Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel--a phase II...

Vinorelbine (VNB) shows high antitumoral activity in advanced breast cancer due to its high affinity for mitotic tubulin and differs from the 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 alkaloids and paclitaxel (P), suggesting a lack of cross-resistance. Thus, VNB was chosen eligible for a phase II study to evaluate both the therapeutic efficacy and the toxicity of VNB in patients (pts) with advanced breast cancer failing first- or second-line chemotherapy with P. A total of 14 pts with advanced breast cancer pretreated with P were entered into the study. Therapy consisted of VNB at 30 mg/m2 diluted in 500 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, injections were repeated at 2-week intervals; thereafter they were repeated at 3-week intervals until evidence of progressive disease or severe toxicity developed. All but one pt was considered assessable for response and all pts were evaluable for toxicity. No objective response was observed; two pts showed no change in their disease. In four pts therapy had to be stopped because peripheral neurotoxicity increased from a pretherapeutic level after therapy with P from National Cancer Institute 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 toxicity exceeded NCI-CTC grade 1. Both observations of this study, the complete resistance to VNB and the increase in peripheral neuropathy, let us assume the existence of a preclinically not anticipated but clinically relevant cross-resistance between these two spindle poisons and the presence of common functional targets. Therefore, P-pretreated pts should be excluded from consecutive VNB-containing therapies.