Introduction

The most common platinum-based agents, cisplatin and carboplatin, are widely used against several childhood and adolescent malignancies including neuroblastoma, osteosarcoma, germ cell tumours, teratoma, hepatoblastoma and a variety of brain tumours (e.g. glioma, astrocitoma, medulloblastoma) [1]. Dose depending sensorineural hearing loss is a common side effect of cisplatin chemotherapy in children. It is typically an irreversible bilateral hearing loss that initially involves high frequencies and with the progressive increase of the cisplatin cumulative dose also affects low frequencies. The prevalence of cisplatin-induced ototoxicity, measured with standard audiometry to 8 kHz, is approximately 60–70% in pediatric population [2-4].
Although deafness is not a life-threatening condition, hearing loss can be detrimental for a child, especially on learning, academic performances and school behavior [5]. Deafness is associated with lower school functioning scores, greater need for special education services and poorer child-reported quality of life [6]. Furthermore, Authors demonstrated that, when hearing loss was serious enough to require hearing-aid use, it was independently associated with decline in cognition and educational performance [7,8].
Unfortunately, the cochlear damage is irreversible, and involves various complex molecular mechanisms such us: induction of oxidative stress (i.e. reactive oxygen species production and lipid peroxidation), inflammation by activating pro-inflammatory factors and induction of p53-dependent signaling pathways [9,10]. It has been experimentally demonstrated that the outer hair cells are the major target for cisplatin ototoxicity, whereas carboplatin affects mainly the inner hair cells although it is considered less ototoxic than cisplatin [11-15]. Therefore, carboplatin may be introduced in children developing cisplatin ototoxicity [15]. In fact, it is possible to limit cisplatin cumulative dose damage by surveillance for hearing loss shifting the treatment by cisplatin to carboplatin at the onset of ototoxicity signs [15].
Implementation of the hospital protocols for auditory monitoring and the optimization of platinum-derived chemotherapy are challenging for children cancer treatment [8,15] because effective preventive or curative therapeutic approaches in counteracting ototoxicity are lacking [14,16-22]. In fact, we demonstrated that the overall incidence of hearing loss was significantly decreased in children treated with cisplatin who underwent to auditory monitoring [Fetoni et al., 2016].
Thus, there is a general agreement on the role of surveillance across the clinical assessment of auditory function in order to early identify deafness during chemotherapy [23-28]. Nonetheless, a progressive worsening of hearing can appear several months after treatment even though it was normal at the end of treatment [29]. Therefore, a long-term follow-up can reveal not only a worsening of hearing loss in children who showed ototoxicity during treatment but also a late onset of hearing loss occurring months to years after therapy. How often and how long surveillance for hearing loss should be performed remains critical issues [29-31].
In this study we aimed to evaluate the risk of late ototoxicity both in terms of late new onset or progression in order to verify the hypothesis that long-term follow-up for ototoxicity is needed in children treated by platinum derived compounds chemotherapy. The early diagnosis in these patients is very important considering the lack of available otoprotectants, and requirement of an early rehabilitation by hearing aids, if needed, especially in children affected by comorbidities caused by their illness condition.