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Phase I Study of Paclitaxel, Carboplatin, and Increasing Days of Prolonged Oral Etoposide in Ovarian, Peritoneal, and Tubal Carcinoma: A Gynecologic Oncology Group Study

From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ohio State University, James Cancer Hospital and Solove Research Institute, Columbus, OH; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL; Division of Gynecologic Oncology, University of Washington School of Medicine, Seattle, WA; Division of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA; University of Mississippi School of Medicine, Jackson, MS; and Chemotherapy Services, Gynecologic Cancer Center, Mercy Medical Center, Baltimore, MD.

Address reprint requests to Gynecologic Oncology Group Administrative Office, Suite 1945, 1234 Market St, Philadelphia, PA 19107.

PURPOSE: Given the activity of prolonged oral etoposide in platinum and paclitaxel-resistant ovarian carcinoma, a phase I trial was conducted that combined increasing days of oral etoposide therapy with paclitaxel and carboplatin in chemotherapy-naive patients with ovarian peritoneal and tubal carcinoma to establish a maximum-tolerated dose (MTD) of this combination.

PATIENTS AND METHODS: Paclitaxel at 175 mg/m² given over 3 hours and carboplatin at an area under the curve of 5 were administered on day 1 followed by oral etoposide 50 mg/m²/d beginning on day 2. The number of days of etoposide therapy was escalated on the basis of toxicity. Toxicity end points included neutropenic sepsis, grade 4 thrombocytopenia, or grade 3 neutropenia or thrombocytopenia during etoposide administration. Cycles were repeated every 21 days for a maximum of six courses. Due to hematologic toxicity, the duration of the paclitaxel infusion was decreased to 1 hour for a second stage of accrual.

RESULTS: Of 52 patients studied, 29 were in the first stage of accrual. Dose-limiting toxicity occurred with 8 days of oral etoposide, making the MTD six days of therapy. Twenty-three patients were entered into the second stage of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide, making the MTD 10 days of therapy. Three patients developed acute myeloid leukemia 16, 27, and 35 months after receiving a cumulative dose of 200 mg/m², 1,200 mg/m², and 2,400 mg/m², respectively.

CONCLUSION: One-hour paclitaxel, carboplatin, and oral etoposide at 50 mg/m²/d for 10 days is tolerable without supportive therapy. The leukemogenic potential is cause for concern and precludes its use in chemotherapy-naive ovarian carcinoma.

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