Discussion
Nowadays, audiological monitoring is strongly recommended for
ototoxicity surveillance [32] in pediatric oncology, especially if
treated with platinum-derived compounds. In fact, it has been recently
demonstrated, that the overall incidence of hearing loss can be
significantly decreased by auditory monitoring during treatment because
of early identification of ototoxicity and therapy shift to carboplatin
[15]. Furthermore, late onset or progression of hearing loss after
the end of therapy has been described [7, 8, 29] even though few
studies have been focused on long-term audiological monitoring. However,
specific guidelines on long-term interventions in reducing late
ototoxicity are still under discussion for health-care professionals in
pediatric oncology.
Our aim was to provide evidence about the effectiveness of long-term
surveillance in preventing platinum-induced hearing effects in children
and adolescents surviving to cancer. In our experience, hearing status
is currently measured after each cycle of cisplatin and adjustment of
chemotherapy can be helped with suitable audiological counseling. When a
child is diagnosed with grade > 2 ototoxicity, cisplatin
administration is stopped and changed to carboplatin. This protocol is
able to achieve hearing loss diagnosis at an early stage and to provide,
jointly with pediatric oncologists, therapeutic strategies to reduce
further progression of ototoxic side effect shifting by cisplatin to
carboplatin [15].
In our series we confirmed that hearing loss may develop and progress in
children during platinum-based therapy [29], however deafness may
increase over the years after the end of therapy. Furthermore, we
interestingly demonstrated the high risk to develop a late
onset/progressive hearing loss at 5-years follow-up (SIOP criteria
> 0) that occurred in 15/38 (39.5%) patients. These
results are particularly important to identify cases requiring early
hearing rehabilitative strategies to prevent harmful effect of hearing
deprivation. In fact, we observed that 25% of monitored children needed
hearing aid intervention.
How the ototoxicity appears or progresses over time is still unclear,
nevertheless a prolonged maintenance of platinum in the body has been
detected up to 20 years after treatment [33]. Furthermore, in
experimental models, cisplatin has been demonstrated to target numerous
cell types including outer hair cells and synapses between inner hair
cells and terminal fibers of spiral ganglion neurons with a following
neuronal degeneration that can appear at months after synaptic damage
[10, 34, 35]. Thus, as in the noise induced hearing loss and aging
[36], the cisplatin-induced synaptopathy and neural degeneration
might explain the compromised speech understanding in noisy environments
especially observed in children that may lead to difficulties in school
performances and psychosocial functioning [37, 38].
Platinum-induced hearing loss is irreversible [2, 15, 29], in fact
in our experience no improvement of hearing was found over time, as
expected we only observed a worsening of hearing after platinum therapy
that was even more common than a late onset of hearing loss (i.e 26.3%
vs 13.1% respectively). Among children having a progressive hearing
loss, a SIOP grade 4 was found in 8/10 (80%) indicating that the
presence of hearing loss at the end of treatment was a negative
prognostic factor for long-term ototoxicity outcomes (Odds Ratio: 7.2 –
CI: 1.67–31.1; p<0.01). Furthermore, median time of the late
onset and progression of ototoxicity was 24 and 18 months respectively
by the end of treatment. The early onset of ototoxicity as detected by
the auditory monitoring is suggestive for a worse audiological outcome
over time likely depending by individual susceptibility that is still
understudied. A genetic predisposition has been proposed based upon
observations of substantial inter-individual variability in the
prevalence and severity of ototoxicity including polymorphisms for genes
involved in the oxidative stress, which is the major target of cisplatin
ototoxicity [15, 39]. Unfortunately, a routinely analysis of genetic
polymorphism is still lacking [40], therefore the long-term
audiological monitoring remains a major target for prevention of
ototoxicity.
Traditionally, cumulative doses, age at treatment, cranial irradiation
and type of malignances have been considered as risk factors for
platinum-induced ototoxicity in pediatric population [40, 41]. In
contrast to previous findings [43], we found that the cumulative
dose of cisplatin, affecting the early onset of hearing loss [15],
did not correlate with long-term development of ototoxicity.
Remarkably, we found that the risk of hearing loss was high associated
with cisplatin-based multimodal therapy that included carboplatin and/or
radiotherapy rather than a cumulative dose of cisplatin alone that is
currently suggested as indicator for hearing screening. Brain
irradiation is then an independent factor for the occurrence of
ototoxicity during platinum chemotherapy [42, 43]. In fact, most of
children treated with carboplatin were those who developed ototoxicity
during cisplatin treatment and then shifted to less ototoxic
carboplatin; probably susceptibility to cisplatin damage remains major
trigger for development of hearing loss. Furthermore, children who
underwent carboplatin therapy alone developed a SIOP grade 4 when
subjected to prior or concurrent cranial irradiation for brain cancers.
Therefore, irradiation remains even in our experience a prognostic
factor for long-term ototoxicity outcomes (Odds Ratio of 5.25 – CI:
1.26–21.86; p < 0.01).
Hence, in the pre-treatment counseling, it is important for pediatric
oncologist to inform families on the possibility to change chemotherapy
avoiding ototoxicity during treatment and indication for a long-term
audiologic follow-up, especially in children affected by brain cancers
treated with radiotherapy. In these cases, whether shifting by cisplatin
to carboplatin the overall survival can be affected is a controversial
issue that needs to be further discussed with family [1].
We found a worse hearing in older children, conversely in literature a
higher ototoxicity is reported in younger age [4, 32, 41, 43]. In
our study, although the limitation in size sample, older children were
affected by medulloblastoma, which is even a rare cancer, and
experienced a worse hearing loss. This could be explained as the most of
them was treated with both platinum compound and irradiation therapy.
While, younger children affected by neuroblastoma and retinoblastoma
were mainly treated with carboplatin.
A great variability of ototoxic outcomes has been reported [41, 43]
that might depend on differences in assessment strategies, such as
inclusion criteria, patient population, methodological techniques,
auditory measurements and duration of follow-up. Worthy of note, among
different scales we use the Boston SIOP ototoxicity scale, which is
sensitive to high frequencies of hearing, the most affected by
platinum-derived ototoxicity, even if in younger children they are more
difficult to detect [32,41,]. Probably there is not a comprehensive
scale for all conditions considering the variability of audiological
assessment for age at treatment, status of illness of children during
testing, concomitant cognitive and sensorial impairment. However, this
grading system seems to be able to include a larger number of affected
children.
In our series, five out of children who progressed hearing at the
long-term follow-up required hearing aid rehabilitation. Deafness,
especially during childhood and even when only borderline to mild, can
have important implications. Therefore, a parental counselling on
auditory diagnosis and benefits of hearing aids is recommended. The
early and appropriate hearing rehabilitation that better suits children
needed is crucial for brain plasticity maintenance during sensitive
period and language development, social integration [44] and quality
of life considering that most of these are multi-handicap patients,
mainly with sensory deprivation (i.e. visual) that further affects
outcomes. While in teenager the high-frequency hearing loss can reduce
speech recognition in noisy environment affecting learning and
communicative abilities, especially during school performances. Thus,
hearing aids and the use of assistive listening devices such as
frequency modulation systems are suitable. Additionally, audiological
surveillance is useful in children affected by central nervous system
tumours since hearing loss is associated with worse physical well-being,
poorer relationship with peers and greater need for social support
compared to normal hearing [45]. Furthermore, most of survival
children live far from tertiary oncologic institutions, therefore many
years after the end of therapies oncological check-ups become less
frequent; many families continue their sporadic radiologic and clinical
controls at their hometown hospital, making it difficult to obtain a
long-term reliable hearing assessment.
Parents may be advocated by the supporting services so that their child
is not lost to follow-up once they enter survivorship. In addition to
monitoring hearing provides beneficial effects on children and young
adults in understanding their hearing status, its impact on
communication and learning, hearing conservation, and their options for
ongoing management.
In conclusion, platinum compounds can lead to bilateral, late onset or
progressive and permanent sensorineural hearing loss affecting language
development. Therefore, long-term monitoring is recommended in all
children considering that deafness is dependent by treatments and
individual susceptibility that likely trigger the onset and progression
of ototoxicity. To date, the long-term monitoring at least of 5 years,
especially in children who underwent multimodal therapy including
irradiation, may offer the highest level of care to our patients and
their families improving quality of life after successful oncological
treatment.