Cisplatin (cis-diamminedichloroplatinum) plus intensity-modulated radiation therapy, also called IMRT, is the mainstay of treatment for head and neck cancer (HNC). In a randomized Phase 2 trial called PREVLAR, the addition of nibrozetone (RRx-001) to chemoradiation (CRT) dramatically reduced the incidence and severity of oral mucositis (SOM) and led to FDA Fast Track designation.
Of the many serious CRT-related side effects including renal impairment, nausea/vomiting, and bone marrow suppression, one of the most overlooked— least heard about? — is ototoxicity or toxicity to the inner ear. Progressive, bilateral hearing loss, ear pain, and tinnitus (the perception of ringing, buzzing or other sounds in the ear) are highly distressing side effects that contribute not only to social isolation, anxiety, depression, and profoundly reduced quality of life as a result but also to treatment nonadherence.
Cisplatin- and radiotherapy-related ototoxicity usually starts within days to weeks after treatment. Susceptibility to ototoxicity increases with cisplatin dose, radiation dose to the inner ear, pre-existing hearing loss, prolonged exposure to damaging levels of noise, and the use of other ototoxic drugs like aminoglycosides and macrolide antibiotics, loop diuretics (Lasix), antimalarials, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as Aleve. To date, no therapeutic intervention has been shown to prevent or reduce it.
Several antioxidants and anti-inflammatories have been tried as otoprotectants, that is, as therapies to prevent or mitigate hearing loss with little success. In a Phase 3 pediatric anticancer trial with cisplatin, one of these antioxidants, sodium thiosulfate (STS), reduced the incidence of hearing loss but at the cost of significantly decreased survival rates for patients with metastatic disease. However, STS is a cisplatin inactivator; free cisplatin remains in human plasma for less than 50 min when STS is present, as compared to more than 3 h when it is not, so these results are not exactly surprising.[1] So, of critical importance for any potential otoprotectant, is non-interference with the efficacy of cisplatin and/or radiation.
Unknown at this point is whether nibrozetone (RRx-001), as an anti-inflammatory/antioxidant, demonstrates otoprotective properties. However, nibrozetone (RRx-001) is definitively not tumor protective, in fact it is toxic to tumors, so in the soon-to-start confirmatory Phase 2b KEVLARx trial, which is the sequel to the above-mentioned Phase 2a PREVLAR trial, we will make sure to keep an ear out for any evidence of otoprotection.
[1] Freyer, DR et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017, 18, 63– 74, DOI: 10.1016/S1470-2045(16)30625-8