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Addition of Epirubicin As a Third Drug to Carboplatin-Paclitaxel in First-Line Treatment of Advanced Ovarian Cancer: A Prospectively Randomized Gynecologic Cancer Intergroup Trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens

From the Department of Gynecology & Gynecologic Oncology, HSK Dr Horst Schmidt Klinik Wiesbaden; Department of Gynecology, St Vincentius Khs Karlsruhe; KKS Marburg, Coordination Center for Clinical Trials, Department of Gynecology and Obstetrics, Evangelisches Krankenhaus, Duesseldorf; Department of Gynecology and Obstetrics, Medizinische Akademie, Magdeburg; Department of Gynecology and Obstetrics, University Muenchen rechts der Isar; Department of Gynecology, University Hospital, Tuebingen; Department of Gynecology and Obstetrics, University of Dresden, Dresden; Department of Gynecologic Oncology, Medizinische Hochschule, Hannover; Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein Campus Kiel; Department of Gynecology and Obstetrics, University of Frankfurt, Frankfurt; Department of Gynecology and Obstetrics, Rheinisch-Westfaelische Technische Hochschule, Aachen; Department of Gynecology and Obstetrics, University Muenchen-Großhadern, Germany; Department of Oncology, Centre Alexis-Vautrin, Vandoeuvre-les-Nancy; Department of Oncology, Centre René Huguenin, Saint-Cloud; Department of Oncology-Hematology, Hôpitaux Civils, Colmar; Department of Oncology-Hematology, Hôpital Fleyriat, Bourg-en Bresse; and Department of Oncology, Hôpital Hôtel-Dieu, Paris, France.

Address reprint requests to Andreas du Bois, MD, HSK Dr Horst Schmidt Klinik, Department of Gynecology & Gynecologic Oncology, Ludwig-Erhard-Str 100, D-65199 Wiesbaden, Germany; e-mail: dubois.hsk-wiesbaden{at}uumail.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Despite the progress that has been achieved, long-term survival rates in patients with advanced ovarian cancer are still disappointing. One attempt to improve results could be the addition of non–cross-resistant drugs to platinum-paclitaxel combination regimens. Anthracyclines were among the candidates for incorporation as a third drug into first-line regimens.

PATIENTS AND METHODS: We performed a prospectively randomized phase III study comparing carboplatin-paclitaxel (TC; area under the curve 5/175 mg/m², respectively) with epirubicin 60 mg/m² added to the same combination (TEC) in previously untreated patients with advanced epithelial ovarian cancer. All drugs were administered intravenously on day 1 of a 3-week schedule for a planned minimum of six courses.

RESULTS: Between November 1997 and February 2000, 1,282 patients were randomly assigned to receive either TC (635 patients) or TEC (647 patients), respectively. Grade 3/4 hematologic and some nonhematologic toxicities (nausea/emesis, mucositis, and infections) occurred significantly more frequently in the TEC arm. Accordingly, quality-of-life analysis showed inferiority of TEC versus TC. Median progression-free survival time was 18.4 months for the TEC arm and 17.9 months for the TC arm (hazard ratio [HR], 0.95; 95% CI, 0.83 to 1.07; P = .3342). Median overall survival time was 45.8 months for the TEC arm and 41.0 months for the TC arm (HR, 0.93; 95% CI, 0.81 to 1.08; P = .3652). Similar nonsignificant differences were observed when strata were analyzed separately.

CONCLUSION: Addition of epirubicin to TC did not improve survival or time to treatment failure in patients with advanced epithelial ovarian cancer; therefore, it cannot be recommended for clinical use in this population.

	INTRODUCTION

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Since the publication of two large studies reporting superiority of platinum-paclitaxel compared with the older combination of platinum with alkylating agents,^1,2 this combination has been widely adopted as a new standard first-line treatment for advanced ovarian cancer. Several attempts have been made to optimize this cisplatin-based regimen and two randomized phase III trials demonstrated that carboplatin can be substituted for cisplatin without loss of efficacy.^3,4 However, the substitution of carboplatin for cisplatin resulted in better tolerance and quality of life (QoL) but did not increase long-term survival rates. The impressive median survival rates approaching 5 years that have been reported by these two trials for optimally debulked patients cannot mask the urgent need for more effective treatment in these patients.

Among others, one option for achieving further progress in the first-line treatment of advanced ovarian cancer might be the addition of non–cross-resistant drugs to the two-drug combination of platinum and paclitaxel. Anthracyclines are among the candidates for the third drug. Three meta-analyses showed a survival benefit for platinum-anthracycline based combinations when compared with platinum-based combinations without anthracyclines.^5-7 Furthermore, both doxorubicin (as liposomal formulation) and epirubicin, a doxorubicin analog, have shown activity as second-line treatment even after prior platinum and (in some patients) paclitaxel-containing first-line chemotherapy.^8,9 Consequently, the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) developed a feasible triple-drug regimen combining carboplatin-paclitaxel with epirubicin (TEC) for additional evaluation.¹⁰ Under the auspices of the Gynecologic Cancer Intergroup (GCIG), the German AGO-OVAR and the French Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) performed a prospectively randomized phase III study comparing TEC with carboplatin-paclitaxel (TC) in advanced epithelial ovarian cancer. Some results of this trial were presented at the 40th Annual Meeting of the American Society of Clinical Oncology,¹¹ and the final results are reported in this article.

	PATIENTS AND METHODS

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The study was designed and carried out in accordance with good clinical practice guidelines, German and French drug laws, and the Declaration of Helsinki. Local ethics committee of each participating center in Germany and France approved the study. All patients provided written informed consent before study entry.

Eligibility Criteria, Randomization, and Quality Assurance
Patients with histologically confirmed International Federation of Gynecology and Obstetrics (FIGO)¹² stages IIB to IV ovarian cancer were eligible. Patients had to have undergone radical debulking surgery within 6 weeks of random assignment. All patients had to be at least 18 years of age and were required to have adequate hematologic, renal, and hepatic function, defined as follows: absolute neutrophil count (ANC) of at least 1.5 x 109 cells/L, platelet count of at least 100 x 109 cells/L, serum creatinine and bilirubin of no more than 1.25 x the upper normal limit. Patients were excluded from the study if they had ovarian tumors with low malignant potential; an Eastern Cooperative Oncology Group performance status of more than 2 or a Karnofsky performance status of less than 60%; an estimated glomerular filtration rate (GFR) of less than 60 mL/min; other malignancies; previous chemotherapy, immunotherapy, or radiotherapy for ovarian cancer; severe neuropathy; cardiac arrhythmias; or congestive heart failure. An evaluation of left ventricular ejection fraction had to be performed if patients had any medical cardiac history or clinical performance indicated any signs of heart disease.

Patients were stratified into one of two a priori strata according to residual tumor size and FIGO stage. Stratum 1 contained patients with a residual tumor size of up to 1 cm and had FIGO stage IIB, IIC, or III disease. Stratum 2 contained patients with a residual tumor size of more than 1 cm or had FIGO stage IV disease. Within each stratum, randomization lists for each study center were prepared before the start of the trial using permuted blocks of randomly varying size. Patients were randomly assigned by the responsible study office of each study group. All participating centers were monitored regularly by trained field monitors who checked all of the data collected on case review forms against the medical records including the surgeon's and pathologist's reports for each patient (ie, 100% monitoring). Additional quality assurance measures consisted of double data entry and extensive programmed plausibility checks.

Treatment Regimens
Patients were randomly assigned to receive TC or TEC. Patients in the TC arm received paclitaxel 175 mg/m² administered intravenously (IV) during 3 hours, followed by carboplatin (area under the time-concentration curve [AUC] 5) administered IV during 30 to 60 minutes. Patients in the TEC arm received epirubicin 60 mg/m² administered IV during 30 minutes or bolus after having received TC. The carboplatin dose was calculated using the method of Calvert et al¹³ in which the required dose is obtained by the following formula: carboplatin dose in milligrams = AUC x (GFR + 25). The GFR was estimated using the Jelliffe formula.¹⁴ Regardless of calculated doses, the maximal absolute dose was limited to 385 mg for paclitaxel, 800 mg for carboplatin, and 130 mg for epirubicin.

Dose reductions were allowed depending on predefined levels of hematologic or nonhematologic toxicity, with dose reduction levels as follows: carboplatin AUC 4 (level –1/level –2); paclitaxel 150 mg/m² (level –1) or 135 mg/m² (level –2); and epirubicin 50 mg/m² (level –1) or 40 mg/m² (level –2). Any subsequent treatment cycle was delayed when the patient's ANC was less than 1.5 x 109 cells/L or the platelet count was less than 100 x 109 cells/L. Primary prophylaxis using granulocyte colony-stimulating factor (G-CSF) was not allowed; however, supportive G-CSF treatment could be initiated at the discretion of the investigator if the patient's ANC recovery took more than 36 days.

All patients received premedication consisting of a single dose of dexamethasone (20 mg), and both a histamine receptor type 1 and histamine receptor type 2 blocking agent (eg, clemastine 2 mg and cimetidine 300 mg) administered 30 minutes before the start of the paclitaxel infusion. Antiemetic prophylaxis consisted of 5-hydroxytryptamine-3 antagonists and corticosteroids. Chemotherapy cycles were repeated every 3 weeks. Patients with disease progression during therapy discontinued protocol treatment. Patients who achieved partial remission and who exhibited residual tumor after six treatment cycles could receive additional treatment cycles if recommended by the physician.

Evaluations and Follow-Up
Adverse events and toxicities were graded by study investigators according to the National Cancer Institute Common Toxicity Criteria version 2.0.¹⁵ All observed toxicities were recorded continuously; blood chemistry parameters were measured before each treatment cycle and hematologic parameters were measured weekly. QoL was evaluated in the German subcohort using global health status/QoL score of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), version 2.0.¹⁶ Patients assessed their own health-related QoL every other treatment cycle, after the last treatment cycle, and every 3 months after cessation of treatment during the first year. QoL responses were evaluated according to the EORTC guidelines.¹⁷ Tumor measurements were made before each treatment cycle by physical examination, before every third treatment cycle by imaging methods in patients with measurable or assessable disease, and after the last treatment cycle. The same tumor assessment methods (ie, ultrasound, x-ray, computed tomography, or magnetic resonance imaging) that were employed for baseline measurement were also used for each repeat evaluation. Tumor response was graded according to the definitions of the WHO.¹⁸ Second-look surgery was not recommended. Follow-up visits were scheduled every 3 months in the first 2 years after cessation of treatment and every 6 months thereafter, for a total follow-up time of 5 years.

Statistical Analyses
The primary outcome measure was overall survival; secondary end points were progression-free survival, response to treatment, toxicity, and QoL. With an estimated 3-year overall survival proportion of 50% in the TC group, the trial aimed to detect an improvement of 8% (to 58%) in the TEC group, with 5% significance (two sided) and 80% power using a stratified log-rank test, which required at least 541 events. Overall survival was defined as the time from random assignment to death as a result of any cause; survivors were censored at the date they were last known to be alive. Progression-free survival was defined as the time from random assignment to disease progression or death as a result of any cause; patients who were still alive without progressive disease at the time of analysis were censored at the date of their last follow-up. Response to treatment was assessed according to WHO criteria. Overall response rate was defined as the number of patients who had a partial or complete response divided by the number of patients with measurable disease at baseline. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria and were evaluated using the worst score over all courses (set C) and over all courses within patients (set P). Time-to-event data were analyzed using the Kaplan-Meier (KM) method, and the (stratified) log-rank test was used to compare the distributions between groups. KM estimates of potential follow-up were used to quantify the median follow-up time. In addition, hazard ratios (HRs) with 95% CIs were estimated using the Cox proportional hazards model. The stratified Cochran-Mantel-Haenszel test was used for the comparison of categoric data. All P values are two sided. Efficacy analyses were performed on all randomly assigned patients (intention-to-treat basis). Patients receiving at least one treatment cycle were qualified for safety analysis. Patients who had completed QLQ-C30 questionnaires for at least three of the four time points (1, baseline; 2, before the second cycle; 3, before the fourth cycle; 4, at end of treatment) were qualified for QoL analysis. The differences of worst respective mean global health score over time points 2 to 4 versus baseline were used as summary measures and compared using the Wilcoxon-Mann-Whitney test. All statistical analyses were done with SAS software (version 8.2; SAS Institute, Cary, NC).

	RESULTS

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Patients
Between November 1997 and February 2000, 1,356 patients were screened by the AGO-OVAR and GINECO study offices. Of these, 74 patients (5.5%) were not enrolled because of low GFR (n = 45), histology of nonepithelial ovarian cancer (n = 10), secondary malignancies (n = 4), surgery more than 6 weeks before study entry (n = 6), wrong FIGO stage (n = 5), or other reasons (n = 4). Of the remaining 1,282 patients, 743 patients fulfilled the criteria for stratum 1 and 539 patients fulfilled the criteria for stratum 2 (Fig 1). After written informed consent was provided, 635 patients were randomly assigned to TC and 647 were randomly assigned to TEC. The treatment arms were well balanced for baseline characteristics (Table 1).

View larger version (19K): [in this window] [in a new window]   Fig 1. Consort diagram. TC, carboplatin-paclitaxel; TEC, carboplatin-paclitaxel plus epirubicin.

Treatment delays of at least 7 days occurred in 231 of 627 (36.8%) patients in the TC arm and 252 of 637 (39.6%) patients in the TEC arm. This difference did not reach statistical significance.

Overall, 183 (14.5%) of the 1,264 patients received at least one dose reduction. Again, there was a statistically significant difference between the treatment arms in the percentage of patients with at least one dose reduction (9.9% in the TC arm v 19.0% in the TEC arm; P < .0001).

The mean carboplatin dose per patient was AUC 4.9 in both arms, and the mean paclitaxel dose per patient was 170.8 and 169.0 mg/m² in the TC and TEC arms, respectively. The achieved mean epirubicin dose per patient in the TEC arm was 57.6 mg/m² according to 87.8% of planned dose-intensity. Overall dose-intensity (ie, received/planned dose for all drugs) was 93.8% and 91.6% in the TC and TEC arm, respectively.

Grade 3/4 hematologic toxicities were significantly more frequent in the TEC arm than in the TC arm, including hemoglobin, leukocytes, neutrophils, and platelets (Table 2). Furthermore, grade 3/4 febrile neutropenia occurred more frequently in the TEC arm than in the TC arm, and patients treated with TEC received more packed RBCs, antibiotics, and G-CSF than patients treated with TC (Table 2).

A total of 968 patients (75.5%) had shown progressive disease or recurrence within the observation period. Median progression-free survival time was 18.4 months (95% CI, 16.2 to 20.2 months) for the TEC arm and 17.9 months (95% CI, 16.3 to 19.7 months) for the TC arm (Fig 2). The stratum-adjusted HR was 0.95 (95% CI, 0.83 to 1.07; stratified log-rank P = .3342). In stratum 1, median progression-free survival time was 27.1 months (95% CI, 23.0 to 35.1 months) for the TEC arm and 23.7 months (95% CI, 20.8 to 26.7 months) for the TC arm, corresponding to an HR of 0.91 (95% CI, 0.76 to 1.09; P = .2955). In stratum 2, median progression-free survival time was 13.5 months (95% CI, 12.3 to 14.4 months) for the TEC arm and 12.8 months (95% CI, 11.5 to 14.5 months) for the TC arm, corresponding to an HR of 0.97 (95% CI, 0.81 to 1.17; P = .7560).

View larger version (12K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates of progression-free survival, all randomly assigned patients by treatment. TC, carboplatin-paclitaxel; TEC, carboplatin-paclitaxel plus epirubicin; E, events.

View larger version (12K): [in this window] [in a new window]   Fig 3. Kaplan-Meier estimates of overall survival, all randomly assigned patients by treatment. TC, carboplatin-paclitaxel; TEC, carboplatin-paclitaxel plus epirubicin; E, events.

View larger version (12K): [in this window] [in a new window]   Fig 4. Kaplan-Meier estimates of overall survival, all randomly assigned patients by treatment within stratum 1. TC, carboplatin-paclitaxel; TEC, carboplatin-paclitaxel plus epirubicin; E, events.

View larger version (11K): [in this window] [in a new window]   Fig 5. Kaplan-Meier estimates of overall survival, all randomly assigned patients by treatment within stratum 2. TC, carboplatin-paclitaxel; TEC, carboplatin-paclitaxel plus epirubicin; E, events.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Despite the progress that had been achieved by the incorporation of paclitaxel into first-line treatment of advanced ovarian cancer, survival rates are still disappointing; eventually, the majority of patients will die as a result of their disease. Therefore, additional efforts to improve efficacy of first-line chemotherapy in ovarian cancer clearly are warranted. One attempt to improve results is adding drugs that are regarded as not completely cross resistant to platinum-paclitaxel combination regimens. Among others, anthracyclines were thought to be candidates for incorporation as a third drug into first-line regimens for advanced ovarian cancer. These assumptions were based on results from meta-analyses and results of smaller studies reporting efficacy in platinum-pretreated relapsed ovarian cancer. However, another large randomized trial comparing single-agent carboplatin with a combination of cisplatin, cyclophosphamide, and doxorubicin failed to show superiority for the anthracycline-containing regimen.¹⁹

Unfortunately, this trial confirmed the lack of benefit of adding an anthracycline to a more modern platinum-based therapy containing paclitaxel. The incorporation of epirubicin in the TEC regimen evaluated in this study did not show any benefit compared with the two-drug platinum-paclitaxel regimen commonly regarded as standard. The nonsignificant and less than 10% reduction in HR for overall survival was traded off by higher toxicity and lower QoL induced by the anthracycline-containing regimen. Similar observations with respect to progression-free survival have been reported in a confirmatory GCIG trial comparing the same TC combination used in our study with a TEC regimen containing a slightly higher epirubicin dose of 75 mg/m².²⁰ A third GCIG trial performed by the US Gynecologic Oncology Group (GOG), the British Medical Research Council, and the Australian-New Zealand GOG is still ongoing and evaluates another anthracycline combination by comparing TC plus liposomal doxorubicin versus TC within a five-arm trial (GOG 182/International Collaborative Ovarian Neoplasm [ICON] -55²¹). However, the optimism regarding the incorporation of anthracyclines has vanished in the light of the negative results currently available from three large trials that have evaluated this question.

The failure of anthracyclines does not prove the failure of the whole concept of incorporating new drugs in first-line regimens in ovarian cancer. The second-generation GCIG trials evaluating three-drug combinations are underway or already completed. Topotecan has been added sequentially to TC in the AGO-OVAR/GINECO trial,²² and is being evaluated within two ongoing trials as a platinum-topotecan doublet followed by TC (GOG 182/ICON5 and National Cancer Institute of Canada/EORTC/Nordic Society of Gynecologic Oncology Group/Intergroup study). Another GCIG study by AGO-OVAR, GINECO, and Nordic Society of Gynecologic Oncology Group comparing the triple-drug regimen of TC plus gemcitabine versus TC recently has completed accrual with 1,742 patients. Results of this series of studies will gather more evidence if the concept of adding non–cross-resistant drugs to TC will provide any benefit. Although the results of this study seem somewhat disappointing, the development of intergroup collaboration within the field of gynecologic oncology is encouraging. The way intergroup studies are performed can systematically answer important questions within reasonable time frames, and make it more probable that the next generation of questions will be answered more quickly. The latter comprise questions about how to integrate translational research and molecular insights in tumor biology into clinical trials, thus helping to create study scenarios that will allow evaluation of targeted therapies.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The following members of the coordinating group of AGO-OVAR participated in design and coordination of this trial and were part of the writing team: C. Jackisch (Münster/Marburg), V. Möbus (Ulm), U. Nitz (Düsseldorf), M. Warm (Stralsund), T. Bauknecht (Freiburg), J.U. Blohmer (Berlin), G. Emons (Marburg/Goettingen).

The following centers recruited more than two patients (presented in alphabetical order by city): AGO-OVAR; K. von Maillot, Aalen; W. Lange, Altenburg; D. Berg, Amberg; E. Schlicht, Aschaffenburg; G. Hasslbauer, Aschersleben; R. Knitza, Bad Hersfeld; H. Peterseim, Bad Mergentheim, M. Hummel, Bad Säckingen, U. Lepsien, Bassum, A.H. Tulusan, Bayreuth; H. Kentenich, Berlin; P. Klare, Berlin; G. Morack, Berlin, E. Nickel, Berlin; U. Torsten, Berlin; H.E. Frank, Braunschweig, Ö. Taylan, Bremen; K. Renziehausen, Chemnitz; A. Feldmann, Cloppenburg; R. Wunder, Delmenhorst; H. Goebel, Dortmund; C. Werner, Duisburg; O. Bergauer, Ebersberg; T. Dewitz, Elmshorn; C. Müller, Erfurt; W. Jäger, Erlangen; S. Niesert, Essen; H. Mickan, Esslingen; G. Völker, Frankenberg; D. Wernicke, Frankfurt; B. Stitz, Fulda; P.G. Habermann, Fulda; B.E. Köhler, Fürstenfeldbruck; D. Nägeli, Gehrden; T. Dinkelacker, Geislingen; H.J. Venn, Gelsenkirchen; M. Hoedemaker, Georgsmarienhütte; M. Kröner, Gera; T. Krauss, Göttingen; E. Petru, Graz; J. Quaas, Greifswald; D. Glaser, Gronau; H. Riedel, Großburgwedel; K. Buchholz, Halle/S.; H. Daneschumand, Altona; P. Schmidt-Rhode, Hamburg; T. Menschik, Hamburg; T. Zeiser, Henstedt-Ulzburg; E.J. Friedrich, Heppenheim; W. Herchenheim, Herzberg; K. Lürmann, Hoyerswerda; M. Mesrogli, Husum; A. Schneider, Jena; G. Deutsch, Karlsruhe; H. Urbanczyk, Kassel; C. Kurbacher, Köln; A. Göppinger, Lahr; E. Oberlechner, Landshut; R. Schuhmann, Langen; K. Kühndel, Leipzig; M. Volk, Limburg; A. Schenck, Ludwigshafen; H.J. Bettex, Lüneburg; B. Schindler, Magdeburg; C. Leissner, Mainz; W. Ernst, Mayen; H. Sommer, München; T. Silz, Neubrandenburg; G.P. Breitbach, Neunkirchen; R. Goebel, Oberhausen; P. Merx, Offenbach; D. Schwörer, Offeburg; M. Schwarz, Oranienburg; M. Butterwegge, Osnabrück; W. Meinerz, Paderborn; P. Richter, Plauen; F. Dreßler, Potsdam; U. Guth, Reutlingen; T. Beck, Rosenheim; D. Rother, Rostock; G. Bartzke, Rottweil; K.J. Neis, Saarbrücken; D. Scharnke, Salzgitter; K.O. Reichl, Schorndorf; S. Lenz-Hoffmann, Siegen, J. Hoffmann, Siegen; J. Meyer-Grohbrügge, Sigmaringen; V. Jovanovic, Solingen; J. Feltz-Süßenbach, Stadthagen; C. Dietz, Stollberg; E. Merkle, Stuttgart; U. Eissler, Tettnang; G. Göretzlehner, Torgau; C. Karg, Waiblingen; W. Burkert, Walsrode; S. Flachsenberg, Wolfsburg; D. Kranzfelder, Würzburg; GINECO; A. Lortholary, Angers: C. Bouleuc, Argenteuil; P. Vincent, Avignon; N. Dohollou, Bordeaux; F. Guichard, Bordeaux; H. Gautier, Briis sous Forge; B. Leduc, Brive; F. Joly, Caen; H. Curé, Clermont-Ferrand; E. Malaurie, Créteil; M. Mousseau, Grenoble; P. Nouyrigat, La Seyne sur Mer; M. Combe, Le Mans; G. Ganem, Le Mans; J.P. Guastalla, Lyon; G. Netter-Pinon, Meaux; J. Plaza, Montbéliard; A. Bichoffe, Montluçon; P. Bouffette, Neuilly-sur-Seine; J.M. Ferrero, Nice; X. Pivot, Nice; J. Cretin, Nîmes-Alès; V. Lucas, Orléans; N. Raban, Orleans la Source; H. Bourgeois, Poitiers; F. Rousseau, Pontoise; M.C. Gouttebel, Roanne; P. Chinet-Charrot, Rouen; A.C. Hardy-Bessard, Saint-Brieuc; F. Mefti, Saint Cloud; R. Ouabdesselam, Saint Cloud; C. Boaziz, Sarcelles; L. Mignot, Suresnes; M. Rios, Vandoeuvre-les-Nancy; D. Mayeur, Versailles.

The following data managers and field monitors helped to perform this study: Katrin Drösler, Ingrid Graf, Michaela Polzin, Katja Kretzschmann, Sabine Oxe, Franz Gottwald, Marion Borinin, Corinna Renné, Sylvia Bigus, Katrin Friccius, and Simone Lang.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Andreas du Bois Bristol-Myers Squibb (A) Bristol-Myers Squibb (B) Uwe Wagner Bristol-Myers Squibb (A) Hans-Joachim Lueck Bristol-Myers Squibb (A) Jacobus Pfisterer Bristol-Myers Squibb (A) Rainer Kimmig Bristol-Myers Squibb (A) Eric Pujade-Lauraine Bristol-Myers Squibb (A) Bristol-Myers Squibb (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Andreas du Bois, Werner Meier, Sigrid Olbricht, Walther Kuhn, Uwe Wagner, Jacobus Pfisterer, Serban Costa, Willibald Schroeder, Eric Pujade-Lauraine Administrative support: Eric Pujade-Lauraine Provision of study materials or patients: Andreas du Bois, Beatrice Weber, Alain Goupil, Jean-Claude Barats, Walther Kuhn, Hubert Orfeuvre, Uwe Wagner, Hans-Joachim Lueck, Jacobus Pfisterer, Serban Costa, Willibald Schroeder, Eric Pujade-Lauraine Collection and assembly of data: Andreas du Bois, Uwe Wagner, Hans-Joachim Lueck, Jacobus Pfisterer, Rainer Kimmig, Eric Pujade-Lauraine Data analysis and interpretation: Andreas du Bois, Justine Rochon, Werner Meier, Uwe Wagner, Jacobus Pfisterer, Serban Costa, Willibald Schroeder, Eric Pujade-Lauraine Manuscript writing: Andreas du Bois, Justine Rochon, Uwe Wagner, Barbara Richter, Hans-Joachim Lueck, Jacobus Pfisterer Final approval of manuscript: Andreas du Bois, Beatrice Weber, Werner Meier, Alain Goupil, Walther Kuhn, Uwe Wagner, Hans-Joachim Lueck, Jacobus Pfisterer, Serban Costa, Willibald Schroeder, Rainer Kimmig, Eric Pujade-Lauraine

 

	Acknowledgment

 
We thank the staff of AGO-OVAR in Wiesbaden (G. Elser and others, and H.P. Adams) and of GINECO in Paris (Christiane Puelo), the statistical department at the KKS Marburg, and the study monitors (Peter Schantl and others).

	NOTES

 
Supported by (and study medication provided by) Bristol-Myers Squibb and Pharmacia-Upjohn.

Presented in part at the 40th Annual Meeting of the Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

The drugs and regimens evaluated in this purely scientific trial may not be registered for this indication in some countries.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
1. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and Stage IV ovarian cancer. N Engl J Med 334:1-6, 1996[Abstract/Free Full Text]

2. Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92:699-708, 2000[Abstract/Free Full Text]

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Submitted July 7, 2005; accepted December 14, 2005.

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