Platinum compounds are the most widely used group of cytotoxic drugs worldwide. Each year more than 5.8 million patients are diagnosed with a cancer for which first-line therapy can potentially include platinating agents. Despite over 30 years of use, there are few means of identifying patients at risk for platinum-induced ototoxicity or neuropathy who might be offered alternative therapy or reduced-dose regimens. For patients who must receive platinum, there are no approved preventive measures and few therapies for these toxicities. To help fill these important gaps, in our initial project period, we established the first well-characterized clinical cohort of over 2,000 testicular cancer survivors (TCS) cured with homogeneous cisplatin-based chemotherapy (without other ototoxic/neuropathic drugs) and made inroads into the genetics of ototoxicity and neuropathy. Our initial project period was highly productive. We published 16 manuscripts (3 in the Journal of Clinical Oncology), plus 3 others under review. Our baseline, cross-sectional results showed that 80% of our patients had hearing loss on audiometric testing, with 1 in 5 classified as severe-to-profound (a level at which hearing aids are recommended); 56% had neuropathy; and 40% had tinnitus. We found that a SNP in deafness gene WFS1 that was related to hearing loss (P=1.4x10-8) also showed a significant interaction with cisplatin dose, thus having potential clinical impact to predict susceptibility. At a young median age (37 years), 38% of TCS already had ?3 adverse health outcomes (range 1-11). Given this early burden, critical unanswered questions remain and will be addressed in the next grant cycle: (1) characterization of the longitudinal trajectory of platinum toxicities, including the role of comorbidities, modifiable risk factors, and residual serum platinum levels; (2) the impact of toxicities on health-related quality of life and patient functioning; and (3) further elucidation of the role of genetic variation in platinum toxicities to identify high-risk subgroups.
Our aims are:
Aim 1. Characterize the longitudinal trajectory of platinum-related ototoxicity and neuropathy, repeating audiometry, and expanding data collection for the first time to include a comprehensive set of physical and psychosocial domains to inform the eventual development of evidence-based guidelines for TCS follow-up;
Aim 2. Evaluate for the first time the impact of cisplatin-related hearing loss, tinnitus and neuropathy and their severity on physical, emotional and social patient functioning;
Aim 3. Identify additional genetic variation that predisposes patients to platinum-related ototoxicity and neuropathy and that influences residual serum platinum levels through genotyping and whole exome sequencing. IMPACT: Findings derived from our unique clinical cohort will provide the first comprehensive, longitudinal assessment of multiple platinum-related toxicities in any large, homogenously treated cohort of adult-onset cancer survivors and help inform the eventual development of evidence-based guidelines for TCS follow- up. Our findings will also provide the basis for the development of preventive and interventional strategies for cisplatin- related toxicities associated not only with significant impairment of quality of life, but substantial morbidity.
The public health significance of this proposal resides in the fact that each year more than 5.8 million patients are diagnosed with a cancer for which first-line therapy can potentially include platinating agents; however, there are few means of identifying patients at risk for platinum-induced toxicities who might be offered alternative therapy, improved symptom management, or reduced-dose regimens. For patients who must receive platinum, there are no approved preventive measures and few treatments for toxicities. Our proposal is designed to fill these gaps.
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