Genetic and Modifiable Risk Factors Contributing to Cisplatin-induced Toxicities

Abstract

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.

Pharmacogenomics of Cisplatin‐Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research

“…The use of genomics to guide the identification of otoprotectants Although there are currently no FDA-approved agents to reduce druginduced ototoxicity, there is substantial research investigating agents that are protective against CIO. In line with this, sodium thiosulfate has received a "fast track designation" by the FDA for reducing CIO in hepatoblastoma, 4,60 highlighting the promise of this agent for certain types of cancer. Furthermore, as reactive oxygen species have been implicated in the development of CIO, free radical scavengers were considered promising otoprotectant candidates.…”

“…The magnitude of the burden associated with these adverse events is illustrated by the fact that at 50 years of age, the cumulative effect of chronic health conditions in survivors of childhood cancer is reported to be 99.9%, compared to only 9.2% in matched community controls . Focusing specifically on cisplatin, the most frequently reported ADRs associated with this treatment are ototoxicity, nausea/emesis, neurotoxicity, myelosuppression, and nephrotoxicity …”

“…This has led to many studies investigating the genetics of CIO, with 72% of cisplatin ADR pharmacogenetics studies focusing on ototoxicity . Nonetheless, there has been a lack of consistency in the results that have been published, with the majority of studies reporting conflicting results.…”

“…3 Focusing specifically on cisplatin, the most frequently reported ADRs associated with this treatment are ototoxicity, nausea/emesis, neurotoxicity, myelosuppression, and nephrotoxicity. 4 The occurrence of cisplatin-induced ototoxicity (CIO) is of particular concern to patients who are undergoing cisplatin treatment, as up to 95% of patients may experience this irreversible ADR. 2 Although devastating to all patients, the loss of hearing may be particularly profound in children who have yet begun to develop language skills.…”

“…9 This has led to many studies investigating the genetics of CIO, with 72% of cisplatin ADR pharmacogenetics studies focusing on ototoxicity. 4 Nonetheless, there has been a lack of consistency in the results that have been published, with the majority of studies reporting conflicting results. As such, there remains a gap in knowledge regarding the contribution of robustly associated genetic variants to the development of CIO.…”