Activity of vinorelbine in gastrointestinal cancers

Abstract

Vinorelbine (VNR) is a semi-synthetic vinca alkaloid (5′nor-anhydro-vinblastine) that differs from other vinca alkaloids by a modification of the catharantine moiety of the molecule. VNR binds to tubulin and inhibits tubulin assembly and microtubule formation. It has less activity than other vinca alkaloids against axonal microtubules and this may account for its reduced neurotoxicity in clinical use. In gastrointestinal tumours, VNR did not show significant activity in advanced pancreatic adenocarcinomas. Two phase II studies in metastatic colorectal cancer resulted in conflicting results: no activity in first-line therapy on lung metastases, but encouraging results in 5-fluorouracil (5-FU)-resistant metastases. Conversely, significant antitumoural effect in oesophageal squamous cell carcinoma has been demonstrated. The first study was performed in 46 patients with metastatic disease. Six of 30 patients (20%) without prior chemotherapy achieved a partial response (95% confidence interval (CI), 8–39%). One of 16 (6%) with prior chemotherapy responded. Grade (gr) 3 or 4 granulocytopaenia occurred in 59% of patients and peripheral neurotoxicity was minor (26% gr 1). These results were confirmed by another group. A phase I study was performed using VNR and concurrent radiation (64 Gy) in previously untreated patients with inoperable locally advanced oesophageal cancer ineligible for cisplatin–5-FU-based chemoradiation. Twenty-four patients entered the study. The maximal tolerated dose has been reached at 25 mg/m 2/week, the dose-limiting toxicities being febrile neutropaenia and infection. Major objective tumour response was observed at each dose level except the first one. Recruitment is ongoing to confirm the recommended dose of VNR (20 mg/m 2/week). A phase II study of a VNR–cisplatin combination in metastatic oesophageal squamous cell carcinoma was recently completed. Seventy-one eligible patients were included. Main toxicities were haematological (gr 3–4 granulocytopaenia, 41%), infection, vomiting and fatigue. The response rate was 37% (95% CI, 26–49%) with a median duration of response of 7.7 months. This 2-day regimen appears at least as active and less toxic than the standard 5-day 5-FU and cisplatin regimen.