Phase I study of paclitaxel administered by ten-day continuous infusion

Purpose: Pre-clinical data have suggested that prolonged exposure to paclit axel enhances its cytotoxicity, but various clinical trials utilizing long- term infusions of paclitaxel have been limited by unacceptable hematologic toxicity, most notably significant neutropenia. A phase I study of paclitax el administered over 10 days, was performed to evaluate the hematologic and non-hematologic toxicities as well as to determine the maximum-tolerated d ose for the 10-day infusion duration. Patients and methods: Twenty-nine solid tumor patients (predominantly non-s mall cell lung cancer and head and neck cancer) were treated with paclitaxe l at doses ranging from 5 mg/m(2)/day to 25 mg/m(2)/day administered as a 1 0-day continuous infusion via a pump every 21 days. Dose escalation was per mitted within individual patients. Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity, ANC less than or equal to 500 or platelet count less than or equal to 25,000 for greater than or equal to 7 days or febrile neutropenia. The maximum tolerated dose (MTD) was defined as the highest dose level at which less than two out of six patients develo ped DLT. All of the patients had received prior chemotherapy; approximately two-thirds had received prior radiation as well. All patients received sta ndard pre-medications for paclitaxel, including anti-histamines and cortico steroids. Prophylactic granulocyte colony-stimulating factor (G-CSF) was no t used. Results: A total of 110 courses of paclitaxel were administered to 29 patie nts. The incidence of hematologic and non-hematologic toxicity was quite lo w among the patients treated at dose levels below 17 mg/m(2)/day. At higher doses, non-hematologic toxicities including arthralgias, myalgias, fatigue , nausea, stomatitis, and peripheral neuropathy were seen, although nearly all of the toxicities were less than grade 3 (NCI toxicity criteria). Hemat ologic toxicity mostly consisted of neutropenia and was more common at dose levels of 17 mg/m2/day or higher. Nevertheless, even at the highest dose l evels (21 mg/m(2)/day and 25 mg/m2/day) grade 3 or 4 neutropenia occurred i n only 50% of patients. Dose-limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25 mg/m(2)/day dose level. Conclusion: Paclitaxel can be safely administered as a 10-day infusion. The MTD for this schedule is 210 mg/m(2). Unlike the 96-hour paclitaxel infusi ons, dose-reduction for myelosuppression may not be necessary because the M TD of paclitaxel when administered over a 10-day infusion is similar to the MTD of paclitaxel when infused over 3 or 24 hours.