Vincristine revisited

Many controversies and questions about vincristine persist, despite extensive clinical application over the past 30-40 years. Further research effort is required to maximize the therapeutic ratio of vincristine. The contribution of vincristine as a component of multi drug protocols require critical evaluation to avoid unnecessary exposure to unwanted side effects without survival benefit. The mechanism of mitotic inhibition of vincristine is well known. New insights in its cytotoxic effects, including induction of apoptosis, are emerging and may lead to the identification of new targets or new strategies in the design of combination therapies [182,315]. Questions remain concerning the clinical scope of vincristine neuropathy. The incidence of long-term sequelae is unclear as is the involvement of the central nervous system. The extent to which muscles are involved and whether these are involved directly by vincristine is also poorly characterized. Uncertainty about optimal dosing regimens continues. Should bolus doses continue to be capped to protect against neurotoxicity? In infants, guidelines are lacking about when to switch from dose calculation according to body weight to calculation according to body surface area. Also, continuous infusion has not been studied sufficiently to establish therapeutic superiority to conventional bolus doses. Knowledge about vincristine pharmacokinetics in relation to cytotoxicity and neuropathy are essential to the development of an optimal dosing regimen. Vincristine metabolism, an important determinant of pharmacokinetics, is poorly understood. The extent to which factors such as age, liver function, underlying or intercurrent disease or concomitant medication influence pharmacokinetics and thereby maybe also neuropathy, is unclear. Further study of these variables is needed to provide better guidelines for dosage adaptations. Currently, the only way to prevent vincristine neurotoxicity is dose reduction or interruption of therapy. Neuroprotective agents may be beneficial in the future. If vincristine neuropathy can be decreased by protective agents it might be possible to increase vincristine dose-intensity, which might increase the oncolytic effect. Besides more intensive study of potential neuro-protective agents, the influence these agents may have on cytotoxicity requires careful evaluation before their routine use can be recommended. Finally, to optimize the use of vincristine, more information is needed about the clinical relevance of in vitro measured resistance and of the different mechanisms involved. Modulators of resistance might be used more specifically once the clinical significance of the various mechanisms of resistance are better understood. At present, many questions about vincristine remain. In this review we outline current knowledge and suggest directions for further research which are likely to improve the therapeutic ratio of this familiar drug and improve individual patient outcomes.