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Sameh E. Soliman, Crystal D'Silva, Helen Dimaras, Helen Chan, Brenda L Gallie; Predictive factors for Carboplatin related ototoxicity in children treated for Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Children with retinoblastoma treated with carboplatin-based chemotherapy are at risk of developing moderate to severe, irreversible hearing loss. We hypothesized that some clinical parameters together with testing a number of variants in candidate genes in drug metabolism pathways previously reported to be associated with ototoxicity (methyltransferases TPMT and COMT, and drug transporter ABCC3), would be predictive of ototoxicity.
DNA samples from 97 patients who were treated with carboplatin-based chemotherapy for retinoblastoma were genotyped for the genetic variants in TPMT, COMT, and ABCC3. A blinded, retrospective review of those patients’ clinical records regarding age at diagnosis and at start of chemotherapy, chemotherapy details (number of cycles, drug details and cumulative carboplatin dose), and audiometric results (graded using multiple ototoxicity grading classifications). Hearing loss was defined as ototoxicity ≥ grade 2 by at least one classification system. Complete clinical data was available for 71/97 samples studied and the remaining 26 samples were excluded from final statistical analysis.
Eighty five percent of patients had bilateral retinoblastoma. The median age was 11 months at diagnosis and 12 months at treatment initiation. Sixty-nine out of 71 patients (97%) at diagnosis and 68 patients (96%) at first chemotherapy were ≤3 years of age. Thirteen patients (18%) were treated with radiation and 4 (6%) with bone marrow transplant. The median carboplatin cumulative dose for all patients was 1400mg/m2 (260 to 5148mg/ m2). Ototoxicity occurred in 18 patients (25%), and was significantly associated with age at diagnosis (p=0.01) and age at chemotherapy initiation (p=0.008). The highest likelihood ratio of hearing loss was associated with chemotherapy initiation of <4.25 months of age. Ototoxicity was not associated with any of the genetic variants in TPMT, COMT, and ABCC3.
Younger age and age at first chemotherapy was predictive of Carboplatin related ototoxicity in Retinoblastoma. None of the studied genetic variants showed any relavant association. Age at treatment initiation was found to be a risk predictor of carboplatin-induced ototoxicity. Further studies directed towards reduction of ototoxicity in these susceptible children is recommended for optimal clinical management of retinoblastoma using carboplatin-containing chemotherapy.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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