VINORELBINE INDUCED NEUROTOXICITY IN PATIENTS WITH ADVANCED BREAST-CANCER PRETREATED WITH PACLITAXEL - A PHASE-II STUDY

Vinorelbine (VNB) shows high antitumoral activity in advanced breast c ancer due to its high affinity for mitotic tubulin and differs from th e other vinca alkaloids with regard to its low degree of neurotoxicity because of its low affinity for axonal tubulin. Preclinical data show the existence of different binding sites on tubulin for vinca alkaloi ds and paclitaxel (P), suggesting a lack of cross-resistance. Thus, VN B was chosen eligible for a phase II study to evaluate both the therap eutic efficacy and the toxicity of VNB in patients (pts) with advanced breast cancer failing first- or second-line chemotherapy with P. A to tal of 14 pts with advanced breast cancer pretreated with P were enter ed into the study. Therapy consisted of VNB at 30 mg/m(2) diluted in 5 00 ml of normal saline given over 30 min after a minimal interval of 4 weeks since the last application of P. For the first four cycles, inj ections were repeated at 2-week intervals; thereafter they were repeat ed at 3-week intervals until evidence of progressive disease or severe toxicity developed. All but one pt was considered assessable for resp onse and all pts were evaluable for toxicity. No objective response wa s observed; two pts showed no change in their disease. In four pts the rapy had to be stopped because peripheral neurotoxicity increased from a pretherapeutic level after therapy with P from National Cancer Inst itute Common Toxicity Criteria (NCI-CTC) grade 1 (n = 3) and 2 (n = 1) to neurotoxicity grade 3 after 1, 2 (n = 2), and 3 cycles of therapy with VNB, respectively. In addition, constipation of grade 2 occurred in 10 pts. Hematologic toxicity was negligible. No other evaluable tox icity exceeded NCI-CTC grade 1. Both observations of this study, the c omplete resistance to VNB and the increase in peripheral neuropathy, l et us assume the existence of a preclinically not anticipated but clin ically relevant cross-resistance between these two spindle poisons and the presence of common functional targets. Therefore, P-pretreated pt s should be excluded from consecutive VNB-containing therapies.