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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

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.

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.

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