Vincristine-induced peripheral neuropathy in pediatric cancer patients

Abstract

Vincristine is a chemotherapeutic agent that is a component of many combination regimens for a variety of malignancies, including several common pediatric tumors. Vincristine treatment is limited by a progressive sensorimotor peripheral neuropathy. Vincristine-induced peripheral neuropathy (VIPN) is particularly challenging to detect and monitor in pediatric patients, in whom the side effect can diminish long term quality of life. This review summarizes the current state of knowledge regarding VIPN, focusing on its description, assessment, prediction, prevention, and treatment. Significant progress has been made in our knowledge about VIPN incidence and progression, and tools have been developed that enable clinicians to reliably measure VIPN in pediatric patients. Despite these successes, little progress has been made in identifying clinically useful predictors of VIPN or in developing effective approaches for VIPN prevention or treatment in either pediatric or adult patients. Further research is needed to predict, prevent, and treat VIPN to maximize therapeutic benefit and avoid unnecessary toxicity from vincristine treatment.

Keywords: Vincristine; assessment; pediatric oncology; peripheral neuropathy; pharmacogenetics; prevention.

Figure 1

Vincristine pharmacokinetics and pharmacodynamics. Vincristine enters the systemic circulation through direct intravenous administration. It is distributed via passive diffusion into organs for metabolism (liver), efficacy (tumor) and toxicity (neuronal cells). Vincristine is a substrate of several efflux transporters including ABCB1 (P-gp) and ABCC2, ABCC3, and ABCC10, which return vincristine to the circulation. In the tumor and neuron vincristine binds to the β subunit of tubulin, causing cellular apoptosis. In the liver vincristine is partially metabolized by CYP3A4 and CYP3A5 to three inactive metabolites, followed by biliary excretion. The inset box and whisker plot is a hypothetical representation of relative systemic vincristine concentrations in patients stratified by their CYP3A5*3 (non-expresser) status. Patients heterozygous (*1/*3) or homozygous (*3/*3) for the non-expresser genotype would have greater systemic concentrations, causing more of these patients to have toxic levels of vincristine.