Phase I clinical trial of weekly paclitaxel, weekly carboplatin, and concurrent radiotherapy for primary cervical cancer

Objectives. Standard primary treatment for locally advanced cervix cancer is radiation (RT) with concomitant platinum-based chemotherapy (CT). Incomplete local control and the appearance of distant disease herald poor survival and warrant evaluation of new primary strategies. Paclitaxel and carboplatin are active agents in recurrent cervical carcinoma, have potent, synergistic in vitro radiosensitization, and are cytotoxic in weekly schedules. This study was done to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly paclitaxel/carboplatin chemoradiotherapy in locally advanced cervix cancer. Methods. Women with primary, previously untreated, squamous cell or adenocarcinoma of the cervix, FIGO stage IB2 to IVA, negative para-aortic lymph nodes, adequate organ function and performance status were eligible. Pelvic RT (45 Gy over 5 weeks-180 cGy/day, four-field) was followed by two brachytherapy applications (Point A low dose rate (LDR): 90 Gy, high dose rate (HDR): 75 Gy). Concurrent weekly CT was paclitaxel 50 mg/m(2) and carboplatin, starting at AUC 1.5 and escalating in three-patient cohorts by AUC 0.5 (Max AUC 3.5). Dose escalation followed a 4-week observation period for toxicity. A grade III-IV toxicity prompted up to three additional patients per dose level. A second event defined DLT. CT was administered concurrently throughout brachytherapy. Results. Fifteen patients were enrolled and treated over four dose levels until DLT was reached. Median age was 44 years (range, 23-70); stages: IB2: 1, IIB: 9, IIIA: 1, IIIB: 4. Median RT treatment time was 61 days (range, 55-79). Fourteen patients received brachytherapy (LDR: 8, HDR: 6), and one received external RT only due to cervical stenosis. The median number of weekly CT cycles was seven (range, 6-7). One CT dose was dropped in one patient for a grade II thrombocytopenia. One grade III ANC was observed at dose level II (AUC 2.0) but not seen in three additional patients. At dose level IV (AUC 3.0), two grade III IV ANC toxicities were observed in two patients (DLT). Nine patients had grade II anemia. One patient had grade III anemia. Grade III/IV nonhematologic toxicity was rare (1/15 GI-nausea/vomiting, 1/15 pneumonia, 1/15 hypokalemia). The MTD of carboplatin is AUC 2.5 with paclitaxel 50 mg/m(2) Median follow-up is 17 months; three patients have recurred and two have died. The estimated 2-year PFS and OS are 80% and 86%. Conclusions. Weekly paclitaxel and carboplatin chemoradiation is feasible and active. The MTD for a phase 11 trial is 50 mg/m 2 and AUC 2.5, respectively. (C) 2004 Elsevier Inc. All rights reserved.