CANCER TREATMENT REVIEWS 2003; 29: 417430

doi:10.1016/S0305-7372(03)00066-5

TREATMENT INDUCED COMPLICATIONS

Radiotherapy-induced ear toxicity

Barbara A. Jereczek-Fossa1, Andrzej Zarowski2,
Franco Milani 3 and Roberto Orecchia1,3

1
Division of Radiation Oncology of the European Institute of Oncology, via Ripamonti 435, Milan 20141, Italy;
2
Medelec and Hearing Sciences Department, University of Antwerp, Belgium; 3Faculty of Medicine of the University of
Milan, Italy

Despite their particular functional consequences, radiotherapy-induced ear injuries remain under-evaluated and under-re-
ported. These reactions may have acute or late character, may affect all structures of the hearing organ, and result in con-
ductive, sensorineural or mixed hearing loss. Up to 40% of patients have acute middle ear side effects during radical
irradiation including acoustic structures and about one-third of patients develop late sensorineural hearing loss (SNHL). Total
radiotherapy dose and tumour site seem to be among the most important factors associated with the risk of hearing impair-
ment. Thus, reduction in radiation dose to the auditory structures should be attempted whenever possible. New radiother-
apy techniques (3-dimensional conformal irradiation, intensity modulated radiotherapy, proton therapy) allow better dose
distribution with lower dose to the non-target organs. Treatment of acute and late external otitis is mainly conservative
and includes the anti-inflammatory agents (applied topically and systematically). Post-radiation chronic otitis media and
the eustachian tube pathology may be managed with tympanic membrane incision with insertion of a tympanostomy tube
(grommet), although the benefit of such approach is controversial and some authors advocate a more conservative ap-
proach. In these patients the functional deficit can be alleviated by application of bone conduction hearing aids such as,
e.g., the bone anchored hearing aid (BAHA). There is no standard therapy for post-irradiation sudden or progressive SNHL
yet corticosteroid therapy, rheologic medications, hyperbaric oxygen or carbogen therapy are usually employed (as for id-
iopathic SNHL), although controversial data on the efficacy of these treatment modalities have been published. In selected
cases with bilateral profound hearing loss or total deafness, cochlear implants may prove effective. Further improvements in
radiotherapy techniques and progress in otologic diagnostics and therapy may allow better prevention and management of
radiation-related acoustic injury.
C 2003 Elsevier Science Ltd. All rights reserved.

Key words: Head and neck cancer; radiotherapy; radiation damage; stereotactic irradiation; toxicity; external; middle; inner
ear; temporal bone; eustachian tube; otitis; hearing loss; cochlear implant.

irradiation (for example in parotid tumours, high-

INTRODUCTION
Radiation therapy is a common management of head
and neck tumours and brain malignancies. Both
definite radiotherapy (e.g., for nasopharyngeal
cancer, oropharyngeal cancer) and postoperative
Correspondence to: Barbara A. Jereczek-Fossa MD, PhD,
Department of Radiation Oncology, European Institute of
Oncology via Ripamonti 435, Milan 20141, Italy. Tel.: 39-02-
57489607. Fax: +39-02-57489036; E-mail: barbara.fossa@ieo.it
grade brain tumours or paranasal sinus malignan-
cies), necessitate the administration of relatively
high doses. Due to complex anatomy, exposure of
non-target organs during irradiation of the brain and
head and neck areas is unavoidable. Of the various
radiotherapy-induced toxicities, neurological com-
plications and hearing impairment are of particular
importance. Despite relatively high number of both
animal and human studies, clear-cut data on the
incidence, type and severity of radiation-induced ear
toxicity are scarce. This may partially be explained

0305-7372/$ - see front matter C 2003 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED.
418
by differences in doses, fractionation techniques
(single fractions are commonly used in animal
models), difficulties in definition of the hearing loss
and other factors. The majority of these reports are
retrospective, lack pre- versus post-irradiation eval-
uation, include heterogenous and small patient
populations and have a short follow-up period (1).
Furthermore different irradiation schemes and doses
are employed in particular head and neck malig-
nancies. In certain tumours, e.g., in nasopharyngeal
carcinoma or vestibular schwannomas, some extent
of hearing damage due to direct tumour invasion,
may be present before radiation treatment. Older
radiotherapy techniques and energies (e.g., ortho-
voltage irradiation) were more likely to produce
serious adverse effects than currently available
megavoltage photons.
References for this review were identified by a
comprehensive search of MEDLINE for the years
1980 to 2002 (with no language restriction). Refer-
ences were supplemented with relevant citations
from older literature and from the reference list of
retrieved papers. Papers were selected on the basis
of their relevance to the topic. Data presented in
abstract form were included in some cases where
they added significant information.
HISTORY
In the past, radiotherapy was involved in the man-
agement of numerous benign and malignant human
disorders, including chronic ear infections, hearing
loss or aerotitis media (2). During the 1920s, a tech-
nique called nasopharyngeal radium therapy was
developed to treat children with hearing loss caused
by repeated ear infections (otitis media). Treatment
usually included insertion of an applicator with a
capsule of radium through each nostril and place-
ment of the radium near the eustachian tube open-
ing for 8 to 12 min. This therapy was also used to
treat sinusitis, tonsillitis, asthma, bronchitis, and re-
peated viral and bacterial infections. Because it was
effective in treating otitis media, military physicians
used it to treat aerotitis media in submariners, avi-
ators and divers (3). As estimated by the US Veteran
Affairs Office 500,000 to two million civilians, mostly
children, received these treatments. Also between
8000 and 20,000 military personnel received them
during World War II and until about 1960 (3).
These treatments were subsequently abandoned
because of significantly increased risk for the devel-
opment of head and neck cancers (especially in chil-
dren) (46). Moreover, the post-radiation inner ear
damage was soon recognized and then intensively
studied in animal and human series (7). In 1905,
B.A. JERECZEK-FOSSA ET AL.
Ewald studied the first animal model using radium
placed in the middle ear of the pigeon. He noted the
signs of labyrinthitis [cited in (7)]. Later animal stud-
ies including also mammals (e.g., dogs, guinea pigs
and rats) showed important effects of radiation on the
middle and inner ear (7). The first human study was
published in 1962 and included audiologic tests in 14
head and neck cancer patients treated with irradiation
(8).
TYPE OF DAMAGE, AETIOLOGY AND
NATURAL HISTORY
Radiation-induced damage can affect any structure
of the hearing organ, from the external, middle and
inner ear up to the central auditory pathways. It may
result in conductive, sensorineural or mixed (i.e.,
with both conductive and sensorineural component)
hearing loss.
External ear
Acute and late skin reactions involving the pinna,
external auditory canal and periauricular region may
occur. Acute events include erythema, dry and moist
desquamation or, rarely, ulceration of the skin of the
auricle and external ear canal which can lead to pain
and otorrhea. Late skin changes include atrophy,
ulceration, external canal stenosis and external otitis.
Wax secretion can be diminished due to the epithelial
damage and destruction of sebaceous and apocrine
glands (9). External otitis can be exacerbated by
maceration of the skin of the external ear canal if the
middle ear is discharging. Skin necrosis has been
observed in up to 13% of patients treated with hypo-
fractionated orthovoltage X-rays or electron irradia-
tion for epithelial tumours of the pinna (1012) and
seems to be lower in case of brachytherapy (13,14) or
irradiation for skin cancer at other sites (1518). Two
studies including respectively 313 and 138 patients
treated with orthovoltage or electrons showed that the
risk of late skin necrosis was higher with high daily
fraction size [> 4 Gy (12) and > 6 Gy (19)] and large
field size > 5 cm2 (12). No impact of patients age,
histology, tumour location, radiation modality and
beam energy has been found, while the impact of total
dose remains controversial (12,19).
Middle ear
Up to 40% of patients have acute middle ear side
effects during irradiation that includes acoustic
RADIOTHERAPY-INDUCED EAR TOXICITY
structures. The most common reaction is otitis media
due to transient oedema and dysfunction of the eu-
stachian tube. These are caused by tumefaction of
the mucosa and blockage within the cartilaginous
part or at the pharyngeal orifice of the eustachian
tube. Gas resorption by the middle ear mucosa to-
gether with compromise of the active mechanism of
pressure equilibration during swallowing or yawn-
ing lead to formation of reduced pressure in the
middle ear cavity (fullness), retraction of the tym-
panic membrane (pain) and increased tension in the
ossicular chain resulting in compromised conduc-
tion of sound (hearing loss).
If the function of the eustachian tube does not
normalize, and the middle ear negative pressure be-
comes high enough, transudation from the engorged
capillaries of the mucous membrane will occur. The
presence of fluid (effusion) in the middle ear cleft will
further irritate the mucosa, resulting in metaplasia of
the normal epithelium into pseudostratified, colum-
nar, ciliated epithelium with an increased number of
mucus-secreting cells. Due to mucus secretion, the
originally serous, liquid transudate transforms into a
tenacious, glue-like deposit. Sometimes prolifera- SNHL can also occur soon after irradiation (acute
tion of fibrovascular granulation tissue and the for-
mation of inflammatory polyps can be observed
leading to perforation of the tympanic membrane and
persistent otorrhea. Permanent changes of the tym-
panic membrane are rarely observed, but a thickened
drum has been observed in some cases several months
after irradiation (9,20).
As a consequence of the secretory otitis media
conductive deafness may develop. The conductive
hearing loss may be transient (8,21) (as long as ef-
fusion or underpressure are present in the middle
ear) or, if atrophic (fibrotic) otitis or necrosis of the
auditory ossicles occur, the conductive deafness may
become permanent (20,22) (with up to approxi-
mately 60 dB of conductive hearing loss). Conduc-
tive hearing loss can also be a complication of
surgery on the muscles of the soft palate (resulting in
the compromised opening of the eustachian tube
followed by middle ear effusion) (23).
Late fibrosis occurring at the pharyngeal orifice of
the eustachian tube and atrophy of its mucosal lining
can occasionally lead to hyperpatency of the tube
which, at its extreme form, can remain open even at
rest (i.e. become patulous) (2426). The patient would
then complain of hearing his/her own breathing in
the ear or of autophony (direct hearing of own voice).
Inner ear
The most serious radiation-induced complication for
the inner ear is sensorineural hearing loss (SNHL).
419
SNHL can have sudden or progressive character.
The following definitions of the SNHL are applica-
ble. Sudden SNHL (SSNHL) can be defined as SNHL
of at least 30 dB in three consecutive frequencies
occurring over three days or less (27). Progressive
SNHL (PSNHL) is defined as at least 30 dB hearing
loss occurring at any frequency with progression of
at least 10 dB at consecutive audiometric tests per-
formed with at least three month intervals (28). Ac-
cording to Anteunis et al. (21) and Chen et al. (29)
significant SNHL is defined as a 20 dB difference
occurring after treatment between the irradiated and
contralateral ears for a minimum of two frequencies.
Other authors defined a clinically relevant hearing
loss at 10 or 15 dB (30,31).
Review of the literature consistently shows that
post-irradiation SNHL occurs in about one-third of
patients treated with definitive radiation with fields
including the inner ear (1,24,29,30,3234). Unlike
otitis media, which usually occurs soon after the
radiation therapy is started, SNHL typically appears
several months or years after completion of treat-
ment. However, depending on the mechanism,
reaction) and in some of these cases may be revers-
ible or partially reversible (1,35). Delayed SNHL,
however, has frequently a chronic, progressive and
irreversible evolution (1, 32). Sometimes it initiates
as a series of transient sudden hearing losses (36). It
develops 6 to 24 months after irradiation and may
progress to complete deafness (cophosis) over weeks
and months (36,37).
SNHL has the features of classical late radiation
damage. The cumulative risk of significant persistent
SNHL (> 15 dB) seems to stabilize within two years
(32,38), whereas for severe SNHL (> 30 dB) the cu-
mulative risk continues to increase through the third
and fourth year (32). In the published series with
long follow-up (median of 13 years), stable rather
then progressive character of SNHL was observed
(33). SNHL involves mainly higher frequencies
(> 2 kHz) (1,32,33).
Radiation-induced vascular insufficiency (small
vessel endothelial reactions) has been proposed by
many authors as the aetiology of SNHL (36,3941).
Within weeks or months after irradiation, vascular
insult to the inner ear structures can cause progres-
sive degeneration and atrophy of the inner ear sen-
sory structures, fibrosis and even ossification of the
inner ear fluid spaces. Extensive animal and human
studies on irradiated ears showed haemorrhages in
the inner ear spaces and oedema of the membranous
labyrinth, loss of cells in the organ of Corti (both
inner and outer hair cells and pillar cells), atrophy
and degeneration of the stria vascularis, a reduced
number of capillaries, degeneration of endothelio-
cytes in vessels, and atrophy of the spiral ganglion
420
cells and the cochlear nerve (34,3942). Both in-
flammation and oedema can damage the cochlear
nerve in the narrow internal auditory bony canal
(43). Studies on the human temporal bones in pa-
tients receiving cisplatin, irradiation, and their
combination showed loss of inner and outer hair
cells with a reduction in spiral ganglion cells, and
atrophy of the stria vascularis (44). Progressive fi-
brosis in connective tissue was particularly evident
in irradiated cases (44).
Even though several histogical studies have
shown extensive lesions in irradiated ears, a case of a
Chinese female with a well-preserved organ of Corti
despite a high radiation dose has been reported (45).
The authors of this report conclude that degenera-
tion in the cochlear nerve pathway rather than
damage to the sensory end-organ could explain the
aetiology of SNHL (45).
Vestibular disturbance, defined here as abnor-
malities in electronystagmography (ENG), have
been observed in 44% of patients who underwent
irradiation that involved the ear (46,47). However,
some of these patients were asymptomatic (no sub-
jective vertigo or dizziness). Experimental animal
data have shown degenerative changes in the ves-
tibular sensory epithelia (40). Absence of the macula
of the utricle and cristae of the semicircular canals
have been seen at autopsy (34). No correlation
between vestibular dysfunction and SNHL was
observed (33).
Other
Other types of ear toxicity include radiation-induced
late bone and cartilage complications (mastoiditis,
osteoradionecrosis of the temporal bone, cartilage
necrosis of the external auditory canal) (9,48). Two
patterns of osteoradionecrosis of the temporal have
been observed. The less serious pattern is the os-
teonecrosis of the tympanic ring, where an area of
exposed dead bone, usually in the floor of the ex-
ternal meatus, becomes evident. When a bone se-
questrum forms and gradually separates, the bony
dehiscence can heal (although the healing process
may take years) (9). The more severe pattern in-
cludes the diffuse radionecrosis of the temporal bone
involving formation of multiple bony sequestra. It
may comprise cranio-spinal fluid otorrhea, SNHL
and attacks of sudden vertigo and nausea resulting
from fistulization of the labyrinth, which in turn may
lead to meningitis (9,49,50). These events, however,
are very rare in the modern radiotherapy series.
There are also anecdotal reports of radiation-in-
duced tumours of the external auditory canal in
patients irradiated for nasopharyngeal cancer (51).
B.A. JERECZEK-FOSSA ET AL.
If hearing loss develops, it can be accompanied by
tinnitus and hyperacusis. Tinnitus is more probable
to occur in SNHL, but conductive hearing loss can
also trigger this symptom.
In cases of focal brain radionecrosis comprising
the auditory pathways, isolated retrocochlear (i.e.,
concerning the acoustic nerve or the central auditory
pathways) auditory symptoms (as in auditory neu-
ropathy) can also be observed. In cases of diffuse
white matter injury, the most apparent symptom
would be progressive cognitive neurological im-
pairment and hearing loss, whereas vestibular or
gait disorders could be concomitant findings.
SCORING SYSTEMS
Radiation-induced ear toxicity has remained under-
evaluated and under-reported and its assessment
usually has included descriptive methods. In recent
decades however, this issue has been given its im-
portance and various scoring systems have been
developed.
There are several systems of ear toxicity classifi-
cation. The Radiation Therapy Oncology Group
(RTOG) criteria include acute but not late ear mor-
bidity and can be applied for retrospective analysis
(Table 1). The more recent Late Effects of Normal
Tissue/Somatic Objective Management Analytic
(LENT/SOMA) scoring system allows detailed pro-
spective evaluation of late radiation-induced ear
toxicity (Table 2). This system has not yet been widely
validated in clinical practice and some modifications
have been recently proposed (for example, omission
of calculation of the average score). Moreover, sev-
eral limitations have recently been raised (lack of
distinction between external, middle and inner ear
toxicity, too narrow categorization of hearing loss)
(32). The Common Toxicity Criteria of the National
TA B L E 1 Acute radiation ear morbidity according to the
RTOG scoring criteria (see text for comments)
Score Ear morbidity
0 No change over baseline
1 Mild external otitis with erythema, pruritus,
secondary to dry desquamation not
requiring medication. Audiogram
unchanged from baseline
2 Moderate external otitis requiring topical
medication, serous otitis media, hypoacusis
on testing only
3 Severe external otitis with discharge or moist
desquamation, symptomatic hypoacusis,
tinnitus, not drug-related
4 Deafness
RADIOTHERAPY-INDUCED EAR TOXICITY 421

TA B L E 2 Late radiation ear morbidity according to the LENT/SOMA scale (see text for comments)

Grade 1 Grade 2 Grade 3 Grade 4

Subjective
1. Pain Occasional and Intermittent and Persistent and Refractory and
minimal tolerable intense excruciating
2. Tinnitus Occasional Intermittent Persistent Refractory
3. Hearing Minor loss, no Frequent difficulties Frequent difficulties Complete deafness
impairment in daily with faint speech with loud speech
activities
Objective
4. Skin Dry desquamation Otitis externa Superficial Deep ulceration,
ulceration necrosis,
osteochondritis
5. Hearing < 10 dB loss in one 10 to 15 dB loss in < 15 to 20 dB > 20 dB loss in one
or more frequencies one or more loss in one or or more frequencies
frequencies more frequencies
Management
6. Pain Occasional non-narcotic Regular non-narcotic Regular narcotic Parenteral narcotics
7. Skin Occasional lubrication/ Regular eardrops or Eardrums Surgical intervention
ointments antibiotics
8. Hearing loss Hearing aid
Scoring: score the 8 SOM parameters with 0 to 4 (0 no toxicity); total the scores and divide by 8 -
LENT score:. . .. . .. . .. . .. . .
Analytic
Pure tone audiometry Assessment of characteristics of sensorineural perception Yes/no date
Speech audiometry Assessment of characteristics of speech perception Yes/no date

TA B L E 3 Ear morbidity according to the NCI CTC criteria (see text for comments)

Grade 1 Grade 2 Grade 3 Grade 4

External auditory External otitis with Extenal otitis with moist External otitis with Necrosis of the canal,
canal erythema or dry desquamation discharge, soft tissue or bone
desquamation mastoiditis
Inner ear/hearing Hearing loss on Tinnitus or hearing loss, not Tinnitus or hearing Severe unilateral or
(including audiometry only requiring hearing aid or loss, correctable bilateral hearing loss
conductive treatment with hearing aid (deafness), not
hearing loss) or treatment correctable
Middle ear/hearing Serous otitis without Serous otitis or infection requiring Otitits with discharge, Necrosis of the canal,
subjective decrease medical intervention; subjective mastoiditis or soft tissue or bone
in hearing decrease in hearing; rupture of conductive hearing
tympanic membrane with loss
discharge

Cancer Institute (NCI CTC) include auditory/hear- RISK FACTORS

ing side effects (conductive hearing loss is graded as
Middle ear/Hearing in the Auditory/Hearing cate- Numerous clinical and physical factors associated
gory). In this system, changes associated with radia- with the risk of hearing loss after irradiation have
tion to the external ear are graded under radiation been reported (Table 4).
dermatitis (Dermatology/Skin category) and earache
is graded in the Pain category (52) (Table 3). NCI CTC
are mainly applied to chemotherapy studies and are Concomitant disorders and treatments
rather insensitive to the small changes in hearing that
may be clinically significant (53). Gardner and Rob-
In the recommendations for trials using potentially
ertsons classification (54) is commonly used in the
ototoxic agents particular attention should be paid to
assessment of hearing preservation after surgery or
the patients history (53). High risk subjects are those
stereotactic irradiation (5563).
422 B.A. JERECZEK-FOSSA ET AL.

TA B L E 4 Factors associated with the high risk of post-irradiation hearing impairment

Factors Associated (references) Not associated (references)

Treatment-related variables
Total radiotherapy dose (29), (31)a , (33), (92), (95), (96) (24), (59), (63)b , (91)
Marginal doseb (55), (7981), (121) (59)
Cisplatin-based chemotherapy (44), (91), (122124) (1), (24), (33)
Fraction dose > 2 Gy (75)
Radiosurgery vs. fractionated stereotactic RTb (36), (78), (79), (82), (83)
Dose rateb (35), (78)
Stereotactic RT based on MRI datab (125)
Number of isocenters useda (63)
Conventional RT (vs. IMRT) (92)
Follow-up time (31)
Patient-related variables
Neurofibromatosis type 2b (1), (3537), (126)
Older age (>50 years at higher risk) (1), (24), (31), (109), (126) (29), (33), (95), (123)c
Hearing deficit before RT (1), (31), (78)
Threshold at <60 dB at 4 kHz (1)
Reduction in static compliance of the (29)
tympanic membrane before RT
Secretory otitis media after RT (24), (34), (126)
Male sex (24)
Tumour-related variables
Site of tumour (nasopharynx, parotid at high risk) (64)
Involvement of the upper cervical lymph nodes (64)
Tumour sizeb (80), (83) (36), (59), (61), (63)
Cystic vs. solid type of tumourb (43), (58)

Legend: RT, radiotherapy; MRI, magnetic resonance imaging; IMRT, intensity modulated radiotherapy.
a
The correlation between dose and hearing impairment at 4000 Hz only.
b
In case of acoustic schwannoma treated with stereotactic irradiation.
c
study on radiation and cisplatin for paediatric brain tumours (younger age correlated with higher risk).

with a pre-existing hearing impairment due to noise,
temporal bone trauma or ototoxic medications (e.g.,
cisplatin, loop diuretics, aminoglycosides). Similarly,
patients with autoimmune disease, recurrent otitis
media, Menieres disease, otosclerosis, diabetes
mellitus, acoustic nerve tumours, paraneoplastic
syndroms, otomastoiditis, surgical damage, micro-
vascular disease, otologic insults with delayed ef-
fects (e.g., previous irradiation, syphilis) and genetic
anomalies (e.g., Cogans syndrome, Ushers syn-
drome) or with idiopathic SSNHL are at high risk
(53).
Risk of post-irradiation ear damage related to the
site of disease
Nasopharynx
Irradiation is the treatment of choice for nasopha-
ryngeal carcinoma. High doses, large fields, relatively
young patient age and good prognosis explain the
well documented frequent occurrence of radiation-
induced ear morbidity. Due to the location of this
malignancy, the cochlea may receive an even higher
dose than the primary tumour and the eustachian
tube receives essentially the full tumour dose (64). In
consequence, serial audiological tests show signifi-
cant SNHL in up to 50% of nasopharyngeal cancer
patients treated with radiotherapy (1,24,29,30).
Importantly, more than 50% of the nasopharyn-
geal cancer patients can present with conductive
hearing loss (due to otitis media with effusion) as the
first symptom (6568). These patients show hearing
loss before radiotherapy is started. More than 20% of
patients develop middle ear effusion after radio-
therapy (67). However, the predictive role of a pre-
radiotherapy tumour pattern (presence of middle
ear effusion with regard to eustachian tube invasion
or displacement) on the outcome of middle ear ef-
fusion after irradiation is controversial (66,69).
Up to 20% of patients present with tinnitus and in
about 50% of patients this symptom may be induced
by irradiation (70). About 30% of all patients treated
with irradiation report intermittent tinnitus at 12
months after treatment (70).
A patulous eustachian tube has been observed in
about 50% of long-term nasopharyngeal cancer
RADIOTHERAPY-INDUCED EAR TOXICITY
survivors. However the correlation between radia-
tion dose and the risk of this late effect remains
unknown (71).
Uncommon otological manifestations of naso-
pharyngeal carcinoma include hemotympanum,
barotrauma, and sudden SNHL (72). There are also
reports of subclinical brainstem damage in naso-
pharyngeal cancer patients treated with irradiation,
but these vary in their conclusions (70,73).
Parotid gland
Parotid malignancies are commonly managed with
postoperative radiation therapy. The anatomical
position of the parotid gland (neighborhood of the
temporal bone) probably explains the high risk of
post-radiation-induced hearing loss. On audiometry,
significant hearing loss (mainly sensorineural) on
the irradiated side can be found in up to 53% of cases
(30,74,75), even though early studies on the ear
toxicity did not report this complication (8).
Brain tumours
There are only a few studies on radiation-induced
ear toxicity in adult patients treated for brain tu-
mours, yet the chance for development of retroc-
ochlear damage is relatively high and has to be taken
into account (21,33). A study including 33 patients
that treated the tumour bearing hemisphere and the
temporal bone with unilateral radiotherapy up to the
mean dose of 53.1 Gy (1.8 Gy/fraction), showed with
a median follow-up of 13 years, deep ulceration of
the outer ear canal and osteoradionecrosis in 10% of
the patients (33). About one third of patients devel-
oped hearing impairment and 10% of the patients
showed dysfunction of the vestibular part of the
inner ear. The authors recommended long-term fol-
low-up in patients irradiated for brain tumours (33).
Hearing impairment has also been reported in 7 out
of 17 adult medulloblastoma patients treated with
surgery, craniospinal irradiation and cisplatin-con-
taining chemotherapy (76).
Vestibular schwannoma
Stereotactic radiosurgery (single fraction) or stereo-
tactic radiotherapy (multiple fractions) is a viable
alternative to surgical excision in selected cases of
vestibular schwannoma of the cerebello-pontine an-
gle (63). However, these treatment modalities carry a
substantial risk for hearing loss due to a high prob-
ability of direct radiation damage to the cochlear
nerve (77). Moreover, in many cases pre-treatment
hearing impairment is caused by the direct nerve
infiltration (36,60,77). Patients with neurofibromato-
sis type 2 run a higher risk for the hearing loss after
stereotactic irradiation as compared to patients with
423
unilateral, non-syndromic vestibular schwannomas
(this however is also valid for traditional surgical
excision) (3537).
Due to continuous improvement in the radio-
therapy techniques, stereotactic irradiation may now
give results that are comparable to microsurgery
with regard to preservation of useful hearing
(36,59,63, 78). Recently, hearing preservation after
single dose radiosurgery has improved due to re-
duction of the peripheral dose (55,7981). The use of
fractionated stereotactic irradiation instead of single
dose therapy allows for similar tumour control with
a lower risk of neurological complications, including
the fifth and seventh nerve deficit and hearing loss
(functional hearing preservation is up to 2.5-fold
higher in patients who receive fractionated stereo-
tactic radiotherapy as compared to the those treated
with radiosurgery) (36,78,79,82,83). The studies of
Sakamoto et al. (57) suggest that fractionated ste-
reotactic radiotherapy is effective in lowering the
rate of hearing loss as compared to hearing loss re-
sulting from the natural tumour growth (the mean
annual hearing loss is greater before treatment than
after, and the rate of hearing loss slows after ste-
reotactic radiotherapy). Comparison of gamma
knife-, linac-, micromultileaf linac radiosurgery and
intensity modulated radiotherapy (IMRT) has been
undertaken (84,85).
Nonacoustic schwannoma and other tumours
Hearing loss has also been reported in patients
treated with radiosurgery for non-vestibular sch-
wannomas or other posterior fossa tumours (86,87).
Pre-irradiation hearing loss is less frequent in the
non-acoustic cerebello-pontine angle tumours than
in vestibular schwannomas (88). A fractionated ra-
diation approach may decrease the risk of cranial
neuropathies (including hearing loss) (89). Eusta-
chian tube dysfunction can be observed in patients
treated with radiosurgery for lower cranial nerve
schwannomas (90).
Paediatric tumours
Several paediatric malignancies (central nervous
system tumours, leukemia, head and neck sarcomas)
are treated with definite or adjuvant irradiation in-
cluding temporal bone and acoustic structures. Due
to the high risk of late radiation complications, the
application of this treatment modality in children
has become more stringent. Avoidance of radio-
therapy has become feasible as more effective che-
motherapy has been developed over recent decades.
Importantly, the association of irradiation and che-
motherapy (particularly including cisplatin) must be
used with particular caution. Indeed, high frequency
hearing loss was more frequent in children treated
424
for intracranial tumours, when cisplatin was com-
bined with postoperative irradiation, compared (in
the multifactorial analysis) to the children treated
with adjuvant irradiation only (91). Several studies
have been performed to compare conventional ra-
diotherapy with three dimensional (3D) conformal
radiotherapy and IMRT in medulloblastoma patients
(see further) (92).
TECHNIQUE AND DOSIMETRY
Dose
Despite numerous reports on radiation-induced
hearing loss, data on the doseresponse relation-
ship for ear morbidity are sparse. Even if a dose of
30 Gy to the acoustic structures is considered as the
threshold for hearing loss, a policy of avoiding
unnecessary irradiation of normal tissue, i.e., a
dose as low as reasonably achievable (ALARA),
should always be attempted (7,29,93). Several
studies performed in the 60s and 70s established
tolerance doses (TD) for ear morbidity [cited in (7)].
TD50=5 for acute radiation otitis has been set at 40
Gy, and for chronic otitis at 65 to 70 Gy [cited in
(7)]. TD5=5 of 60 Gy and TD50=5 of 70 Gy for SNHL
or vestibular damage have been reported [cited in
(7)]. The review of nine studies showed that at
least one third of patients receiving a dose of 70 Gy
in 2 Gy per fractions near the inner ear, develop
hearing impairment of 10 dB or more in the 4 kHz
region (30). A nomogram indicating the mean inner
dose producing the risk of 15% for development of
SNHL as a function of pre-therapeutic hearing
threshold and patients age has been recently pro-
posed by Honore et al. (31). Tubal patency and
clearence function of the eustachian tube showed
deterioration if the dose was higher than 70 Gy,
whereas dynamic function of tube was preserved
(94). The risk of radio-oto-mastoiditis is higher if
the dose exceeds 50 Gy and if the portals include a
field that is both anterior and posterior to the clival
line (48). These data have been generally confirmed
by several authors (29,9597). However, in some
studies an apparent relation between radiation
dose and some types of ear damage have not been
reported (26,47,91,98). However, larger patient se-
ries, wider dose ranges and a prospective assess-
ment are necessary to adequately evaluate this
issue.
Even though the risk of hearing impairment after
radiotherapy for head and neck tumours and brain
malignancies is well known, the radiation dose to
the inner ear structures is not routinely assessed.
Moreover, there are only a few dosimetric studies
B.A. JERECZEK-FOSSA ET AL.
addressing this issue. Ondrey et al. (64) in a series of
head and neck cancer patients (pharyngeal and oral
cavity cancer) observed up to 102% of the prescribed
dose administered to the cochlea. Mastoid cells re-
ceive 35 to 75% of the prescribed dose and eusta-
chian tubes 20 to 102% (67% of patients received to
the eustachian tube more than 50% of the prescribed
dose). Even 3D irradiation of the posterior fossa can
deliver as much as 75% of the prescribed dose to the
cochlea (93). A study by Paulino et al. (99) showed,
however, that the use of a 3D photon posterior fossa
boost in medulloblastoma is associated with twice
the cochlear dose when compared to 2-dimensional
radiotherapy with parallel-opposed lateral fields
(50% and 100% of the prescribed posterior fossa
dose, respectively). Similarly a reduction in the
cochlear dose was observed by other investigators
using a 3D cochear-sparing technique for posterior
fossa irradiation (100). The use of conformal proton
radiotherapy of the posterior fossa also limited the
dose to the inner and middle ear to a mean of
25
4%, of the prescribed dose compared to 75
6%
of the dose delivered to these structures with 3D
photon therapy (93). A reduction in the ear dose and
toxicity may also be achieved by the use of IMRT.
Huang et al. (92) showed that IMRT in medullo-
blastoma patients delivered 68% of the radiation
dose to the acoustic structures, when compared to
conventional irradiation. Despite having a higher
dose of cisplatin, the IMRT group had lower inci-
dence of ototoxicity (92).
Importantly, when monolateral radiotherapy is
administered (for example in parotid tumours), the
dose to the contralateral ear can be as high as 10% of
the prescribed dose due to scattered irradiation
(101). At the European Institute of Oncology in
Milan, Italy we currently investigate the dose dis-
tribution in the inner and middle ear structures in
parotid cancer patients receiving postoperative ra-
diotherapy. Importantly, high quality computer to-
mography planning (with perhaps 1 or 2-mm
spacing) is necessary to provide good visualization
of otologic organs (64,93). For example, in the Lin
et al. study (93), median volumes of the cochlea, the
inner ear (including cochlea) and the middle ear
were 0.25, 0.95 and 0:65 cm3 , respectively.
To assess the dose distribution in the auditory
structures, the use of a 3D treatment plan is neces-
sary with a detailed analysis of the dose-volume
histograms (DVHs) and isodose curves in different
planes. The maximum dose, average mean dose and
the DVHs should be assessed and recorded to allow
future clinical studies on late non-target tissue
complications. The average mean dose appears to
be a good indicator of the radiation dose delivered
to small structures (for example, cochlea), given
the high sensitivity of the DVH curve to slight
RADIOTHERAPY-INDUCED EAR TOXICITY
volumetric changes and positional variations within
a steep dose gradient (31,93).
DIAGNOSTICS OF RADIATION INDUCED
EAR TOXICITY
Even though most head and neck cancer patients are
referred for radiotherapy by ENT specialists, base-
line audiological data are missing or are incomplete
in many cases. It should be stressed that before ra-
diation therapy involving the hearing organ, all
patients should undergo basic otological evaluation.
This should comprise morphological evaluation by
microscopic otoscopy (MO) as well as basic func-
tional tests, such as pure tone audiometry (PTA),
tympanometry (TM) and stapedial reflexes (SR). Air
and bone conduction PTA allows for assessment of
the patients subjective hearing thresholds and en-
ables detection of conductive/sensorineural/mixed
hearing loss. PTA measurements are usually per-
formed at frequencies at which most speech is rec-
ognized (for example, 500, 1000, 2000, and 4000 Hz)
(30). TM is an objective measure of the middle ear
acoustic impedance and provides information on
middle ear aeration, ossicular chain mobility and
eustachian tube function. In some studies PTA is
proceeded by TM to exclude otitis media as a cause
of hearing loss (30). Testing of SR (contraction of the
stapedial muscle in reaction to loud sounds) com-
plements tympanometric measurements and pro-
vides important additional information on the status
of the neural reflex loop (acoustic-facial nerves). In
small children, where obtaining reliable audiomet-
rical data can be difficult, PTA should be replaced
by objective tests such as the transient evoked ot-
oacoustic emissions (TEOAE). The TEOAE test is
based on the recording of a feed-back acoustic signal
generated by vibrating outer hair cells of the inner
ear and is only detectable if the function of the ex-
ternal, middle and inner ear is normal or close to
normal. The above mentioned tests are the reason-
able minimum, in patients with age-adjusted normal
values (102). If the results show any abnormalities, a
full specialist otological assessment should be per-
formed (this includes patients with known retroc-
ochlear pathology). Availability of the baseline
results is the foundation for accurate diagnosis and
appropriate management of radiation-induced
damage.
In the case of ear complications following radio-
therapy an extended otological assessment is war-
ranted. External and middle ear side effects are best
diagnosed by micro-otoscopy and TM. Micro-otos-
copy can reveal different forms of external and
middle ear inflammation and, together with TM,
425
helps evaluate the middle ear aeration (and ex-
clude/confirm presence of effusion). In cases of a
patulous eustachian tube, otoscopic examination
reveals a tympanic membrane that moves medially
on inspiration and laterally on expiration. This di-
agnosis can also be confirmed by TM, which shows
fluctuation in the tympanometric line that coincides
with respiration.
Hearing loss in adults is best assessed by PTA. In
non-cooperating children, a hearing assessment
might require a combination of objective tests such
as TEOAE, TM, SR and auditory brainstem re-
sponses (ABR), the latter test allowing not only for
objective evaluation of the hearing thresholds but
also for functional assessment of the acoustic nerve
and the central auditory pathways.
If a purely conductive hearing loss is observed
then, when associated with otoscopic findings and
TM, the diagnosis is usually straightforward. When,
however, a sensorineural component of the hearing
loss is discovered then the main questions are the
progression of the hearing deficit and the site of
lesion (cochlear or retrocochlear). The stability/pro-
gression of the hearing thresholds should be con-
trolled by repeated PTA and a long follow-up of at
least 3 years after radiotherapy. The site of damage
can be audiologically diagnosed by a combination of
PTA, TEOAE, ABR, SR, speech audiometry and
other specific audiometric tests. However, modern
radiological imaging techniques are becoming
equally valuable in localizing damage.
Magnetic resonance imaging (MRI) is able to
show and differentiate such post-radiation injuries
as labyrinthitis, haemorrhage to the inner ear spaces,
neuronitis and white matter lesions. MRI, together
with computed tomography (CT), allows for evalu-
ation of the patency of the inner ear fluid spaces and
can show fibrotic processes occluding the inner ear
fluid spaces among others (103). Ideally, all patients
with post-irradiation SNHL should be evaluated
by MRI involving the inner ear and the auditory
pathways.
CT, bone scan and positron emission tomography
(PET) can also be useful in accurate imaging of the
bony structures and be helpful in evaluation of the
extent of osteoradio-necrosis or (together with MRI)
the amount of brain necrosis (48,104).
In patients with bilateral cophosis or profound
hearing loss who are candidates for cochlear im-
plantation, electrostimulation tests of the acoustic
nerve have to be performed in order to evaluate
preservation of the electrical functionality of the
nerve fibers. This is especially important in patients
treated with stereotactic surgery for cerebello-pon-
tine angle tumours. In this group the risk for total
electrical nerve dysfunction is relatively high, which
may preclude cochlear implantation.
426
Electronystagmography (ENG) or videonystag-
mography (VNG) are indicated for assessment and
follow-up of the vestibular (balance) disorders.
These tests evaluate the vestibulo-ocular reflexes,
i.e., the movements of eyeballs in response to specific
stimulation of the vestibular parts of the inner ear.
MANAGEMENT
External ear
Acute and late external otitis is typically managed
with the anti-inflammatory agents applied topically
and systematically. Lubrication and ointments can
be necessary in case of the reduction of wax secre-
tion. Rarely, surgical procedures are performed for
late skin ulceration (14,19).
Middle ear
Complaints caused by the reduction in middle ear
pressure should be managed by vasoconstricting
medication (nasal sprays, tablets) and, if conserva-
tive therapy is ineffective, by early paracenthesis
(incision of the ear-drum) with insertion of a venti-
lation tube ( grommet) in the tympanic membrane.
This approach can relieve the pain and improve
hearing (in one randomized trial, hearing improve-
ment and lower risk of SNHL in patients treated
with ventilation tube has been demonstrated (15,74).
If the problem is however not only limited to simple
underpressure caused by eustachian tube dysfunc-
tion but also involves the middle ear mucosal
changes (productive mucosa, granulation tissue),
grommet insertion might be insufficient or even
contra-indicated. In such ears ventilation treatment
may initiate and sustain inflammatory processes
and pain has been observed, resulting in persistent/
recurrent otorrhea and hearing deterioration
(9,6769,94,105). Therefore, according to some au-
thors (106), repeated myringotomies with aspiration
of effusion from the middle ear rather than grommet
insertion should be employed in these cases.
The functional deficit (the conductive or mixed
hearing loss) in patients with persistent post-irradi-
ation middle ear effusion and/or external otitis and/
or otorrhea can be effectively alleviated by applica-
tion of bone conduction hearing aids, such as, e.g.,
the bone anchored hearing aid (BAHA). The ad-
vantage of the BAHA is that in these type of hearing
aids the acoustic signal (transformed into vibration)
is transferred via the skull bones and directly stim-
ulates the inner ear, bypassing the dysfunctional
B.A. JERECZEK-FOSSA ET AL.
external and middle ear. Another advantage of the
BAHA is that being affixed directly to the skull they
do not require earmoulds which could additionally
irritate the skin in the external ear canal, already
compromised in function by irradiation.
Paracentesis with a grommet insertion may also
be performed in patients who developed patulous
eustachian tube following radiotherapy. However,
in such cases mere venting is often insufficient and
additional procedures obstructing the widened lu-
men of the eustachian tube are necessary (107).
Inner ear
Post-irradiation SSNHL and PSNHL should be
treated as idiopathic SSNHL and PSNHL. There is
no standard treatment of idiopathic sudden or pro-
gressive SNHLs. All ENT departments have their
own schemes of management of these cases, in-
cluding a combination of corticosteroid, and rheo-
logic therapies. Corticosteroid intake may improve
inflammation and oedema in the inner ear after ra-
diotherapy-induced damage (43), but in some cases
no improvement has been seen (35,108). Younger
age, a good pre-irradiation hearing level, and a short
time between the onset of the hearing loss and ra-
diotherapy are correlated with better chances for
recuperation of the hearing acuity (109).
Additional hyperbaric oxygen therapy (HBO) or
carbogen therapy have been reported to ameliorate
results of treatment of the idiopathic SSNHL by
promoting regeneration capabilities (initiation of
cellular and vascular repair mechanisms) through
improved circulation and increased O2 concentra-
tions (110,111). The benefit appears greatest in
younger patients (<50 years) (110), although its
value has not been confirmed by other groups (111).
Some authors have not observed any benefit of HBO
in idiopathic SSNHL (112).
Moderate SNHL is best managed with classical
air conduction hearing aids. In cases of radiation-
induced cophosis or bilateral profound SNHL,
successful hearing with cochlear implants has been
reported (113). However the results in patients who
lost their hearing after irradiation tends to be worse
than in other post-lingually deaf persons. This is due
to a higher risk of total electrical afunctionality of
the acoustic nerve after irradiation. For deaf patients
with bilaterally dysfunctional acoustic nerves the
only remaining functional alternative is a brainstem
implant (114116). Successful hearing restoration
with auditory brainstem implants after radiosurgery
for neurofibromatosis type 2 has been reported (the
device was implanted at the time of removal of tu-
mour which progressed after radiosurgery) (117).
RADIOTHERAPY-INDUCED EAR TOXICITY
In patients with deafness caused by a vascular
insult to the inner ear (by irradiation or microsur-
gery), fibrosis of the inner ear fluid spaces may de-
velop within 3 to 4 months following the insult.
Since this may restrain the use of cochlear implants,
a close follow-up with MRI is necessary. At the first
signs of fibrosis seen on MRI, cochlear implantation
should not be delayed. In these cases intraoperative
intracochlear injection of depot steroids might help
to reduce the fibrotic reaction around the implanted
electrode array and improve performance of the
implant (118).
Post-irradiation balance disturbances require ac-
tive vestibular rehabilitation. It is based on com-
pensational capabilities of the brain and in most
cases is sufficient to relieve the symptoms.
Other
Antibiotics, HBO therapy and surgery are employed
in treatment of the post-irradiation osteoradione-
crosis, whereas corticosteroids, HBO and some-
times surgery are used in management of the brain
necrosis (10,104, 119,120).
CONCLUSIONS
Radiotherapy for the head and neck area is associ-
ated with an increased risk of considerable acute and
late radiation-related ear toxicity. The post-irradia-
tion damage possibly involves all levels of the
hearing organ, from the external, middle and inner
ear up to the central auditory pathways, and may
result in conductive, sensorineural or mixed hearing
loss. Due to its relatively high frequency, and po-
tential serious implications, this sequel should attract
more attention. Any attempt should be undertaken
to prevent, diagnose and effectively treat early and
late ear morbidity. Among preventive measures,
new radiotherapy techniques and modalities (3-D
conformal irradiation, IMRT, proton therapy, frac-
tionated stereotactic irradiation) are of paramount
importance, since they allow for a better dose dis-
tribution and a lower dose to the non-target organs.
ACKNOWLEDGEMENTS
We thank Prof. J. Jassem from the Department of
Oncology and Radiotherapy of Medical University
of Gdansk, Poland, for his critical comments on the
manuscript.
427
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