PURPOSE: To determine the maximum-tolerable dose (MTD) of paclitaxel in a phase I dose-escalation study when combined with cisplatin in patients with advanced ovarian cancer receiving filgrastim for prophylaxis of myelosuppression. PATIENTS AND METHODS: A total of 23 patients with stage II (bulky residual), III, or IV epithelial ovarian cancer were treated (following debulking surgery) with paclitaxel as a 3-hour infusion followed by cisplatin (75 mg/m2) administered over 4 hours on day 1, repeated every 21 days for six cycles. Filgrastim (5 micrograms/kg/d) was administered subcutaneously (SC) beginning on day 2 of each cycle through neutrophil recovery (absolute neutrophil count [ANC] > 10,000/microL). Patients were assigned to one of six escalating dose levels of paclitaxel: 150 (n = 3), 175 (n = 3), 200 (n = 3), 225 (n = 4), 250 (n = 4), and 275 mg/m2 (n = 6). RESULTS: At each paclitaxel dose level (150, 175, 200, 225, 250, and 275 mg/m2), the numbers of patients who completed six cycles without dose reduction were three (100%), three (100%), two (66%), two (50%), three (75%), and zero (0%), respectively. The numbers of patients who experienced a grade III/IV adverse event (hematologic or nonhematologic) were zero (0%), two (66%), two (66%), one (25%), four (100%), and five (80%), respectively. Reasons for dose reduction included neurotoxicity (225 mg/m2, n = 1; 275 mg/m2, n = 2), neutropenia (225 mg/m2, n = 2), diarrhea (275 mg/m2, n = 2), and nephrotoxicity (225 mg/m2, n = 1). Reasons for not completing six cycles at full or reduced dose included neuropathy (200, 225, and 275 mg/m2, n = 1 each) physician request (275 mg/m2, n = 1), and death (275 mg/m2, n = 1). Hematopoietic toxicity was minimal. Six patients developed grade III/IV neutropenia. No patient developed thrombocytopenia below a level of 50,000/microL. CONCLUSION: The MTD of paclitaxel was determined to be 225 mg/m2 when administered as a 3-hour infusion and combined with cisplatin (75 mg/m2). Nonhematologic dose-limiting toxicities were neuropathy and diarrhea. The neuropathy often had a rapid onset, especially at the higher dose levels.
PURPOSE: To determine the maximum-tolerable dose (MTD) of paclitaxel in a phase I dose-escalation study when combined with cisplatin in patients with advanced ovarian cancer receiving filgrastim for prophylaxis of myelosuppression. PATIENTS AND METHODS: A total of 23 patients with stage II (bulky residual), III, or IV epithelial ovarian cancer were treated (following debulking surgery) with paclitaxel as a 3-hour infusion followed by cisplatin (75 mg/m2) administered over 4 hours on day 1, repeated every 21 days for six cycles. Filgrastim (5 micrograms/kg/d) was administered subcutaneously (SC) beginning on day 2 of each cycle through neutrophil recovery (absolute neutrophil count [ANC] > 10,000/microL). Patients were assigned to one of six escalating dose levels of paclitaxel: 150 (n = 3), 175 (n = 3), 200 (n = 3), 225 (n = 4), 250 (n = 4), and 275 mg/m2 (n = 6). RESULTS: At each paclitaxel dose level (150, 175, 200, 225, 250, and 275 mg/m2), the numbers of patients who completed six cycles without dose reduction were three (100%), three (100%), two (66%), two (50%), three (75%), and zero (0%), respectively. The numbers of patients who experienced a grade III/IV adverse event (hematologic or nonhematologic) were zero (0%), two (66%), two (66%), one (25%), four (100%), and five (80%), respectively. Reasons for dose reduction included neurotoxicity (225 mg/m2, n = 1; 275 mg/m2, n = 2), neutropenia (225 mg/m2, n = 2), diarrhea (275 mg/m2, n = 2), and nephrotoxicity (225 mg/m2, n = 1). Reasons for not completing six cycles at full or reduced dose included neuropathy (200, 225, and 275 mg/m2, n = 1 each) physician request (275 mg/m2, n = 1), and death (275 mg/m2, n = 1). Hematopoietic toxicity was minimal. Six patients developed grade III/IV neutropenia. No patient developed thrombocytopenia below a level of 50,000/microL. CONCLUSION: The MTD of paclitaxel was determined to be 225 mg/m2 when administered as a 3-hour infusion and combined with cisplatin (75 mg/m2). Nonhematologic dose-limiting toxicities were neuropathy and diarrhea. The neuropathy often had a rapid onset, especially at the higher dose levels.
Authors: Don S Dizon; Michael W Sill; Natalie Gould; Stephen C Rubin; S Diane Yamada; Robert L Debernardo; Robert S Mannel; Eric L Eisenhauer; Linda R Duska; Paula M Fracasso Journal: Gynecol Oncol Date: 2011-08-05 Impact factor: 5.482
Authors: William P Tew; Delia Radovich; Eileen O'Reilly; Gary Schwartz; Deborah Schrag; Leonard B Saltz; David P Kelsen; Stacey Kepler; David H Ilson Journal: Invest New Drugs Date: 2008-10-28 Impact factor: 3.850
Authors: Krystyna M Wozniak; Ying Wu; Mohamed H Farah; Bruce A Littlefield; Kenichi Nomoto; Barbara S Slusher Journal: Neurotox Res Date: 2013-04-30 Impact factor: 3.911