentro de Coimbra, Portugal: C. F. de Oliviera; Instituto di Science Biomediche San Paolo, Italy: U. Radaelli; Ospedale Civile, Italy: C. Scarabelli; Instituto Mangiagalli, Milan, Italy: G. Scarfone; University Medical Centre Nijmegen, The Netherlands: Ch. Schijf; Ospedale Generale di Zona san Carlo di Nancy, Italy: Scotto di Palumbo; Atrium Medisch Centrum, The Netherlands: J. E. G. M. Stoot; Stichting Streekziekenhuis Midden-Twente, The Netherlands: R. van der Sijde; Policlinico San Matteo, Pavia, Italy: S. Tateo; Leiden University Medical Center, The Netherlands: P. Timmers; Academisch Medisch Centrum, The Netherlands: C. Veenhof; Ospedale San Gerardo, Monza, Italy: G. Zanetta; Academisch Ziekenhuis Groningen, The Netherlands: A. van der Zee; Academic Medical Center, Amsterdam, The Netherlands: A. H. Zwinderman. Medical Supervisor: Ivana Teodorovic, EORTC Data Center, Brussels, Belgium. Data Management: Livia Giurgea, EORTC Data Center, Brussels. Statistical Supervision: Corneel Coens, Richard Sylvester, EORTC Data Center, Brussels. Data Monitoring Committee: J. Pater (chair), M. Buyse, G. Omura.
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NOTES |
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Supported in Italy by Fondazione Nerina e Mario Mattioli, in the U.K. by the U.K. Medical Research Council, and in Switzerland by the Swiss Group for Clinical Cancer Research.
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Manuscript received April 17, 2002; revised November 7, 2002; accepted November 14, 2002.
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