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.