Predictors of cisplatin-induced ototoxicity and survival in chemoradiation treated head and neck cancer patients

Abstract

ObjectivesCisplatin-induced ototoxicity is a common permanent consequence of curative chemoradiation for locally advanced head and neck squamous cell carcinoma (HNSCC). Predictors of ototoxicity in HNSCC were examined. Materials and methodsIn this prospective, observational cohort study, 206 adult HNSCC patients underwent audiometric testing at baseline, during and after treatment with cisplatin-based chemoradiation. Ototoxicity was defined as ≥grade 2 audiometric change from baseline (CTCAE v4.02). Relationships between clinical and pharmacogenetic (TPMT, COMT, ACYP2, CTR1, OCT2, MATE1, ABCC2, ABCC3, and ABCG2) covariates and ototoxicity, progression-free (PFS) and overall survival (OS) were assessed by Cox regression. ResultsWeekly cisplatin resulted in lower ototoxicity risk while PFS and OS were similar compared to high dose cisplatin (P = 0.00035; HR = 0.18; 95% CI, 0.07–0.46). COMT (rs9332377) carriers had higher ototoxicity risk (P = 0.00556; HR = 1.72; 95% CI, 1.17–2.52) while MATE1 (rs2289669) A/A carriers were protected from ototoxicity (P = 0.01062; HR = 0.46; 95% CI, 0.26–0.84). Absence of the protective MATE1 allele among those who carry the risk allele in COMT predicted increased ototoxicity risk, (P = 0.00414; HR = 3.22; 95% CI, 1.45–7.17 and P = 0.00022; HR = 4.89; 95% CI, 2.11–11.36). Survival outcomes did not differ between carriers of protective or risk alleles. ConclusionsWeekly cisplatin dosing, COMT and MATE1 are predictors of ototoxicity without affecting treatment efficacy. COMT and MATE1 genotyping and weekly dosing may be a potential strategy for mitigating cisplatin-induced ototoxicity in HNSCC.