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

Wendy A Teft; Eric Winquist; Anthony C Nichols; Sara Kuruvilla; Suzanne Richter; Christina Parker; Peggy Francis; Maureen Trinnear; Jelena Lukovic; Nedal Bukhari; Yun-Hee Choi; Stephen Welch; David A Palma; John Yoo; Richard B Kim

doi:10.1016/j.oraloncology.2018.12.010

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

Oral Oncol. 2019 Feb:89:72-78. doi: 10.1016/j.oraloncology.2018.12.010. Epub 2018 Dec 21.

Authors

Wendy A Teft¹, Eric Winquist², Anthony C Nichols³, Sara Kuruvilla⁴, Suzanne Richter⁴, Christina Parker⁵, Peggy Francis⁶, Maureen Trinnear⁷, Jelena Lukovic⁸, Nedal Bukhari⁴, Yun-Hee Choi⁹, Stephen Welch⁴, David A Palma¹⁰, John Yoo³, Richard B Kim¹¹

Affiliations

¹ Department of Medicine, Western University, 1151 Richmond St., London, ON N6A3K7, Canada.
² Department of Oncology, Division of Medical Oncology, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada; Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada.
³ Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada; Department of Oncology, Division of Surgical Oncology, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada.
⁴ Department of Oncology, Division of Medical Oncology, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada.
⁵ Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada.
⁶ London Regional Cancer Program, London Health Sciences Centre, 800 Commissioners Rd. E., London, ON N6A5W9, Canada.
⁷ Lawson Health Research Institute, 750 Baseline Rd. E., London, ON N6C2R5, Canada.
⁸ Department of Oncology, Division of Radiation Oncology, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada.
⁹ Department of Epidemiology and Biostatistics, Kresge Building, UWO, London, ON N6A 5C1, Canada.
¹⁰ Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada; Department of Oncology, Division of Radiation Oncology, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada.
¹¹ Department of Medicine, Western University, 1151 Richmond St., London, ON N6A3K7, Canada; Department of Physiology and Pharmacology, Medical Sciences Building, UWO, London, ON N6A 5C1, Canada; Department of Oncology, Division of Experimental Oncology, London Health Sciences Centre, Western University, 800 Commissioners Rd. E., London, ON N6A5W9, Canada. Electronic address: Richard.Kim@lhsc.on.ca.

PMID: 30732962
DOI: 10.1016/j.oraloncology.2018.12.010

Abstract

Objectives: Cisplatin-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 methods: In 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.

Results: Weekly 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.

Conclusions: Weekly 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.

Keywords: COMT; Cisplatin; Head and neck cancer; MATE1; Ototoxicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Chemoradiotherapy / methods*
Cisplatin / adverse effects*
Female
Head and Neck Neoplasms / complications*
Head and Neck Neoplasms / drug therapy
Head and Neck Neoplasms / mortality
Humans
Male
Middle Aged
Multidrug Resistance-Associated Protein 2
Ototoxicity / etiology*
Ototoxicity / pathology
Prospective Studies
Survival Rate

Substances

ABCC2 protein, human
Multidrug Resistance-Associated Protein 2
Cisplatin