Risk factors for cisplatin-associated ototoxicity in pediatric oncology patients.

BACKGROUND: Cisplatin is an effective chemotherapy agent against several pediatric malignancies. One of its side effects is irreversible sensorineural hearing damage that is highly variable with a reported incidence of 22-70%. The aim of this study was to evaluate the incidence and identify clinical predictors of cisplatin-related ototoxicity. PROCEDURES: We performed a retrospective chart review of 102 pediatric patients who had completed cisplatin therapy for osteosarcoma, neuroblastoma, hepatoblastoma, or germ cell tumor. Patients were diagnosed at Riley Hospital for Children between January 1995 and June 2008, were less than 18 years old at diagnosis, and had normal hearing prior to therapy. Audiograms were scored using the Brock scale (0-4), a validated grading system for cisplatin-related hearing loss. RESULTS: Forty-two percent of the patients experienced hearing loss and 28% had moderate to severe ototoxicity (Brock score ≥2). Males were at significantly greater risk for developing hearing loss than were females (P = 0.005, OR 4.812). Age at cancer diagnosis was inversely related to severity of ototoxicity. Patients who suffered Brock grade 3 ototoxicity had a mean age of 4.5 years versus 11.5 years and 7.2 years for grades 1 and 2, respectively (P = 0.02). Cumulative cisplatin dose was also identified as a risk factor for development of ototoxicity (P = 0.03). CONCLUSIONS: Gender and cumulative dose are important clinical biomarkers of cisplatin ototoxicity. Severity of ototoxicity may be inversely related to age at time of exposure, with very young patients exhibiting higher grades of hearing loss following cisplatin therapy.

Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia.

BACKGROUND: This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy (VIPN) in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70% express CYP3A5) than in Caucasians. We test the hypothesis that CYP3A5 expressers experience less vincristine neuropathy than do CYP3A5 non-expressers. PROCEDURE: This study of pharmacogenetics of vincristine neuropathy in children with preB ALL was completed at Indiana University Simon Cancer Center. Whole blood for DNA extraction and genotyping was collected as well as plasma from a single time-point for analysis of vincristine and primary metabolite (M1) concentrations. Vincristine neuropathy was captured via chart review and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Eighty-nine percent of CYP3A5 expressers experienced neurotoxicity versus 100% of non-expressers (P = 0.03). The proportion of treatment months with neurotoxicity was significantly different between the expressers and non-expressers (16% vs. 27%, P = 0.0007). Limited pharmacokinetic data suggest different rates of vincristine metabolism between CYP3A5 genotype groups with higher primary metabolite (M1) plasma concentrations (P = 0.0004) and lower metabolic ratios ([vincristine]/[M1]) (P = 0.036) in the CYP3A5 expressers compared to the CYP3A5 non-expressers. M1 concentration was also inversely related to severity of neuropathy (P = 0.0316). CONCLUSIONS: In children with preB ALL, CYP3A5 expressers experience less VIPN, produce more M1, and have lower metabolic ratios compared to CYP3A5 non-expressers.