Vinorelbine

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Abstract
Vinorelbine is a semisynthetic vinca alkaloid that is effective as monotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC). In the large comparative Elderly Lung Cancer Vinorelbine Italian Study (ELVIS), patients receiving vinorelbine monotherapy achieved an objective response rate of 19.7%. The median survival time and the 1-year survival rate were significantly higher in recipients of vinorelbine plus best supportive care than in recipients of best supportive care alone. Vinorelbine recipients generally scored better than recipients of best supportive care on quality-of-life (QOL) functioning scales and experienced significantly fewer lung cancer-related symptoms; however, QOL scores were worse with vinorelbine for parameters relating to drug tolerability. Comparative phase III trials investigating the efficacy of combination therapy with vinorelbine and other agents specifically in elderly patients with advanced NSCLC have been conducted only for the combination of vinorelbine and gemcitabine [the Southern Italy Cooperative Oncology Group (SICOG) trial and the Multicenter Italian Lung Cancer in the Elderly Study (MILES)]. Objective response rates for vinorelbine/gemcitabine combination therapy in these phase III trials were 22 and 20%, respectively. The SICOG trial was closed early when an interim analysis demonstrated a significant survival advantage for combination therapy with vinorelbine plus gemcitabine over vinorelbine monotherapy. However, a survival advantage for combination therapy versus vinorelbine monotherapy was not demonstrated in the larger MILES trial. The main adverse effect of vinorelbine monotherapy in the elderly is myelo-suppression. Adverse events associated with most antineoplastic agents, such as mild alopecia, nausea, vomiting and mucositis, were reported in clinical trials; however, these events were rarely severe. Mild-to-moderate neurotoxicity, including constipation (presumably from autonomic neuropathy), was also reported. The addition of gemcitabine to vinorelbine increased the incidence of both haematological and nonhaematological adverse events. However, there was no significant increase in the incidence of life-threatening toxicity. Vinorelbine as a single agent is effective in elderly patients with NSCLC and is associated with improved survival and at least a trend towards improved QOL parameters compared with best supportive care alone. Vinorelbine was associated with a generally manageable tolerability profile. The benefit of adding gemcitabine to vinorelbine for the treatment of NSCLC in the elderly is equivocal; improved survival was reported in one comparative trial, but not in another larger one. Vinorelbine is an effective and well tolerated palliative treatment option for elderly patients with advanced NSCLC. Vinorelbine is a semisynthetic vinca alkaloid that arrests cell cycle progression, resulting in an accumulation of cells in mitosis. Vinorelbine interacts with tubulin (the basic protein subunit of the microtubule system) at the vinca alkaloid binding domain. The relative tubulin binding affinities of the vinca alkaloids are very different, with that of vinorelbine being lower than that of vinblastine or vincristine. Vinorelbine’s lesser activity than other vinca alkaloids against axonal microtubules may account for the lower incidence of neurotoxicity associated with vinorelbine therapy. At relatively high concentrations (micromolar), vinorelbine inhibits microtubule polymerisation. However, at concentrations lower than those required to inhibit polymerisation, vinorelbine disrupts microtubule dynamics. Vinorelbine also induces apoptotic cell death. Vinorelbine exerts time- and concentration-dependent cytotoxic effects in vitro and in vivo. In vitro, vinorelbine was more active against non-small cell lung cancer (NSCLC) cell lines than vinblastine, vindesine and vincristine. In in vivo models of NSCLC, vinorelbine demonstrated superior activity to that of vincristine or vinblastine, and was at least as active as vindesine. Combinations of vinorelbine with cisplatin in NSCLC cell lines generally showed additivity or synergy, whilst combinations with cisplatin or gemcitabine in murine lung cancer models produced additive antitumour effects. Vinorelbine, like other vinca alkaloids, is involved in P-glycoprotein-mediated multidrug resistance in vitro and in vivo, although other mechanisms of resistance have also been implicated. The pharmacokinetics of vinorelbine are best described by an open three-compartment model. In patients with NSCLC, vinorelbine is widely distributed to the body, with a high steady-state volume of distribution (38 to 76 L/kg). Vinorelbine is mainly distributed to the blood cells, especially platelets (78%) and the unbound fraction is around 2%. Vinorelbine concentrations in lung tissue were higher than those in serum by up to 340-fold, 3 hours after administration. Metabolism of vinorelbine is primarily by cytochrome P450 3A isoenzymes. Thirteen metabolites of vinorelbine have been detected, but only desacetyl-vinorelbine is active. Vinorelbine undergoes substantial hepatic elimination, with a large proportion recovered in the faeces. Urinary elimination of vinorelbine is low. Total clearance (CL) of vinorelbine ranged from 0.98 to 1.28 L/h/kg in patients with NSCLC. Patients with massive secondary liver disease had a lower CL than those who had no liver disease or lesser invasion. An age-related decrease in CL of vinorelbine was observed in one study in elderly patients with metastatic cancer. However, a population pharmacokinetic model applied retrospectively to data from three phase I studies indicated that age did not influence CL. The pharmacokinetic profile of vinorelbine was not influenced by coadministration with cisplatin. Vinorelbine shows efficacy as a single agent in previously untreated elderly patients with advanced NSCLC. In...