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\begin{document}

\title{Long-term auditory follow-up in counteracting platinum-induced
ototoxicity in paediatric oncology}



\author[1]{ANNA FETONI}%
\author[1]{eugenio de corso}%
\author[2]{Francesca Brigato}%
\author[1]{Daniela Lucidi}%
\author[2]{walter di nardo}%
\author[1]{EMANUELE SCARANO}%
\author[2]{JACOPO GALLI}%
\author[3]{Antonio Ruggiero}%
\affil[1]{Policlinico Universitario Agostino Gemelli}%
\affil[2]{Universita Cattolica del Sacro Cuore Facolta di Medicina e Chirurgia}%
\affil[3]{Fondazione Policlinico Universitario Gemelli IRCCS - Università Cattolica del Sacro Cuore Roma}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background. Irreversible bilateral sensorineural hearing loss is a
common side effect of platinum compounds. Because of extended overall
survival period of children, a prolonged hearing surveillance and
management of hearing impairments are emerging concerns for pediatric
oncology. Methods. In this retrospective observational study we enrolled
38 children out of 116 treated at our institution by chemotherapy
(cisplatin and/or carboplatin) with or without irradiation between
2007--2014, and submitted to hearing monitoring before every cycle of
chemotherapy and that completed a 5 years long-term follow-up.
Chemotherapy regimens, demographic findings, cumulative doses and
cranial irradiation were compared. Results. At the end of 5-years
follow-up ototoxicity was significantly increased compared to that at
observed the end of chemotherapy (52.5\% vs 39.5\%, p\textless{}0.001).
A late onset of hearing loss was experienced in 13.1\% of children while
in 26.3\% progressive hearing loss was measured. Deafness at the end of
chemotherapy and irradiation was significant prognostic factor for late
ototoxicity outcomes (Odds Ratio 7.2 -- CI:1.67--31.1 --
p\textless{}0.01 and 5.25 -- CI:1.26--21.86 -- p\textless{}0.01
respectively). No significant differences were found between cisplatin
and combined treatment (i.e. cisplatin shifted to carboplatin during
monitoring for the onset of ototoxicity) and ototoxicity was not
associated with platinum compounds cumulative dose
(p\textgreater{}0.05). 13.1\% of children needed hearing aids at the end
of follow-up. Conclusions. Our study confirms the effectiveness of
long-term follow-up in identifying late onset/progressive hearing loss
after platinum compound chemotherapy and allows us to avoid the harmful
effects of hearing deprivation with hearing aid intervention.%
\end{abstract}%



\sloppy


Long-term auditory follow-up in counteracting platinum-induced
ototoxicity in paediatric oncology

Anna R. Fetoni\textsuperscript{1}, Francesca Brigato\textsuperscript{1},
Eugenio De Corso\textsuperscript{1}, Daniela Lucidi\textsuperscript{1},
Walter Di Nardo\textsuperscript{1}, Emanuele Scarano\textsuperscript{1},
Jacopo Galli\textsuperscript{1\#}, Antonio Ruggiero\textsuperscript{2\#}

\textsuperscript{1}Department of Otolaryngology Head and Neck Surgery
Fondazione Policlinico Universitario A. Gemelli IRCSS, Universit\selectlanguage{ngerman}à
Cattolica Sacro Cuore, 00168 Rome, Italy

\textsuperscript{2}Pediatric Oncology Unit, Fondazione Policlinico
Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, 00168
Rome, Italy

Word Count for:

a) Abstract: 245 words

b) Main Text: 3494 words

table:1

Figures: 4

Running title: Long term auditory follow up in pediatric cancers

Keywords: ototoxicity; cisplatin; hearing aids; audiological monitoring;
personalized medicine

\textbf{Corresponding Authors}

Anna R. Fetoni MD, PhD

Dept. of Otolaryngology Head and Neck Surgery

Università Cattolica Sacro Cuore,

Largo Francesco Vito 1, 000168 Roma, Italy

E-mail:\emph{annarita.fetoni@unicatt.it}

Orcid \#: https://orcid.org/0000-0002-6955-7603

Eugenio De Corso MD, PhD

Dept. of Otolaryngology Head and Neck Surgery

Fondazione Policlinico A. Gemelli, IRCCS

Largo A. Gemelli, 8 00168 Roma, Italy

E mail: eugenio.decorso@policlinicogemelli.it

Table of abbreviations\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
dB HL & decibel hearing level\tabularnewline
\midrule
\endhead
ABR & Auditory Brain Response\tabularnewline
SIOP & International Society of Pediatric Oncology\tabularnewline
\bottomrule
\end{longtable}

Abstract

Background. Irreversible bilateral sensorineural hearing loss is a
common side effect of platinum compounds. Because of extended overall
survival period of children, a prolonged hearing surveillance and
management of hearing impairments are emerging concerns for pediatric
oncology.

{\label{background.-irreversible-bilateral-sensorineural-hearing-loss-is-a-common-side-effect-of-platinum-compounds.-because-of-extended-overall-survival-period-of-children-a-prolonged-hearing-surveillance-and-management-of-hearing-impairments-are-emerging-concerns-for-pediatric-oncology.}}

Methods. In this retrospective observational study we enrolled 38
children out of 116 treated at our institution by chemotherapy
(cisplatin and/or carboplatin) with or without irradiation between
2007--2014, and submitted to hearing monitoring before every cycle of
chemotherapy and that completed a 5 years long-term follow-up.
Chemotherapy regimens, demographic findings, cumulative doses and
cranial irradiation were compared.

{\label{methods.-in-this-retrospective-observational-study-we-enrolled-38-children-out-of-116-treated-at-our-institution-by-chemotherapy-cisplatin-andor-carboplatin-with-or-without-irradiation-between-20072014-and-submitted-to-hearing-monitoring-before-every-cycle-of-chemotherapy-and-that-completed-a-5-years-long-term-follow-up.-chemotherapy-regimens-demographic-findings-cumulative-doses-and-cranial-irradiation-were-compared.}}

Results. At the end of 5-years follow-up ototoxicity was significantly
increased compared to that at observed the end of chemotherapy (52.5\%
vs 39.5\%, p\textless{}0.001). A late onset of hearing loss was
experienced in 13.1\% of children while in 26.3\% progressive hearing
loss was measured. Deafness at the end of chemotherapy and irradiation
was significant prognostic factor for late ototoxicity outcomes (Odds
Ratio 7.2 -- CI:1.67--31.1 -- p\textless{}0.01 and 5.25 --
CI:1.26--21.86 -- p\textless{}0.01 respectively). No significant
differences were found between cisplatin and combined treatment (i.e.
cisplatin shifted to carboplatin during monitoring for the onset of
ototoxicity) and ototoxicity was not associated with platinum compounds
cumulative dose (p\textgreater{}0.05). 13.1\% of children needed hearing
aids at the end of follow-up.

{\label{results.-at-the-end-of-5-years-follow-up-ototoxicity-was-significantly-increased-compared-to-that-at-observed-the-end-of-chemotherapy-52.5-vs-39.5-p0.001.-a-late-onset-of-hearing-loss-was-experienced-in-13.1-of-children-while-in-26.3-progressive-hearing-loss-was-measured.-deafness-at-the-end-of-chemotherapy-and-irradiation-was-significant-prognostic-factor-for-late-ototoxicity-outcomes-odds-ratio-7.2-ci1.6731.1-p0.01-and-5.25-ci1.2621.86-p0.01-respectively.-no-significant-differences-were-found-between-cisplatin-and-combined-treatment-i.e.-cisplatin-shifted-to-carboplatin-during-monitoring-for-the-onset-of-ototoxicity-and-ototoxicity-was-not-associated-with-platinum-compounds-cumulative-dose-p0.05.-13.1-of-children-needed-hearing-aids-at-the-end-of-follow-up.}}

Conclusions. Our study confirms the effectiveness of long-term follow-up
in identifying late onset/progressive hearing loss after platinum
compound chemotherapy and allows us to avoid the harmful effects of
hearing deprivation with hearing aid intervention.

{\label{conclusions.-our-study-confirms-the-effectiveness-of-long-term-follow-up-in-identifying-late-onsetprogressive-hearing-loss-after-platinum-compound-chemotherapy-and-allows-us-to-avoid-the-harmful-effects-of-hearing-deprivation-with-hearing-aid-intervention.}}



\section*{Introduction}

{\label{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.

\section*{Material and methods}

{\label{material-and-methods}}

\emph{Study population and study design.}

This is a retrospective observational study of children that underwent
5-years long-term hearing monitoring after chemotherapy and that were
selected among 116 children treated with platinum compounds for solid
tumours in our Institution from 2007 to 2014. The inclusion criteria
were: age at the first platinum course [?]18 years, no administration of
other ototoxic drugs, audiological baseline evaluation (within 2 weeks
of the beginning of treatment), audiological monitoring during
chemotherapy (including a re-evaluation prior to each chemotherapy
cycle) and an yearly audiological long-term follow-up for at least 5
years after the end of chemotherapy. Exclusion criteria was a diagnosis
of hearing loss at the baseline evaluation before chemotherapy.

Based on inclusion criteria we enrolled 38 children treated with
platinum compounds and that completed a 5 years long-term follow-up.
Patient's demographic characteristics, disease status and therapeutic
strategies are summarized in Table 1. Briefly, median age at the
beginning of treatments was 6 (range 1--18), the male-to-female ratio
was 1,375. Most of the primitive lesions were brain tumours (glioma,
medulloblastoma and astrocytoma), but aggressive tumours like
neuroblastomas, osteosarcomas, germ cell tumours and retinoblastomas
were also included.

About treatment modalities:

\begin{itemize}
\tightlist
\item
  Twenty-one patients (55.3\%) were treated with cisplatin with or
  without radiation therapy, of which 12 (57.1\%) switched to
  carboplatin because of toxicity onset, with a cisplatin's median
  cumulative dose of 245 mg/sqm (range 40--1080 mg/sqm) and six received
  a cumulative dose \textgreater{} 400 mg/sqm;
\item
  Seventeen patients (44.7\%) were treated with carboplatin with or
  without radiation therapy, with a median cumulative dose of 3400
  mg/m\textsuperscript{2} (range 800--6050 mg/ m\textsuperscript{2}) of
  which one received a cumulative dose \textgreater{} 5000 mg/
  m\textsuperscript{2}
\end{itemize}

\emph{Audiological monitoring.}

Audiological monitoring was performed in our Institution by the same
team of physicians and audiologists. At least a yearly evaluation was
scheduled in patients with normal hearing whereas a six-monthly
evaluation was performed in patients with a hearing loss diagnosis.
Accordingly, with our previous paper {[}15{]}, audiological evaluation
included otoscopy and tympanometry and acoustic reflex measurements in
order to exclude middle ear pathology (Grason Stadler, Eden Prairie
Minn., USA).

Pure-tone air conduction thresholds were evaluated at frequencies of
0.25, 0.5, 1, 2, 4 and 8 kHz in decibel hearing level (dB HL). Pure-tone
bone conduction thresholds were assessed at frequencies of 0.25, 0.5, 1,
2 and 4 kHz to determine the type of the hearing impairment (i.e.
conductive, sensorineural or mixed). Visual reinforcement audiometry was
performed in a calibrated sound field or via earphones for children
6--30 months of age. Sound-field results reflect hearing in the better
ear if there is a difference in hearing between ears. In general,
frequencies at 0.5, 1, 2 and 4 kHz were obtained when visual
reinforcement audiometry was used to measure hearing. Conditioned play
audiometry (train show) was used for children able to cooperate (30
months to 5 years). Standard pure-tone audiometry was used for older
children (\textgreater{}5 years) under standard conditions using an
Amplaid 319 audiometer (Amplaid Inc., Milan, Italy) in a double-walled,
sound-proof room testing conventional frequency ranges from 0.25 to 8
kHz (see www.asha.org/policy).

Auditory brain response (ABR) evaluation consisted of threshold searches
using 100-\selectlanguage{greek}µ\selectlanguage{english}s clicks as well as tone bursts at 1, 2 and 4 kHz (GN
Otometrics, Copenhagen, Denmark). Responses were obtained by averaged
electroencephalic responses via three scalp electrodes positioned during
sleep. We considered these examinations normal as their threshold was 20
dB HL bilaterally. Patients who had their baseline evaluations recorded
by ABR where subsequently monitored by behavioural audiometry, and thus
no patient underwent exclusive ABR evaluation.

Audiological records were examined and classified according to the SIOP
(International Society of Pediatric Oncology) Boston ototoxicity scale
(grade 0--4). Families of children received adequate and comprehensible
information about side effects of the administered therapy and scheduled
audiological monitoring and gave their written consent to perform the
tests. All protocol procedures were approved by the Ethical Committee of
Fondazione Policlinico Universitario A. Gemelli IRCCS (Number of
protocols: 0019971/20- ID 3074).

\emph{Statistical analyses.}

Statistical analysis of data was performed through Microsoft EXCEL and
IBM SPSS statistics 25 software package Armonk, NY IBM corp. Comparisons
between groups were performed using the \selectlanguage{greek}χ\selectlanguage{english}2 test, ANOVA test (Bonferroni)
and Kruskal-Wallis test for independent samples. An uninominal logistic
regression analyses was performed to analyze if prognostic factor
hearing loss at the end of treatment was a significant prognostic factor
for late ototoxicity outcomes. The results were considered significant
with a p-value \textless{} 0.05.

\section*{Results}

{\label{results}}

\emph{Results at the end of chemotherapy and during the long-term
follow-up.}

Auditory assessment was performed in all children involved in this study
before the beginning of chemotherapy and they showed normal hearing.
Thirty-eight children completed the long-term audiological follow-up
equal or longer than five years (range 60--108 months with a mean of 74
months). At the end of chemotherapy 15/38 (39.5\%) children presented
ototoxicity (SIOP criteria \textgreater{} 0), of which 10/38 (26.3\%)
exhibited a progressive hearing loss during the long-term follow-up
whereas 5/38 (13.1\%) did not progress furtherly hearing loss. In
addiction at the long-term follow-up we observed 5/38 (13.1\%) new cases
with late onset hearing loss. Finally, at the end of the 5-years
follow-up 20/38 (52.5\%) had ototoxicity (SIOP criteria \textgreater{}
0). No patient showed hearing improvement during the hearing monitoring.
Details on grading percentages are showed in Fig. 1. The percentage of
children with ototoxicity at the long-term follow-up was significantly
increased compared to that at the end of chemotherapy 39.5\% versus
52.5\% (p \textless{} 0.001).

\emph{Sub-analyses on the late onset/progression cases.}

Median time of the late onset/progression of ototoxicity was 24 months
by the end of treatment (range: 3--84 months).

In the group of five children with a ``late onset hearing loss'' (Median
age 10years; range 4-12; male/female ratio 4), four children showed a
SIOP grade 1-2 and only one child a SIOP grade 4 at the end of 5-year
follow-up. In this group four patient were exposed to cisplatin (no one
with a cumulative dose \textgreater{} 400 mg/sqm), and one to
carboplatin therapy.

In the group of ten children (median age: 12.5 years; range: 2--18,
male/female ratio was 2.33) that worsened over time a ``progressive
hearing loss'', eight children developed a SIOP grade 4 and 2 children a
SIOP grade 1-2. In this group five patients (50\%) were exposed to
cisplatin plus carboplatin therapy (one with a cisplatin's cumulative
dose \textgreater{} 400 mg/sqm), one patient was exposed to cisplatin
alone with a cumulative dose \textgreater{} 400 mg/sqm, and four
patients were exposed to carboplatin plus cranial irradiation therapy.

These results demonstrated that proportion of patients with SIOP grade 4
hearing loss was significantly higher in patients with hearing loss at
the end of chemotherapy compared with patients with new late onset of
ototoxicity, respectively 8/10 (80\%) versus 1/5 (20\%)
(p\textless{}0.05).

Finally, at the logistic regression analyses we observed that the
presence of hearing loss at the end of treatment was a significant
prognostic factor for long-term ototoxicity outcomes with an Odds Ratio
of 7.2 (CI: 1.67--31.1; p \textless{} 0.01).

\emph{Prognostic factors of late ototoxicity outcomes.}

According to our monitoring protocol, children treated with a second
line carboplatin were those who shifted by cisplatin for the development
of ototoxicity. Furthermore, children who underwent carboplatin therapy
developed a SIOP grade 4 when subjected to prior or concurrent cranial
irradiation for brain cancers. In fact, a significant difference (p =
0.002) existed between children who underwent exclusive carboplatin
therapy and those who were subjected to exclusive carboplatin and
radiotherapy. Irradiation independently, if combined with cisplatin or
carboplatin, was associated with a greater ototoxicity SIOP grade (Fig.
2) with a p-value of 0.001. In addition, increasing age at treatment was
correlated to greater hearing loss (p = 0.013) as seen in Fig. 3, even
if the older children underwent irradiation (p = 0.012) as seen in Fig.
4. A severe late onset/progression ototoxicity was observed in 4/12
(33.3\%) of patients treated by cisplatin and carboplatin and in 1/8
(12.5\%) of patients treated by cisplatin alone (p \textgreater{} 0.05).

The relationship between cumulative dose and incidence of hearing
impairment has been analysed. Despite it is well known that ototoxicity
is dose-dependent {[}15{]}, in this cohort late onset/progression of
hearing loss was not significantly associated with the cumulative dose
of platinum compounds (p \textgreater{} 0.05). In addition, no
significant differences have been observed between genders (p
\textgreater{} 0.05).

During follow-up, for five children (13.1\%), all of which developed a
progressive hearing loss, audiological counselling was performed to
inform family on hearing aids indication and support decision on hearing
rehabilitation. In two aided children the progression of hearing loss
occurred after 5 years of follow-up (i.e. 72 and 84 months after the end
treatment). All of them were affected by medulloblastoma and were
treated with platinum-derived compounds and brain irradiation therapy.
Namely, three children were treated with cisplatin but for the onset of
ototoxicity during audiological monitoring, shifted to carboplatin.
Taken together, these data demonstrate that the early onset of
ototoxicity during chemotherapy and concomitant brain irradiation
significantly affect long-term hearing outcomes. At the logistic
regression analyses we observed that the irradiation was a significant
prognostic factor for long-term ototoxicity outcomes with an Odds Ratio
of 5.25 (CI: 1.26--21.86; p \textless{} 0.01).

\section*{Discussion}

{\label{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 \textgreater{} 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
\textgreater{} 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\textless{}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 \textless{} 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.

\section*{Conflict of Interest}

{\label{conflict-of-interest}}

The authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a
potential conflict of interest.

{\label{the-authors-declare-that-the-research-was-conducted-in-the-absence-of-any-commercial-or-financial-relationships-that-could-be-construed-as-a-potential-conflict-of-interest.}}

\section*{Acknowledgments}

{\label{acknowledgments}}

The authors express their gratitude to Bianca Maria Martina, Paola
Torraco, Francesco Minioto and Mauro De Carlini for their helpful
contribution and technical assistance in audiological assessments

{\label{the-authors-express-their-gratitude-to-bianca-maria-martina-paola-torraco-francesco-minioto-and-mauro-de-carlini-for-their-helpful-contribution-and-technical-assistance-in-audiological-assessments}}





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\textbf{Legends.}

TABLE 1 Patients' demographic characteristics and treatments

FIGURE 1: SIOP grading at the end of the therapy and at 5-years
follow-up

FIGURE 2: Differences in ototoxicity SIOP grade in children who were
subjected to radiotherapy and who were not.

FIGURE 3: Distribution of hearing loss according to the age

FIGURE 4: Distribution of radiotherapy according to the age\selectlanguage{english}
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