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Randomized Phase III Trial of Standard Timed Doxorubicin Plus Cisplatin Versus Circadian Timed Doxorubicin Plus Cisplatin in Stage III and IV or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study

Holly H. Gallion, Virginia L. Brunetto, Michael Cibull, Samuel S. Lentz, Gary Reid, John T. Soper, Robert A. Burger, Willie Andersen

From the Division of Gynecologic Oncology, Magee Women’s Hospital/University of Pittsburgh, Pittsburgh, PA; Roswell Park Cancer Institute, Buffalo, NY; Department of Pathology, University of Kentucky, Lexington, KY; Section on Gynecologic Oncology, Wake Forest University School of Medicine, Winston-Salem; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC; Division of Gynecologic Oncology, Riverside Methodist Hospital, Columbus, OH; Department of Obstetrics and Gynecology and Clinical Research Office, Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, CA; and Department of Obstetrics and Gynecology, University of Virginia Medical School, Charlottesville, VA.

Address reprint requests to Denise Mackey, GOG Administrative Office, Four Penn Center, 1600 John F. Kennedy Blvd, Suite 1020, Philadelphia, PA 19103; e-mail: hgallion{at}mail.magee.edu.

Purpose: To determine if circadian timed (CT) chemotherapy results in improved response, progression-free survival (PFS), overall survival (OS), and lower toxicity, when compared with standard timed (ST) chemotherapy.

Materials and Methods: Eligibility criteria were stage III, IV, or recurrent endometrial cancer with poor potential for cure by radiation therapy or surgery; measurable disease; and no prior chemotherapy. Therapy was randomized to schedules of ST doxorubicin 60 mg/m² plus cisplatin 60 mg/m², or CT doxorubicin 60 mg/m² at 6:00 AM plus cisplatin 60 mg/m² at 6:00 PM. Cycles were repeated every 3 weeks to a maximum of eight cycles.

Results: The ST arm included 169 patients, and the CT arm included 173 patients. The objective response rate (complete responses plus partial responses) was 46% in the ST group compared with 49% in the CT group (P = .26, one tail). Median PFS and OS were 6.5 and 11.2 months, respectively, in the ST group; and 5.9 and 13.2 months, respectively, in the CT group (PFS: P = .31; OS: P = .21, one tail). Median total doses were 209 mg/m² doxorubicin and 349 mg/m² cisplatin in the ST group, versus 246 mg/m² doxorubicin and 354 mg/m² cisplatin in the CT group. Grade 3 or 4 leukopenia occurred in 73% of patients in the ST arm and in 63% of patients in the CT arm. There were eight treatment-related deaths.

Conclusion: In this trial, no significant benefit in terms of response rate, PFS or OS, or toxicity profile was observed with CT doxorubicin plus cisplatin in patients with advanced or recurrent endometrial carcinoma.

Supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517).

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