Increasing the dosage of vincristine: a clinical and pharmacokinetic study of continuous-infusion vincristine in children with central nervous system tumors

Abstract

Background: Vincristine (VCR) is widely used to treat patients with malignant disease; among the patients treated with VCR are children with brain tumors. In vitro studies have demonstrated that the cytotoxic activity of VCR is related to both extracellular concentration and duration of exposure. The attainment of higher plasma concentrations by injecting larger bolus doses of VCR has been limited by concerns about neurotoxicity. One possible alternative strategy for enhancing the antitumor efficacy of VCR involves prolonging the duration of in vivo exposure. Therefore, the authors explored the neurotoxicity and pharmacokinetics of VCR administered via a 96-hour continuous infusion after administration of a conventional bolus dose in a pediatric population.

Methods: The current study included 16 patients, 11 of whom were males. The median age of the study population was 4.8 years (range, 1.7-15.8 years). The diagnoses included intrinsic pontine glioma (n = 4), ependymoma (n = 5), astrocytoma (n = 3), medulloblastoma/primitive neuroectodermal tumor (PNET; n = 2), ganglioglioma (n = 1), and choroid plexus carcinoma (n = 1). Of the 16 patients, 5 were newly diagnosed, and the remaining 11 had disease recurrences, 8 of which arose after radiotherapy. Treatment included cyclophosphamide 65 mg/kg administered intravenously over 1 hour on Day 1, a bolus of VCR 1.5 mg/m(2) administered intravenously on Day 2, and VCR 0.5 mg/m(2) per 24 hours administered via continuous intravenous infusion on Days 2-5. Thus, a total VCR dose of 3.5 mg/m(2) was administered via infusion over 4 days. Fifteen patients received 2 courses of treatment at 21-28-day intervals, and a total of 31 treatment courses were administered. VCR concentrations in plasma samples were measured using high-performance liquid chromatography.

Results: Jaw pain, constipation, mild abdominal pain, and depressed reflexes were common. However, only 1 of 31 courses was associated with Grade III toxicity, and no Grade IV toxicity (e.g., cranial nerve palsy, ileus, inappropriate antidiuretic hormone secretion, seizures, hallucinations, etc.) was noted. The steady-state plasma concentration of VCR during continuous infusion ranged from 1 to 3 microg/L in all patients. Responses after 2 courses were evaluated in 14 of 16 patients. A complete response was noted in one patient (astrocytoma), a partial response in three patients (one each with astrocytoma, ependymoma, and PNET), stable disease in seven patients, and disease progression in three patients.

Conclusions: Continuous infusion of VCR after a conventional bolus dose plus cyclophosphamide for children with tumors of the central nervous system did not result in significant neurotoxicity and appeared to be a safe strategy for achieving increased systemic exposure.