Long After Chemotherapy, Cisplatin and Hearing Loss Remain

Abstract

It is an unfortunate reality that cancer survivors face a lifetime of health consequences related to their cancer treatment. As the population of cancer survivors continues to grow, so does the importance of addressing their medical needs. For patients treated with the chemotherapeutic drug cisplatin, one common consequence of treatment is permanent hearing loss. Reported rates of cisplatin ototoxicity vary widely, though it is believed that at least half of all patients treated with cisplatin will suffer hearing loss. As cisplatin is widely used, this rate of ototoxicity translates to hundreds of thousands of patients affected each year in the United States alone.chemo, cancer, hearing lossAs was detailed in a recent article in this journal, efforts to prevent ototoxicity during cisplatin chemotherapy are ongoing (Hearing Journal. 2018;71(1):26). The success of these efforts likely hinges upon understanding why the cochlea is particularly susceptible to damage by cisplatin. Our recent study, reported in the journal Nature Communications, illustrates the importance of cisplatin pharmacokinetics—the movement of the drug within the body—in understanding ototoxicity (Nat Commun. 2017 Nov 21;8(1):1654). CISPLATIN OTOTOXICITY To effectively study cisplatin ototoxicity in the laboratory, we needed to be able to generate cisplatin-induced hearing loss in mice. Just as a patient receives multiple cycles of cisplatin, each separated by several days of recovery, so did the mice in our study. Auditory brainstem response and distortion product otoacoustic emission testing was performed on the mice, and it showed that cisplatin caused progressive hearing loss that worsened with each successive cycle of administration. Notably, hearing loss also continued to progress weeks after cisplatin administration was ceased, as has been reported for some human patients (J Pediatr Hematol Oncol. 2010 Mar;32(2):119; J Pediatr Hematol Oncol. 2004 Oct;26(10):649; Int J Pediatr Otorhinolaryngol. 2010 Aug;74(8):913). At the core of the cisplatin drug is the metal platinum. In fact, the name cisplatin (“cis-platinum”) is derived from the platinum that gives the drug its cancer-killing properties. This core platinum allowed us to measure tissue concentrations of cisplatin using a highly sensitive technique for detecting metals known as inductively coupled plasma mass spectrometry (ICP-MS). As the mice received successive cycles of cisplatin, drug concentrations across different organs were measured by ICP-MS. Most organs (like the liver, heart, kidney, etc.) effectively eliminated cisplatin in the days and weeks after the drug was given. However, cisplatin remained in the cochlea for much longer, showing no significant decrease in concentration even two months later. We went on to analyze postmortem inner ear tissue from human patients who had received cisplatin, and we found that the drug was retained in their cochleae even 18 months after treatment. In both the laboratory mice and these deceased patients, concentrations of retained cisplatin were highest in the stria vascularis region of the cochlea. This region is responsible for providing blood supply to the cochlea and for maintaining the composition of cochlear fluid. PREVENTIVE OPTIONS Our results demonstrated that over time the cochlea has a higher cumulative exposure to cisplatin than other organs and that, unlike other tissues, the cochlea has very little capacity for removing cisplatin. This may explain why the cochlea is particularly susceptible to cisplatin toxicity. For researchers working to develop a method of preventing cisplatin ototoxicity, our results suggest that the best method of preventing cisplatin ototoxicity may be via prevention of cisplatin uptake into the cochlea in the first place. Once inside the cochlea, cisplatin seems to be there to stay. Identification of drugs that block the uptake of cisplatin through the stria vascularis or directly bind and/or inactivate cisplatin as it enters the cochlea may be a viable path toward prevention of cisplatin ototoxicity. For audiologists, the results of our study underscore the importance of long-term hearing monitoring in patients who have received cisplatin therapy. Late-onset hearing loss is known to occur long after cessation of cisplatin treatment, and these study results suggest that this delayed hearing loss may be related to long-retained cisplatin in the cochlea. Until researchers make significant progress in preventing cisplatin ototoxicity in cancer therapy, it is crucial to continue identifying and treating cancer survivors with cisplatin-induced hearing loss.Andrew M. Breglio, DPhilLisa L. Cunningham, PhD