Review Article

Ototoxicity and Cancer Therapy

Wendy Landier PhD, CRNP

Ototoxicity is a well-established toxicity associated with a subgroup of antineoplastic therapies that includes platinum chemother-
apy, radiation or surgery involving the ear and auditory nerve, and supportive care agents such as aminoglycoside antibiotics and
loop diuretics. The reported prevalence of ototoxicity in patients who have received potentially ototoxic therapy ranges from 4% to
90% depending on factors such as age of the patient population, agent(s) used, cumulative dose, and administration techniques.
The impact of ototoxicity on subsequent health-related and psychosocial outcomes in these patients can be substantial, and the
burden of morbidity related to ototoxic agents is particularly high in very young children. Considerable interindividual variability in
the prevalence and severity of ototoxicity has been observed among patients receiving similar treatment, suggesting genetic sus-
ceptibility as a risk factor. The development and testing of otoprotective agents is ongoing; however, to the author’s knowledge, no
US Food and Drug Administration-approved otoprotectants are currently available. Prospective monitoring for ototoxicity allows
for comparison of auditory outcomes across clinical trials, as well as for early detection, potential alterations in therapy, and audi-
tory intervention and rehabilitation to ameliorate the adverse consequences of hearing loss. Cancer 2016;122:1647-58. V C 2016 Amer-

ican Cancer Society.

KEYWORDS: antineoplastic therapy, genetic predisposition, grading scales, management of hearing loss, otoprotection, ototoxicity.

INTRODUCTION
Ototoxicity, manifesting as hearing loss, tinnitus, and/or vertigo, is a well-established toxicity associated with a subgroup
of antineoplastic therapies that include platinum chemotherapy and radiation or surgery involving the ear and auditory
nerve. Supportive care agents, such as aminoglycoside antibiotics and loop diuretics, also may contribute to ototoxicity in
patients with cancer. The impact of ototoxicity on subsequent health-related and social outcomes in these patients can be
substantial. Long-term effects may include permanent, severe to profound hearing loss or deafness, resulting in problems
with communication and social interaction, and impaired health-related quality of life. In young children, ototoxicity also
may significantly impair cognitive performance and the development of language and social skills.

Magnitude of the Problem

The reported prevalence of ototoxicity in patients who have received potentially ototoxic therapy ranges widely, from 4%
to 90%,1-7 depending on many factors, such as agent(s) used, age of the patient population, cumulative dose, and adminis-
tration techniques. A summary of the recent literature reporting the prevalence of ototoxicity associated with various can-
cer populations is presented in Table 1.1-13 It is interesting to note that the burden of morbidity related to ototoxic agents
is substantially higher in very young children2,3,6,14 and in those who receive higher cumulative doses of ototoxic
agents.2,3,13,14 However, interindividual variability in the prevalence and severity of ototoxicity, even in these vulnerable
populations, suggests that genetic susceptibility also may play an important role.15-18

Mechanisms of Ototoxicity
Normal anatomy and physiology of the ear
The ears comprise 3 compartments known as the external, middle, and inner ears (Fig. 1). The external ear serves to
amplify and direct sound toward the middle ear, in which the ossicles transform the sound waves into mechanical energy,
which is transmitted to the inner ear. In the inner ear, sound is transmitted by hydraulic waves in the cochlea that stimulate
the sensory hair cells lining the organ of Corti, releasing neurotransmitters that cause the eighth cranial nerve to fire and
transmit the neural impulses through the brainstem to the auditory cortex in the temporal lobe of the brain (Fig. 2).

Corresponding author: Wendy Landier, PhD, CRNP, Division of Pediatric Hematology/Oncology, Institute for Cancer Outcomes and Survivorship, University of
Alabama at Birmingham, 1600 7th Ave S, Lowder 500, Birmingham, AL 35233; Fax: (205) 623-2121; wlandier@peds.uab.edu

Department of Pediatric Hematology/Oncology, Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, Alabama.

DOI: 10.1002/cncr.29779, Received: September 8, 2015; Revised: October 13, 2015; Accepted: October 14, 2015, Published online February 9, 2016 in Wiley
Online Library (wileyonlinelibrary.com)

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Review Article
TABLE 1. Prevalence of Ototoxicity in Various Cancer Populations
Study Cancer Population
Bokemeyer 19988 86 patients with testicular carcinoma
who received platinum-based
chemotherapy; median age at
diagnosis was 26 y (range, 19-50
y); 100% male.
Dean 20087 99 pediatric patients who received
platinum-containing regimens;
median age at diagnosis was 3.6 y
(range, 1-17 y); 59% male.
Gupta 20061 39 patients who received cisplatin for
the treatment of germ cell tumors;
median age at diagnosis was 9 y
(range not reported); 41% male.
Ilveskoski 19969 35 patients who received “8-in-1”
chemotherapy for treatment of
malignant brain tumors; mean age
at diagnosis was 5.3 y (range,
birth-15 y); 63% male.
Knight 20053 67 patients who received platinum-
based chemotherapy for the
treatment of cancer; mean age
was 9.6 6 6.2 y (range, 8 mo-23 y);
67% male.
Landier 20142 333 patients with high-risk
neuroblastoma; median age at
diagnosis was 3.3 y (range,
birth-29 y); 56% male.
Lewis 20094 36 children with osteosarcoma were
treated with cisplatin; median age
at diagnosis was 14 y (range, 3-18
y); 39% male.
Low 200610 115 patients with nasopharyngeal
carcinoma; median age was 45 y
(range, 15-74 y); 83% male.
Nitz 20135 129 patients with bone or soft tissue
sarcoma; median age at diagnosis
was 13.6 y (IQR, 10-16 y); 51%
male.
1648
Ototoxic Therapy
Mean cumulative cisplatin doses in
patients with no, transient, and
persistent ototoxicity: 297 mg/m2,
337 mg/m2, and 678 mg/m2,
respectively.
Mean cumulative dose of carboplatin
alone: 3987 mg/m2; cisplatin alone:
391 mg/m2; combined: cisplatin,
401 mg/m2 plus carboplatin,
1566 mg/m2; 36% of patients also
underwent cranial radiation.
Median cumulative cisplatin dose:
400 mg/m2; all doses were
administered by continuous
infusion at 20 mg/m2/d for 5 d per
course.
Mean cumulative dose of cisplatin:
548 mg/m2 (range, 180-900 mg/m2);
54% had a VP shunt; all patients
also received cranial radiation.
Mean cisplatin dose: 493 6 174 mg/
m2; mean carboplatin dose:
4701 mg/m2; 34% had received
cranial radiation prior to platinum.
Cisplatin dose: up to 400 mg/
m2 6 myeloablative carboplatin
1700 mg/m2.
Cisplatin cumulative dose ranged
from 210-480 mg/m2
58 patients received cisplatin; median
dose: 160 mg (range, 112-213 mg)
combined with radiotherapy; 47
patients received radiotherapy
alone; all patients received 70 Gy
in 35 fractions to the nasopharynx.
108 patients received cisplatin at a
median cumulative dose of
360 mg/m2; 13 patients received
carboplatin with a median
cumulative dose of 1500 mg/m2;
8 patients received both cisplatin
and carboplatin.
Prevalence of Ototoxicity
Symptomatic ototoxicity was present
in 20% of patients (tinnitus in 59%,
hearing loss in 18%, and both in
23%); symptoms were bilateral in
81% of patients and 66% of
patients had abnormal audiograms,
42% of which were compatible
with chemotherapy-related hearing
loss. In patients who received
cumulative cisplatin doses >400 mg/
m2, > 50% of patients had sympto-
matic and persistent ototoxicity.
Brock grade  1 hearing loss was
observed in 4% of patients who
received carboplatin alone; 70% of
patients who received a
combination of carboplatin and
cisplatin; and 57% of patients who
received cisplatin alone.
Brock grade 1-2 hearing loss was
observed in 12.5% of patients;
85% of patients had Brock grade
0 hearing loss.
Hearing loss > 25 dB was considered
significant; 57% had normal
hearing, 23% had high-frequency
hearing loss (4000-8000 Hz), and
20% had severe hearing loss in the
speech range (500-2000 Hz).
Bilateral hearing loss was observed in
61% of patients per the ASHA
criteria; 17 patients required
hearing aids.
Prevalence of any postplatinum
hearing loss (per Brock, ASHA, NCI
CTCAE, and Chang scales) ranged
from 64%-90%; prevalence of
severe hearing loss differed by
scale; by NCI CTCAE, the preva-
lence of severe hearing loss was
47% among those not receiving
myeloablative carboplatin and 71%
among those receiving myeloabla-
tive carboplatin; 29% and 58% of
patients, respectively, who did not
and did receive myeloablative
carboplatin required hearing aids.
Prevalence of hearing loss of any
grade was 42% (Boston scale
grade 1 in 31% and grade 2 in
11%).
At 1 y after therapy, hearing
thresholds were statistically
significantly worse at all
frequencies in the
chemoradiotherapy group
compared with the
radiotherapy-alone group.
After treatment, 47% of patients
demonstrated hearing impairment
ranging from grade 1-3 on the
Muenster scale.
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 Ototoxicity and Cancer Therapy/Landier

TABLE 1. Continued

Study Cancer Population Ototoxic Therapy Prevalence of Ototoxicity

Orgel 201211 29 children with brain tumors; median
age at diagnosis was 2.0 y (range,
birth-9 y); 66% male.
Schell 19896 177 children and young adults with
cancer who received cisplatin (146
patients), cranial irradiation (18
patients), or both (13 patients);
mean age at diagnosis was 10.6 y
(range, 1-27 y); sex not reported.
Sivaprakasam 201112 38 patients with hepatoblastoma who
were treated with cisplatin; median
age at diagnosis was 1.5 y (range,
birth-11 y); 69% male.
Stohr 200513 74 patients with osteosarcoma
treated with cisplatin; mean age at
diagnosis was 14.1 6 5.8 y (range,
3-38 y); sex not reported.
Cisplatin dose: 281 6 88 mg/m2;
carboplatin dose: 1205 6 277 mg/
m2; no cranial radiation.
Mean cumulative cisplatin dose:
407 mg/m2; mean cranial radiation
dose: 4747 cGy.
Median cumulative cisplatin dose:
400 mg/m2 (range, 100-600 mg/m2).
Median cisplatin dose: 360 mg/m2.
After treatment, 62% of children had
abnormal hearing and 38%
required hearing aids.
Substantial hearing loss was defined
as a hearing threshold of 50 dB;
11% of patients had substantial
hearing loss in the speech
frequencies and 50% had
substantial deficits at 4000 Hz; 14
patients required hearing aids.
Hearing loss was graded as per the
Brock scale: grade 0: 55.2%;
grade 1: 15.8%; grade 2: 18.4%;
grade 3: 5.3%; and grade 4: 5.3%;
4 patients required hearing aids.
After completion of therapy, 51% of
patients had hearing loss of >20
dB at  4 kHz; 3 patients required
hearing aids.

Abbreviations: ASHA, American Speech-Language-Hearing Association; cGy, centigrays; dB, decibels; Gy, grays; Hz, Hertz; IQR, interquartile range; kHz, kilo-
hertz; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; VP, ventriculoperitoneal.

Although the ears are fully formed at birth, maturation of
neuronal pathways and auditory structures continues dur-
ing infancy and early childhood, making young children
particularly vulnerable to the ototoxic effects of cancer
therapies.
Radiation-related toxicity
Ototoxicity related to radiation involving the auditory
structures is multifactorial in nature (Fig. 1).19 Patients
receiving higher (30 grays) doses of radiation to the pos-
terior nasopharynx and mastoid are at risk of developing
serous otitis media and associated conductive hearing
loss.20 Radiation involving the external auditory canal
may result in an increased susceptibility to soft-tissue
infections as well as excessive cerumen production and/or
dry cerumen that may require periodic removal.21 Radia-
tion to the cochlea may lead to sensorineural hearing loss,
the exact mechanism of which is unknown to our knowl-
edge, but which is believed to be related to direct damage
to cochlear apparatus or damage to small vessels resulting
in hypoxia involving inner ear structures; in addition,
radiation damage to the brainstem may indirectly contrib-
ute to hearing loss.21 Sensorineural hearing loss related to
radiation is generally permanent and progressive; the
onset may occur during the acute phase of treatment or be
delayed for several years after the completion of therapy.22
Chemotherapy-related and drug-related toxicity
Platinum-induced and aminoglycoside-induced ototoxic-
ity is characterized by the production of toxic levels of
reactive oxygen species within the cochlea, with resultant
destruction of cochlear hair cells and damage to the stria
vascularis and spiral ganglion cells.23 Cochlear hair cell
damage is generally dose-dependent,23 bilateral, and irre-
versible.6,24 Given the tonotopic arrangement of cochlear
hair cells,25 the initial insult begins at the base of the coch-
lea, in which high-frequency sounds are processed; addi-
tional drug exposure results in damage that progresses
toward the cochlear apex, in which the processing of lower
(speech frequency) sounds occurs.6,24 In young children,
the implications of even mild to moderate high-frequency
hearing loss are particularly detrimental because they are
generally in the process of acquiring language and com-
munication skills at the time that hearing loss occurs, and
therefore are dependent on the high-frequency fricative
sounds (eg, “th,” “s”) that are critical for speech discrimi-
nation,26 which may be unintelligible to a child with
high-frequency hearing loss. Once the cochlear sensory
hair cells are destroyed, they cannot regenerate; therefore,
drug-related sensorineural hearing loss is almost always
bilateral and irreversible, and also can be accompanied by
tinnitus and vertigo.27 The ototoxicity of loop diuretics is
believed to be associated with shifts in fluid and electrolyte
concentrations in the inner ear, which may result in
edema of cochlear tissue and an associated decrease in
endocochlear potential.28 Hearing loss associated with
loop diuretics alone is generally transient28; however, the
administration of these agents concomitantly with plati-
num chemotherapy or aminoglycosides may potentiate
the ototoxic effects of these drugs.29,30

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Figure 1. Anatomy of the ear. The etiology of ototoxicity related to cancer therapy is multifactorial and may affect the structures
of the external or middle ear (eg, radiation-related toxicity resulting in conductive hearing loss) or the inner ear/cochlea (eg,
toxicity related to platinum-based chemotherapy resulting in sensorineural hearing loss). Tumor growth or surgical resection also
can result in damage to auditory structures with resultant hearing loss.

Surgery-related toxicity Risk Factors for Ototoxicity

Tumors located in or near the auditory structures or au-
ditory nerve may cause damage by placing pressure on or
infiltrating auditory apparatus. Surgical resection has the
potential to result in further damage to the ear and audi-
tory nerve.31 Patients with central nervous system
tumors may experience rapid changes in intracranial
pressure associated with lumbar puncture, tumor resec-
tion, or ventriculostomy, which are associated with hear-
ing loss; these patients also often require temporary or
permanent shunting of cerebrospinal fluid, which is in-
dependently associated with an increased risk of ototox-
icity (Fig. 3).32
Chemotherapy
Platinum-based chemotherapy is widely used and particu-
larly effective against solid tumors involving the head and
neck, lung, ovary, testicle, and bladder in adults.18 In chil-
dren, platinum compounds are commonly used in the treat-
ment of neuroblastoma, osteosarcoma, hepatoblastoma,
germ cell and central nervous system tumors.33 The 3 major
platinum compounds (cisplatin, carboplatin, and oxalipla-
tin) differ with regard to their chemical structure and
adverse effect profiles. A major adverse effect associated with
cisplatin is irreversible sensorineural hearing loss.34 Younger
age (particularly < 5 years) at the time of therapy, diagnosis

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 Ototoxicity and Cancer Therapy/Landier

Figure 2. Auditory pathways. Sound waves enter the external ear via the auditory canal; are converted to mechanical energy in
the middle ear; and subsequently are transmitted via hydraulic waves in the inner ear (cochlea), stimulating the release of neuro-
transmitters and causing the eighth cranial (auditory) nerve to fire. These neural impulses are transmitted via the medulla,
midbrain, and thalamus to the auditory cortex in the temporal lobe of the brain.

of a central nervous system tumor, diminished renal func-
tion, rapid intravenous administration, and treatment with
multiple potentially ototoxic agents increase the risk of oto-
toxicity.27,33,35 Carboplatin is generally less ototoxic than
cisplatin, although the risk increases substantially when this
agent is used in infants36 or in myeloablative doses.2,37
Oxaliplatin-related ototoxicity is rare, although there have
been some isolated case reports of hearing loss associated
with this agent.38
required to attain curative treatment for many central nerv-
ous system tumors,40 as well as for malignancies involving
structures in the head, such as rhabdomyosarcoma41 and
nasopharyngeal carcinoma.10 The effects of radiation to
the ear appear to be dose-related, with sensorineural hear-
ing loss generally occurring at doses >30 grays.40,42 How-
ever, the risk of ototoxicity increases in patients who
require multimodality therapy, such as those receiving
both radiation and platinum-based chemotherapy.43,44

Radiation Tumor/surgery
Radiation involving the ear or auditory nerve is often asso- Hearing loss may be a presenting symptom of tumors
ciated with ototoxicity.39 Nevertheless, radiation may be located in or near the auditory structures or auditory

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Figure 3. Cochlear aqueduct. The cochlear aqueduct provides
a direct connection between cerebrospinal fluid and the peril-
ymphatic space in the cochlea; rapid changes in intracranial
pressure and shunting of cerebrospinal fluid have been asso-
ciated with hearing loss.
nerve,45 including nasopharyngeal, parameningeal, ves-
tibular, and base of skull tumors, as well as tumors affect-
ing the temporal bone. The surgical management of
tumors involving essential components of the auditory
system46 and the surgical shunting of cerebrospinal fluid32
also may result in ototoxicity.
Other ototoxic agents
Additional agents with known ototoxic properties that are
commonly used during therapy for cancer include amino-
glycoside antibiotics30 and loop diuretics28; risk increases
with elevated serum trough levels,47 rapid intravenous
administration,28 and the administration of loop diuretics
concurrent with or shortly after the administration of
aminoglycosides.30
Genetic predisposition
Considerable interindividual variability in the prevalence
and severity of ototoxicity has been observed among
patients receiving similar treatment with agents of known
ototoxic potential, with some patients remaining unaf-
fected at high cumulative doses whereas others experience
severe damage at low doses.2,48,49 This interindividual vari-
ation is likely to be at least partially explained by genetic
susceptibility to the ototoxic effects of therapy.15,17 Candi-
date genes identified as being potentially involved in oto-
toxicity related to cancer therapy include megalin50 (a
transport protein), glutathione-S-transferase51 (GSTs;
involved in cellular detoxification), excision repair cross-
complementation groups 1 and 252,53 (ERCC1 and
ERCC2; involved in repairing drug-induced damage), acyl-
phosphatase 254 (ACYP2; involved in calcium and magne-
sium transport), and mutations in mitochondrial genes55
(essential mediators for some apoptotic pathways); the
biologic association between ototoxicity and variants in thi-
1652
opurine S-methyltranferase (TPMT) and catechol-O-
methyltransferase (COMT) are less clear.15,27 In what to
the author’s knowledge is the small body of genetic associa-
tion studies of ototoxicity in cancer therapeutics published
to date, genetic variants in TPMT, COMT, and ACYP2
have been associated with platinum-related hearing loss in
children,49,54 variants of the megalin gene have been associ-
ated with platinum-related hearing loss in adults,50 mito-
chondrial mutations have been associated with
aminoglycoside ototoxicity,55 variants in GSTP1 have been
associated with increased susceptibility to radiation-related
hearing loss in children,56 and conflicting results have been
noted regarding associations between GSTs and platinum-
related hearing loss.51,57 A summary of candidate genes
potentially involved in ototoxicity related to cancer therapy
is presented in Table 2.49-58
Detection of Ototoxicity
Types of testing
Given the substantial risk of ototoxicity associated with
platinum chemotherapy and radiation involving the ear
and auditory nerve, prospective auditory evaluations to
allow for the early detection of hearing loss are indicated
for patients receiving therapy with ototoxic potential.
Pure-tone audiometry is the standard method used for
hearing assessments,59 and generally involves the presen-
tation of sounds across a wide range of frequencies (ie, low
to high pitches, generally 500 to 8000 Hertz at mini-
mum). Each sound is presented at increasing intensity (ie,
loudness, measured in decibels) until the patient is able to
hear it. The lowest level of intensity at which the patient
can first hear a sound at a given frequency approximately
50% of the time is considered the “pure-tone threshold;”
a normal pure-tone threshold is  20 decibels.60 Thresh-
old shifts in patients with sensorineural hearing loss typi-
cally begin in the high-frequency range (>4000 Hertz),
and generally progress to the lower frequencies in a stair-
step pattern over time with continued exposure to the oto-
toxic agent (Fig. 4).61 The majority of patients aged >5
years are able to complete conventional pure-tone audio-
metric testing in an acoustically treated (sound-attenuat-
ing) test booth. The technique can be adapted for younger
children using play (for those aged 3-5 years) or visual
reinforcement (for those aged 9-36 months) techniques.62
Patients who are too young or unable to cooperate
with behavioral testing can be assessed using electrophy-
siologic techniques, such as brainstem auditory-evoked
response.59 In addition, distortion product otoacoustic
emissions are objective, noninvasive measures that do not
require the child’s active participation and may be more
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TABLE 2. Candidate Genes Potentially Involved in Ototoxicity Related to Cancer Therapy

Gene/Protein Possible Mechanism Study Population/Exposure

Megalin Potential mediator of ototoxic drug Riedemann 200850 Adults/platinum

uptake
51
Glutathione S-transferases (GSTs) Cellular detoxification Peters 2000 Adults/platinum
Oldenburg 200757 Adults/platinum
Rednam 201356 Children/radiation
Excision repair cross- Repair of drug-induced damage Caronia 200952 Children and adults/platinum
complementation groups 1 and 2 Suk 200553 Adults/platinum
(ERCC1 and ERCC2)
Acylphosphatase-2 (ACYP2) Calcium and magnesium transport Xu 201554 Children/platinum
Mitochondrial gene mutations Mediators for some apoptotic Xing 200655 Children and adults/
pathways aminoglycosides
Thiopurine S-methyltransferase Unknown (possibly related to Ross 200949 Children/platinum
(TPMT) and catechol-O- S-adenosyl methionine [SAM])58
methyltransferase (COMT)

and/or cranial radiation have been established previ-

ously,65,66 and current efforts are aimed at standardizing
and refining these guidelines, particularly for young chil-
dren.15,59 For older patients, less frequent testing may be
indicated; however, all patients receiving potentially oto-
toxic therapy should undergo auditory testing at baseline
and at the completion of therapy, at minimum, to deter-
mine whether auditory intervention or rehabilitation is
indicated.

Monitoring during long-term follow-up

Figure 4. Threshold shifts shown in an audiogram of the right
ear from a patient with platinum-related sensorineural hear-
ing loss. (A) Hearing loss appears first in the high-frequency
range, and (B) progresses to the lower frequencies in a stair-
step pattern after additional exposure to platinum.
sensitive to initial changes in auditory function than con-
ventional auditory testing.63,64
Frequency of testing
The frequency of auditory testing indicated for an indi-
vidual patient depends on several factors, including age,
planned therapy with potentially ototoxic agents, and per-
sonal risk profile. Because young children are at the high-
est risk of sustaining both ototoxicity and its related
adverse outcomes (ie, delays in linguistic development
and poor psychosocial and cognitive outcomes), baseline
and ongoing auditory monitoring (ie, before initial plati-
num dose and every 1-2 courses of platinum-based chem-
otherapy) is often recommended for children to allow for
early detection, auditory intervention, and, when possible,
modification of ototoxic therapy. Clinical practice guide-
lines for patients receiving platinum-based chemotherapy
Monitoring for ototoxicity after the completion of cancer
therapy is recommended in several standardized long-
term follow-up guidelines.67-69 For patients with a history
of treatment with platinum chemotherapy, an auditory
assessment is generally recommended at the baseline long-
term follow-up visit (usually  2 years after the comple-
tion of cancer therapy) and then as clinically indicated.
For patients who have received radiotherapy to the head
or ear, ongoing audiologic monitoring every 5 years (or
more frequently if clinically indicated) is advised due to
the potential for progression of hearing loss over time.22
Grading/classification of hearing loss
Several ototoxicity grading systems are currently in use
(Table 3).15,61,65,70-73 Due to significant variability
between grading scales,2,15 efforts are currently underway
to develop expert consensus regarding a uniform ototoxic-
ity grading method.15 The accurate classification of hear-
ing loss has implications for both the clinical management
of patients and for the evaluation and comparison of
audiologic outcomes on clinical trials.59 Across most
scales, hearing loss is assigned a grade ranging from 0 (nor-
mal hearing, or clinically insignificant loss) to 4 (severe or
profound hearing loss); however, there is significant

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TABLE 3. Common Ototoxicity Grading Scales

Target
Grading Scale Description Population Features Limitations

Brock (Brock 1991)61
ASHA (1994)65
Muenster (Schmidt 2007)70
Chang (Chang &
Chinosornvatana 2010)71
NCI CTCAE, version 4 (2010)72
SIOP Boston (Brock 2012)15
TUNE grading system
(Theunissen 2014)73
Designed to grade hearing loss Pediatric Widely used; baseline Does not capture
progression from high to low assessment not hearing loss
frequencies in the configuration required <40 dB, misses
commonly associated with significant
ototoxic cancer therapy; hearing functional deficits
loss is graded on 5-point scale
Hearing is compared with baseline in Pediatric Designed for early Does not classify
absolute terms (ie, presence/ and detection of severity of
absence of hearing loss in adult hearing loss hearing loss;
comparison with baseline) baseline
assessment
is required
8-point scale accounts for minimal Pediatric Designed for early Complexity of use
hearing loss (>10-20 dB), detection of
subgroups within major hearing loss
classifications, and tinnitus
Modification of Brock scale with Pediatric Addresses functional Complexity of use
similar configuration and deficits; baseline
expansion to 7-point scale; grades assessment not
hearing loss > 20 dB and measures required
interval frequencies (ie, 3000 and
6000 Hz)
4-point scale includes both objective Pediatric Familiar to oncologists; Not configured for
and subjective criteria; grades are and widely used in high- to low-
assigned based on threshold shift adult NCI-sponsored frequency hearing
from baseline and not actual clinical trials loss commonly
hearing loss associated with
cancer treat-
ments; baseline
assessment
required
5-point scale designed to grade Pediatric Proposed through consensus of Limited reliability
hearing loss progression from high international working group; and validity
to low frequencies; grades hearing potential application across testing to date
loss > 20 dB; uses absolute clinical trials worldwide;
hearing levels baseline assessment not
required
7-point scale designed to provide Adults Includes subjective symptoms Time-consuming to
insight into the effect of hearing and threshold shifts at higher use; feasibility
loss on specific daily life situations frequencies (up to 12.5 kHz); testing
(such as speech intelligibility and uses air conduction thresholds completed; needs
ability to appreciate ultrahigh only; designed to represent the external validation
sounds) auditory system’s
real-world functionality

Abbreviations: ASHA, American Speech-Language-Hearing Association; dB, decibels; Hz, Hertz; kHz, kiloHertz; NCI CTCAE, National Cancer Institute Com-
mon Terminology Criteria for Adverse Events; SIOP, International Society of Pediatric Oncology Boston ototoxicity scale.

variability in the definitions of the grades among the
scales, and some scales are designed for use in children
whereas others are designed for use in adult popula-
tions.2,15,59,61,65,71,73 In addition, there are classification
systems designed to detect early ototoxicity3 that desig-
nate hearing solely as “normal” versus “impaired,” with-
out assigning a severity grade.59
Management of Ototoxicity
Hearing aids
Hearing aids are a crucial component of the management
of significant hearing loss in both children and adults;
however, it is important to understand that although hear-
ing aids amplify sound, they do not restore normal hear-
ing. Thus, in patients requiring hearing aids, hearing
quality will remain distorted to some extent, resulting in a
reduced ability to discriminate speech in noisy environ-
ments. The daily use and care of hearing aids, particularly
in young children, also can be challenging.74 Neverthe-
less, there are many types and models of hearing aids avail-
able, including behind-the-ear, in-the-ear, and in-the-
canal models, and continued improvements in digital
technology have resulted in increased programmability
and advanced speech processing in newer models.75

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TABLE 4. Summary of Approaches to the Management of Ototoxicity

Approach Benefits Limitations

Hearing aids Amplification of sound; numerous models and
features available; increased programmability
and advanced speech processing in newer
models
Cochlear implants Direct stimulation of auditory neural pathway in the
cochlea provides a pathway for the
transmission of sound to the brain in patients
with severely damaged sensory hair cells
Assistive devices Provide augmentation to hearing aids or
(eg, auditory trainers, supplementary communication; particularly
telephone amplifiers, useful in noisy environments
audio streamers, use
of text messaging and
social media)
Special accommodations Provision of specialized services at public
expense; particularly helpful for children,
adolescents, and young adults attending
school; free of charge to the patient/family
Hearing quality remains distorted to some extent;
reduced ability to discriminate speech in noisy
environments; daily care required
Requires ongoing audiology and speech therapy
rehabilitation program
Some devices must be compatible with the
particular model of hearing aid; devices may
become outdated and need to be replaced as
technologies continue to rapidly evolve
Requires awareness of applicable laws and
completion of appropriate applications and
evaluative procedures; often requires
reevaluation and renewal of service
authorizations on an annual basis

Cochlear implants Education Act Amendments of 1997, and related provi-

In patients with severe to profound hearing loss who are
unable to benefit from hearing aids, a cochlear implant
may provide significant benefit.76 Cochlear implants are
surgically placed devices that directly stimulate auditory
neural pathways in the cochlea. By circumventing the
damaged sensory hair cells, cochlear implants provide a
pathway for the transmission of sound waves to the
brain.77 Hybrid cochlear implants are specifically
designed for patients with severe to profound hearing loss
limited to the high frequencies and combine both acoustic
and electrical stimulation; these hybrid implants may be
particularly useful in adults with steeply sloping high-
frequency sensorineural hearing loss typically noted after
exposure to ototoxic agents.78
Assistive devices
In addition to hearing aids, devices such as auditory train-
ers, telephone amplifiers, telephone devices for the deaf,
audio streamers, and more recently, the wide availability
of text messaging and social media provide alternate com-
munication methods for patients with severe hearing
loss.79 These assistive devices can be used with compatible
hearing aids in difficult listening environments to
improve the delivery of sound directly to the affected
patient.
Special accommodations
Hearing loss is generally recognized as a disability under
the law. For example, in the United States, 2 public laws,
Public Law 105-17 (Individuals With Disabilities
sions in “Part B” of this law)80 and Public Law 101-336
(Americans With Disabilities Act of 1990), provide for
equal access and free and appropriate public education for
those with special needs such as hearing loss. This includes
the provision of specialized services and devices, provided
at public expense.81
A summary of approaches to the management of
ototoxicity is presented in Table 4.
Prevention of Ototoxicity
Monitoring during treatment
Implementation of standardized audiologic monitoring
protocols has the potential to allow for the early detection
of ototoxicity in patients receiving therapy for cancer, and
thus also may provide an opportunity for treatment modi-
fication, if possible, before auditory damage becomes
severe. Even when no reasonable alternative is available
and therapy with the ototoxic agent must continue, moni-
toring may still be of value in allowing for early interven-
tion and auditory rehabilitation.
Otoprotective agents
Much preclinical work has been done to develop otopro-
tective agents, some of which have moved into clinical
studies. Trials of amifostine, an antioxidant, in children
receiving cisplatin for hepatoblastoma82 and germ cell
tumors83 failed to demonstrate otoprotection; however, a
more recent trial of amifostine in children with medullo-
blastoma demonstrated otoprotection in those with
average-risk but not high-risk disease.84 Several clinical

Cancer June 1, 2016 1655

Review Article
trials evaluating additional agents, including sodium thio-
sulfate, another antioxidant, currently are ongoing.
Because the mechanism of platinum-related cytotoxicity
to normal tissues, including the cochlea, may be similar to
the platinum-related cytotoxicity aimed at the tumor cells
(ie, interaction with nuclear DNA), the potential for oto-
protectant interference with the efficacy of the chemother-
apy has been raised as a concern.27 To the author’s
knowledge to date, there are no otoprotectants approved
by the US Food and Drug Administration that currently
are available for use in pediatric or adult oncology.27
Identification of patients at highest risk
Risk-prediction models for platinum-related ototoxicity,
based on age and cumulative dose, have been developed14;
however, these models do not accurately predict risk for
individual patients.27 Although there currently is not suf-
ficient evidence to identify genetic predictors of suscepti-
bility to ototoxicity before the implementation of therapy,
continued progress is being made in ototoxicity-related
pharmacogenomics, making the prospect of personalized
therapy based on the identification of high-risk genotypes
a future possibility for the prevention of ototoxicity.
Conclusions
Ototoxicity is a serious consequence associated with sev-
eral agents commonly used in contemporary cancer ther-
apy, including platinum-based chemotherapy, radiation
and surgery involving the ear, and supportive care drugs
including aminoglycoside antibiotics and loop diuretics.
Progress has been made toward the early identification of
ototoxicity, and rehabilitative strategies are available to
help ameliorate the associated adverse social and educa-
tional consequences. Progress is also being made toward
the identification of those individuals at highest risk of
developing toxicity as a result of genetic susceptibility, as
well as the development of otoprotective agents to dimin-
ish toxicities associated with current regimens. Future
directions include the development of reliable profiles to
identify at-risk individuals, and the implementation of
personalized strategies such as the use of otoprotective
agents or avoidance of ototoxic drugs in susceptible indi-
viduals to decrease the prevalence of ototoxicity and
improve health-related quality of life in these patients.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The author made no disclosures.
1656
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