Thoracic radiotherapy and daily vinorelbine as radiosensitizer in locally advanced non small cell lung cancer: a phase I study

Experimental studies have shown that vinorelbine is a powerful radiosensiti zer in vitro. To date, no reports on clinical activity of the single agent vinorelbine as radiosensitizer have been published. The aim of the present phase I study was to determine the maximum tolerated dose (MTD) of vinorelb ine administered daily concurrently with thoracic radiotherapy, with or wit hout amifostine support, in the treatment of locally advanced non small cel l lung cancer. In vitro studies have shown that vinorelbine can potentiate the antitumor effects of radiation therapy. Amifostine is a sulphydril comp ound that has shown to protect normal tissues from chemotherapy and radioth erapy-induced toxicities. Radiotherapy lasted 6 weeks and the total dose wa s 55 Gy. The daily fraction was 1.8 Gy, administered 5 days a week for 5 we eks and increased to 2.0 Gy during the sixth and last week. Concurrent vino relbine was administered daily with a planned escalation of the dose from 4 , to 5 and 6 mg/m(2). Fourteen patients were enrolled in the study. The fir st dose of vinorelbine was 4 mg/m(2) and it showed to be feasible without d ose-limiting toxicity (DLT). Instead, the second dose level of 5 mg/ml(2) w as unfeasible because three out of six patients had DLT (grade 4 neutropeni a, treatment interruption longer than 2 weeks for prolonged grade 2 neutrop enia and treatment interruption longer than 2 weeks for prolonged grade 3 e sophagitis together with grade 4 dyspnea). At that time, the study continue d adding amifostine to vinorelbine in order to increase its MTD. Amifostine was administered by means of subcutaneous injection 15 min before each rad iotherapy fraction at the fixed dose of 300 mg/m(2) However, 5 mg/m(2) of v inorelbine were considered unfeasible even with amifostine support because three out of five patients showed DLT (grade 4 neutropenia, febrile grade 4 neutropenia and grade 3 liver toxicity). Among 14 patients enrolled in the study, eight completed the planned treatment because sis patients experien ced DLT: which determined treatment interruption. Overall, four partial and two complete responses were observed. Two partial and one complete respons e were observed in those three patients who had been treated with the first dose of vinorelbine. In conclusion, our data show that the MTD of daily vi norelbine is 4 mg/m(2). Therefore, this is the recommended dose of daily vi norelbine to be administered with concurrent thoracic radiotherapy in a pha se II trial. Finally, amifostine administered subcutaneously failed to incr ease the MTD of daily vinorelbine. (C) 229 Elsevier Science Ireland Ltd. Al l rights reserved.