Clinical Practice Recommendations for the Management and Prevention of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers

Abstract

Abstract:Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field; (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment and management of cisplatin-induced hearing loss in children and adults; and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin based chemotherapy.

Ototoxicity monitoring in children treated with platinum chemotherapy

“…Pharmacogenomic studies investigating genetic variants in methyltransferases (thiopurine S-methyltransferase gene [TPMT] (Ross et al, 2009), catechol-o-methyltransferase gene [COMT]) (Ross et al, 2009) cisplatin transporters (ATP-binding cassette sub-family C member 3 [ABCC3], CTR1) (Pussegoda et al, 2013), glutathione-S-transferases (GSTs) and megalin (LRP2) (Choeyprasert et al, 2013) have found mixed results, likely due to variability of patient populations and treatment regimens. Genetic variants in TPMT were strongly associated with cisplatin ototoxicity in three independent paediatric cohorts (Ross et al, 2009;Pussegoda et al, 2013) and it has been recommended that all children receiving cisplatin therapy have testing for genetic variants in TPMT, ideally before the initiation of therapy (Lee et al, 2016). However, despite the high predictive value of TPMT (92%), only approximately 25% of children who acquire cisplatin-associated ototoxic hearing loss have a genetic variant in TPMT.…”

“…Individual risk factors for acquiring hearing loss from cisplatin therapy are age less than 5 years (Li et al, 2004), cisplatin cumulative dose and dose intensity (Lewis et al, 2009;Yancey et al, 2012), prior or concurrent cranial radiation (Warrier et al, 2012), concomitant treatment with other ototoxins, such as myeloablative carboplatin, aminoglycosides and loop diuretics (Parsons et al, 1998;Landier et al, 2014) and genetic susceptibility (Rednam et al, 2013;Carleton et al, 2014;Lee et al, 2016). Several studies suggest that platinum-induced hearing loss can worsen after treatment is completed (Bertolini et al, 2004;Einarsson et al, 2010) and survivors who received cranial radiation prior to cisplatin therapy appear to be at the highest risk (Bass et al, 2016;Kolinsky et al, 2013).…”

Physician-Reported Benefits and Barriers to Clinical Implementation of Genomic Medicine: A Multi-Site IGNITE-Network Survey

“…Many of these drug–gene interactions are clinically “actionable”, meaning they merit inclusion in the clinical decision-making process. The growing number of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines [ 6 ] and those from other pharmacogenetics guideline-writing groups [ 7 , 8 , 9 , 10 , 11 , 12 ] is a testament to the expanding robust evidence demonstrating the value of adding genetic information to the clinical decision-making process.…”

Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines

“…Genetic factors associated with cisplatin-induced ototoxicity have been reported, many in genes associated with reactive oxygen species detoxification and drug absorption, metabolism, distribution and excretion (ADME)[12]. One such pharmacogenomic association was identified, and subsequently replicated, in two independent cohorts of Canadian children (approximately 300 cisplatin-treated children)[13, 14].…”