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. 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.
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.
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.
Authors: Kevin M Huang; Muhammad Erfan Uddin; Duncan DiGiacomo; Maryam B Lustberg; Shuiying Hu; Alex Sparreboom Journal: Expert Opin Drug Metab Toxicol Date: 2020-04-26 Impact factor: 4.481
Authors: Zulfan Zazuli; Naut J C B Duin; Katja Jansen; Susanne J H Vijverberg; Anke H Maitland-van der Zee; Rosalinde Masereeuw Journal: Int J Mol Sci Date: 2020-09-10 Impact factor: 5.923