1. Introduction
Compared with other types of malignancies,
nasopharyngeal carcinoma (NPC) occurs infrequently and is ranked as
the 22nd most prevalent cancer worldwide (1,2).
However, the incidence rate of NPC ranks first among different
types of head and neck cancer (3).
According to statistics from the International Agency for Research
on Cancer, there were ~129,000 new cases of NPC in 2018, with
>70% of the new cases occurring in East Asia and Southeast Asia,
indicating a geographical imbalance (4). Based on the burden and trend of NPC
in China from 1990 to 2019, the crude incidence rate has increased
from 2.71 per 100,000 to 7.76 per 100,000 individuals, highlighting
an increasing trend (5). The
disease imposes a substantial global mortality burden, with ~80,000
annual NPC-related mortalities worldwide (6). China, as the most endemic country,
accounts for >43% of global NPC mortalities, with 28,000 to
34,800 annual mortalities and a national age-standardized mortality
rate of 1.18-1.5 per 100,000 population (7). Radiation therapy is considered the
primary treatment modality for NPC, demonstrating an overall
survival rate of up to 85% after 5 years for patients with
early-stage disease (8). However,
patients often experience long-term side effects following
radiation therapy. For example, hearing impairment is the second
most common long-term side effect after xerostomia (9). Hearing impairment impacts the
cognitive function and emotional well-being of patients and
diminishes their quality of life. Therefore, the present study
aimed to comprehensively review the classification of hearing
impairment following radiotherapy for NPC and investigated the
assessment tools and intervention measures used in practice. The
present review may provide guidance for clinical practice and aid
in the rehabilitation of patients following radiotherapy.
2. Categories of hearing loss
Hearing loss is classified into three types based on
pathological mechanisms, namely: i) Conductive hearing loss (CHL);
ii) sensorineural hearing loss (SNHL); and iii) mixed hearing loss
(MHL) (10). Healthy hearing is
considered when both air conduction and bone conduction thresholds
are <25 decibels (dB). An increased air conduction threshold, a
bone conduction threshold at the expected level and an air-bone gap
>10 dB are indicative of CHL. SNHL is considered when both the
air and bone conduction thresholds are increased, but the
difference between them is <10 dB. An increased air and bone
conduction threshold accompanied by an air-bone gap of >10 dB
indicates MHL. Among these, radiation therapy may result in
patients developing CHL, while a combination of chemotherapy and
radiotherapy may result in MHL (11,12).
CHL
During radiotherapy for NPC, the primary radiation
target encompasses the middle ear structures, including the
tympanic cavity, Eustachian tube, mastoid sinus and petrous apex
(13). The middle ear serves a
pivotal role in sound transmission by converting sound waves from
the outer ear into mechanical waves for further conduction.
Radioactive damage to the middle ear may lead to CHL, and
radiation-induced otitis media is considered the predominant
clinical manifestation (14).
Previous studies demonstrate that radiation-induced injury
primarily affects the Eustachian tube and tympanic cavity, where
direct radiation damages both mucosa and cartilage of the
Eustachian tube (15,16). In addition, radiation damages the
innervating muscles, including the tensor veli palatini muscle,
resulting in an impaired opening function of the Eustachian tube
(17). Radiation injury to the
middle ear mucosa, blood vessels and lymphatic endothelium disrupts
the local mucociliary clearance system. This process not only
increases tissue fluid exudation, but also slows lymphatic
drainage, eventually leading to retention and obstruction of
secretions. Radiation-induced necrosis of the nasal-pharyngeal or
sinus mucosa may result in a bacterial infection (18), which subsequently involves the
Eustachian tubes (19). The
interplay between the aforementioned pathological processes leads
to secretory otitis media, resulting in CHL. Post-radiotherapy, CHL
is typically transient, with recovery of Eustachian tube function
and improvement in middle ear effusion. As the negative pressure
within the middle ear is relieved, hearing loss resolves. The
development of atrophic (fibrotic) otitis media and ossicular chain
necrosis after radiotherapy is multifactorial, which explains why
these complications only arise in partial patients rather than all
cases. Based on clinical cohort studies focusing on head and neck
radiotherapy, the overall incidence of radiation-related
atrophic/fibrotic otitis media is approximately 1 out of 5 to 1 out
of 4 patients (20).
SNHL
SNHL is caused by damage to the cochlea and auditory
nerve (21). Following
radiotherapy, SNHL is categorized into two types based on its time
of onset, namely: i) Early-onset (acute); and ii) late-onset
(chronic). Early-onset SNHL may occur within hours to 1 week after
exposure to ionizing radiation and, in certain cases, this type of
hearing loss may be reversible or partially reversible. Conversely,
late-onset SNHL manifests as a chronic, progressive and
irreversible process that arises within 6-24 months
post-irradiation (22,23). In a number of patients, complete
deafness may develop within weeks or months (24). The reported incidence rate of
post-radiotherapy SNHL varies between 15 and 30%, with a notably
increased occurrence rate observed in patients receiving
cisplatin-based chemotherapy compared with those receiving
radiotherapy alone (25,26). Additionally, >50% of patients
that suffer with SNHL will experience permanent SNHL (27). SNHL develops through complex
mechanisms that are not fully understood. Possible contributing
factors include blood vessel abnormalities, atrophy of the spiral
ligament and basilar membrane, loss of outer hair cells and
deterioration of the eighth cranial nerve (28).
MHL
MHL is a composite manifestation of both CHL and
SNHL, which typically occurs at the same time as damage to the
outer or middle ear. MHL impacts the cochlea and auditory nerve,
further complicating the intricacy and challenges associated with
treating auditory impairment (29).
3. Implications of hearing loss
Impact of hearing loss on the quality
of life of patients
Hearing loss can impair the communication abilities
of patients, leading to limited participation in everyday listening
situations. This may affect daily functions and negatively impact
the quality of life of the patient (30). A study by Sano et al
(31) reveals the limitations of
social and daily activity experienced by individuals with hearing
loss compared with those without hearing loss, from both a
physiological and psychological perspective (31). In addition, a study by Wie et
al (32) reports that severe
unilateral hearing impairment, such as deafness, notably disrupts
speech perception, communication skills and social interactions
among patients with hearing loss compared with those without
hearing loss (32). In addition,
symptoms such as dizziness and tinnitus, which are associated with
sudden SNHL (SSHL), may also contribute to anxiety surrounding the
potential recurrence or fear of hearing loss in the unaffected ear,
further impacting the quality of life of patients (33).
Potential association between hearing
loss and mental disorders
A number of studies substantiate the association
between hearing loss and neurocognitive impairments (34,35).
Compared with patients without hearing loss, individuals with
moderate to severe hearing loss who do not utilize hearing aids
exhibit impaired language expression, increased social isolation
and accelerated cognitive decline (36). A multi-center, parallel-group,
randomized controlled trial conducted in the United States
investigated untreated hearing loss among adults aged 70-84 years
without severe cognitive impairments. The findings demonstrate that
interventions, such as provision of hearing aids and health
education, may mitigate the risk of cognitive decline within a
3-year period, promoting stability in the cognitive capacities of
older patients (37). A further
study examining the association between hearing aid usage and
cognitive abilities reveals that patients who wear hearing aids
exhibit a notably reduced risk of cognitive decline, compared with
those lacking auditory correction during a long-term follow-up
period ranging from 2-25 years (38). This long-term protective
association has been validated by recent population-based
longitudinal cohorts and clinical observational research (38). Large-sample prospective evidence
verified that standardized hearing aid intervention effectively cut
down dementia and global cognitive deterioration risk in elderly
hearing-impaired individuals during multiyear follow-up (39). Additionally, real-world cohort data
focusing on middle-aged and elderly subjects further confirmed
sustained hearing aid application independently alleviates
progressive cognitive impairment and brain function regression in
long-term observational trials (40). Moreover, an analysis elucidating
the potential association between auditory restoration and changes
in short-term cognitive test scores indicates a notable 3%
improvement following hearing aid use (24), further corroborating the positive
impact of auditory intervention on cognitive function.
Previous studies reveal an association between
anxiety and hearing loss, with generalized anxiety being
particularly prominent (41,42).
Compared with individuals without hearing loss, those with mild
hearing impairment may exhibit a markedly increased incidence of
anxiety, which may also increase as the degree of hearing loss
increases (41). Hearing loss
weakens cognitive reserves, exacerbates executive dysfunction and
disrupts normal emotional responses and regulatory mechanisms,
leading to decreased cognitive performance and increased risk of
depression (42).
A 5-year follow-up study demonstrated that patients
with existing or deteriorating hearing loss exhibited far more
noticeable progression of depressive symptoms than those with
intact hearing (43). Meanwhile,
aggravated depressive symptoms were accompanied by increased
hearing loss at low and mid frequencies, implying a potential
correlation between the two conditions (44). A previous study, focusing on the
mental health of adolescents, aged 10 to 19 years, also reveals an
association between mental health and auditory function (45). The survey conducted among
adolescent patients with impaired auditory function reveals that
30% of patients exhibit symptoms of depression, such as persistent
low mood, social withdrawal, poor concentration and loss of
interest in daily activities, while 21% of patients have symptoms
of anxiety, including excessive worry, restlessness and
palpitations. Moreover, older adolescents (aged 15 to 19 years)
score higher on measures for depressive symptoms than younger
adolescents with hearing loss. Among the group with severe to
profound auditory impairments, the incidence rates for both
depression and anxiety were more pronounced (45). Additionally, results of a previous
study reveal that the prevalence rate for depression in deaf or
hard-of-hearing populations is ~7%, whereas the lifetime prevalence
of depression in this group can be as high as 26% (46). Children who experience ridicule due
to their impaired auditory function or other disabilities, such as
visual impairments, neurological disorders or developmental delays
during upbringing, may face an increased risk of developing
depression compared with those who do not endure such ridicule
(46).
4. Objective evaluation tools for hearing
loss
Hearing handicap inventory for adults
screen (HHIA-S)
The HHIA-S is a preliminary diagnostic scale for
hearing impairment, which is used worldwide (47). This scale comprises 10 items,
including five emotional and five social/contextual aspects
(Table I). The scoring criteria
are as follows: A response of ‘yes’ receives four points; a
response of ‘sometimes’ receives two points; and a response of ‘no’
receives zero points. The total score ranges from 0-40, with higher
scores indicating more severe hearing loss. A score of more or
equal to eight suggests the presence of an impairment, while scores
between eight and 24 indicate mild impairment, and scores >24
indicate severe impairment (47).
In China, the HHIA-S was translated in 2014(48), a score >8 on the scale was used
as the cut-off to identify participants with hearing loss, those
scoring exactly 8 were classified as having normal hearing. When
conducting hearing screens for individuals with an average pure
tone air conduction threshold (pure tone average; PTA) of >40 dB
Hertz, HHIA-S is a user-friendly self-assessment questionnaire that
can be administered without the need for specialized personnel or
equipment, thereby conserving medical resources (47). However, this method may exhibit
certain limitations, as subjective evaluations may introduce
inherent biases, and specific types of hearing impairments
including conductive hearing loss, retrocochlear hearing
impairment, mixed hearing loss, subclinical noise-induced or
ototoxic sensorineural hearing loss, asymmetric hearing loss,
auditory processing disorder, as well as hearing dysfunction in
children and cognitively impaired populations still require
integration with objective screening methods to achieve accurate
identification and classification (49).
 | Table IHearing handicap inventory for adults
screen (47). |
Table I
Hearing handicap inventory for adults
screen (47).
| Item |
Questiona | Yes (4) | Sometimes (2) | No (0) |
|---|
| S-1. | Does a hearing
problem cause you to use the phone less often than you would
like? | | | |
| E-2.b | Does a hearing
problem cause you to feel embarrassed when meeting new people? | | | |
| S-3. | Does a hearing
problem cause you to avoid groups of people? | | | |
| E-4. | Does a hearing
problem make you irritable? | | | |
| E-5.b | Does a hearing
problem cause you to feel frustrated when talking to members of
your family? | | | |
| S-6. | Does a hearing
problem cause you difficulty when attending a party? | | | |
| S-7.b | Does a hearing
problem cause you difficulty hearing/understanding coworkers,
clients, or customers? | | | |
| E-8.b | Do you feel
handicapped by a hearing problem? | | | |
| S-9.b | Does a hearing
problem cause you difficulty when visiting friends, relatives, or
neighbors? | | | |
| E-10. | Does a hearing
problem cause you to feel frustrated when talking to coworkers,
clients, or customers? | | | |
| S-11.b | Does a hearing
problem cause you difficulty in the movies or theater? | | | |
| E-12. | Does a hearing
problem cause you to be nervous? | | | |
| S-13. | Does a hearing
problem cause you to visit friends, relatives, or neighbors less
often than you would like? | | | |
| E-14.b | Does a hearing
problem cause you to have arguments with family members? | | | |
| S-15.b | Does a hearing
problem cause you difficulty when listening to TV or radio? | | | |
| S-16. | Does a hearing
problem cause you to go shopping less often than you would
like? | | | |
| E-17. | Does any problem or
difficulty with your hearing upset you at all? | | | |
| E-18. | Does a hearing
problem cause you to want to be by yourself? | | | |
| S-19. | Does a hearing
problem cause you to talk to family members less often than you
would like? | | | |
| E-20.b | Do you feel that
any difficulty with your hearing limits or hampers your personal or
social life? | | | |
| S-21.b | Does a hearing
problem cause you difficulty when in a restaurant with relatives or
friends? | | | |
| E-22. | Does a hearing
problem cause you to feel depressed? | | | |
| S-23. | Does a hearing
problem cause you to listen to TV or radio less often than you
would like? | | | |
| E-24. | Does a hearing
problem cause you to feel uncomfortable when talking to
friends? | | | |
| E-25. | Does a hearing
problem cause you to feel left out when you are with a group of
people? | | | |
Seven-item Eustachian tube dysfunction
questionnaire (ETDQ-7)
The ETDQ-7 is a valuable tool for evaluating
symptoms associated with abnormal Eustachian tube function,
encompassing issues such as ear fullness, ear pain, autophony and
hearing loss (50). This
comprehensive survey comprises seven questions that gauge the
severity of these subjective symptoms on a scale ranging from one
to seven, where higher scores indicate more pronounced
manifestations (Table II). A
study by Cao et al (51)
utilized the Chinese version of the ETDQ-7 to assess patients with
Eustachian tube dysfunction alongside healthy individuals. The
results of the aforementioned study demonstrates that the Chinese
version of the ETDQ-7 exhibits high levels of reliability
(coefficient, 0.879), sensitivity (96.1%) and specificity (85%).
Therefore, these results indicate the efficacy of utilizing the
Chinese version of the ETDQ-7 in evaluating Eustachian tube
dysfunction.
| Table IISeven-item Eustachian tube
dysfunction questionnaire (50). |
Table II
Seven-item Eustachian tube
dysfunction questionnaire (50).
| Over the past 1
month, how much has each of the following been a problem for
you? | No problem | | | Moderate
problem | | | Severe problem |
|---|
| 1. Pressure in the
ears? | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2. Pain in the
ears? | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 3. A feeling that
your ears are clogged or ‘under water’? | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 4. Ear symptoms
when you have a cold or sinusitis? | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 5. Crackling or
popping sounds in the ears? | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 6. Ringing in the
ears? | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 7. A feeling that
your hearing is muffled? | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
The ETDQ-7 may be used to gather information on the
symptoms experienced by patients in an efficient manner, with
comprehensible content and convenient completion. However, relying
only on the ETDQ-7 scores does not allow for a differentiation
between obstructive and patulous Eustachian tube disorders. This
limits its utility as a diagnostic tool for obstructive Eustachian
tube dysfunction or an objective measurement method for Eustachian
tube function (52).
Patient-reported outcomes version of
the common terminology criteria for adverse events (PRO-CTCAE)
Ototoxicity constitutes a treatment-related adverse
event induced by antitumor therapies. The ototoxicity grading
criteria assess patients' symptomatic conditions in the week prior
to each clinical assessment, incorporating three evaluation
dimensions: Symptom frequency, severity and interference with daily
functioning. This grading system adopts a 1-5 point rating scale
(Table III) (53). A higher score indicates more
pronounced symptoms. There are multiple versions of the PRO-CTCAE
assessment, which also has extensive dissemination capabilities.
Therefore, this serves as a valuable addition to adverse event
reporting by healthcare professionals during clinical trials
focused on tumors (54).
| Table IIIPatient-reported outcomes version of
the common terminology criteria for adverse events (53). |
Table III
Patient-reported outcomes version of
the common terminology criteria for adverse events (53).
| CTCAE Term | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
|---|
| Ear pain | Mild pain | Moderate pain;
limiting instrumental ADL | Severe pain;
limiting self care ADL | - | - |
| Definition | A disorder
characterized by a sensation of marked discomfort in the external
ear region | | | | |
| Hearing
impaired | Adults enrolled on
a Monitoring Program (on a 1, 2, 4, 3, 6, and 8 kHz audiogram):
Threshold shift of 15-25 dB averaged at 2 contiguous test
frequencies in at least one ear; Adults not enrolled on a
Monitoring Program: Subjective change in hearing in the absence of
documented hearing loss; Pediatric (on a 1, 2, 3, 4, 6, and 8 kHz
audiogram): Threshold shift >20 dB hearing loss (HL) (i.e., 25
dB HL or greater); sensorineural hearing loss (SNHL) above4 kHz
(i.e., 6 or 8 kHz) in at least one ear | Adults enrolled on
a Monitoring Program (on a 1, 2, 3, 4, 6, and 8 kHz audiogram):
Threshold shift of >25 dB averaged at 2 contiguous test
frequencies in at least one ear; Adults not enrolled on a
Monitoring Program: Hearing loss with hearing aid or intervention
not indicated; limiting instrumental ADL; Pediatric (on a 1, 2, 3,
4, 6, and 8 kHz audiogram): Threshold shift >20 dBat 4 kHz in at
least one ear | Adults enrolled on
a Monitoring Program (on a 1, 2, 3, 4, 6, and 8 kHz audiogram):
Threshold shift of >25 dB averaged at 3 contiguous test
frequencies in at least one ear; therapeutic intervention
indicated; Adults not enrolled on a Monitoring Program: Hearing
loss with hearing aid or intervention indicated; limiting self care
ADL; Pediatric (on a 1, 2, 3, 4, 6, and 8 kHz audiogram): Hearing
loss sufficient to indicate therapeutic intervention, including
hearing aids; threshold shift >20 dB at 2 to <4 kHz in at
least one ear | Adults: Decrease in
hearing to profound bilateral loss (absolute threshold >80 dB HL
at 2 kHz and above); nonserviceable hearing Pediatric:Audiologic
indication for cochlear implant; >40 dB HL (i.e., 45 dB HL or
more); SNHL at 2 kHz and above | - |
| Definition: | A disorder
characterized by partial or complete loss of the ability to detect
or understand sounds resulting from damage to ear structures. | | | | |
HHIA-S, ETDQ-7 and PRO-CTCAE complement one another
in evaluating hearing impairment from separate perspectives
(Table IV): HHIA-S measures
psychosocial hearing handicap in daily life, ETDQ-7 assesses
eustachian tube-related conductive ear symptoms, and PRO-CTCAE
provides standardized toxicity grading of treatment-related hearing
loss for clinical trials. Concurrent administration of the three
tools achieves full-spectrum auditory outcome assessment
integrating middle ear symptoms, functional handicap and treatment
adverse events.
| Table IVComparison of hearing impairment
assessment tools. |
Table IV
Comparison of hearing impairment
assessment tools.
| Tool | HHIA-S | ETDQ-7 | PRO-CTCAE |
|---|
| Application | Preliminary
screening for hearing impairment | Evaluation of
symptoms associated with Eustachian tube dysfunction | Assessment of
adverse events in oncology clinical trials |
| Items | A total of 10 items
(five emotional and five social/situational) | A total of seven
questions | Domains: Frequency,
severity and impact of adverse events |
| Scoring | Scored zero points
for ‘No’, two points for ‘Sometimes’ and four points for ‘Yes’ | Scored one to seven
points (based on symptom severity) | A one to five
graded scale |
| Score cut-off | Impairment
indicated by a score of ≥8 (8-24, mild; >24, severe) | A score of ≥14.5
indicates Eustachian tube dysfunction | Grade 5, mortality;
grade 4, life-threatening toxicity requiring intervention |
| Localization | Chinese version
validated, no modification was made to the questionnaire's official
name | Chinese version
validated, no modification was made to the questionnaire's official
name | Chinese version
validated, no modification was made to the questionnaire's official
name |
| Country | USA | USA | USA |
| Strengths | Self-administered,
simple operation, and no specialized equipment required | Easy symptom
collection and high operability | Broad applicability
and complements clinician-reported adverse event data |
| Limitations | Subjective bias and
requires objective screening for specific hearing loss | Fails to
differentiate obstructive Eustachian tube dysfunction vs. patulous
Eustachian tube dysfunction | None |
| Population | Adults (28-59
years) | Mean age, 49.8±13.9
in the Eustachian tube dysfunction group and 53.4±11.2 years in the
control group | Median age, 59
years |
| Reliability | Original test:
Test-retest reliability, r=0.930. Chinese test: Sensitivity,
68.4%; and specificity, 96.7% | Original test:
Cronbach's, α=0.711; and test-retest reliability, r=0.780.
Chinese test: Cronbach's, α=0.897; sensitivity, 96.1%; and
specificity, 85.0% | Original test:
Internal consistency, α=0.760; and test-retest reliability,
r=0.700-0.910. Chinese test: Cronbach's, α=0.900 |
5. Rehabilitative measures for hearing
loss
Eustachian tube insufflation
Eustachian tube insufflation is a treatment method
that aims to loosen adhesions, reduce swelling and reopen the
Eustachian tube passage in order to restore healthy ventilation
functions through the introduction of air into the tube (Table V) (55-59).
This technique eliminates negative pressure in the middle ear,
thereby increasing the oxygen partial pressure within the middle
ear, facilitates efficient mucus diffusion and accelerates fluid
absorption and drainage. Moreover, Eustachian tube insufflation is
a useful therapeutic option for secretory otitis media-related
hearing loss and can be considered as part of the overall
management of otitis media with effusion, alongside other
approaches such as watchful waiting, hearing surveillance, periodic
reevaluation, and surgical intervention when indicated,
particularly tympanostomy tube insertion with or without
adenoidectomy depending on the child's age (60). According to published
auto-inflation protocols, the patient sits upright while a probe
tip is inserted into one nostril and the other nostril is manually
compressed. The patient holds a small amount of water in the mouth,
airflow is delivered into the nasal cavity, and swallowing is
performed after 1-2 sec of airflow to facilitate middle ear
inflation. The procedure may be performed twice daily and should be
suspended temporarily if an upper respiratory tract infection
occurs (61,62).
| Table VSummary of the therapeutic approaches
and studies on hearing loss associated with nasopharyngeal
carcinoma. |
Table V
Summary of the therapeutic approaches
and studies on hearing loss associated with nasopharyngeal
carcinoma.
| First author,
year | Therapeutic
approach | Mechanism of
action | Specific
procedures | Study design and
sample size | Statistical
data | Qualitative
data | (Refs.) |
|---|
| Fermo et al,
2022 | Eustachian tube
inflation therapy. | Relieves adhesions,
restores ventilation function of the Eustachian tube, eliminates
negative pressure in the middle ear and promotes effusion
absorption and drainage. | Patients hold water
in their mouth, place the silicone treatment head against one
nostril, seal both nostrils and inhale air for ~3 sec.
Subsequently, patients swallow the water while the device is
running. Repeat twice daily for 6-8 weeks. | None. | None. | In total, 50
patients were cureda, 3 patients
improvedb and 1
patient was unaffectedc. | (55) |
| Kong et al,
2022 | Hydrogen-oxygen
inhalation. therapy | Enhances immune
function, antioxidant effects, protects auditory hair cells and
improves hearing. | Patients inhale a
mixture of hydrogen (2 l/min) and oxygen (1 l/min) via a nasal
cannula for 3-6 h daily, for 4-12 weeks. | Prospective cohort
study, the sample size was formed of 17 patients. Follow-up
duration, the median time from radiotherapy to present was 228
months. The median time from hearing loss diagnosis to present was
92 months. | Notable reduction
in Eustachian tube dysfunction score, air conduction threshold and
bone conduction threshold after 4 weeks of hydrogen inhalation. The
pre-inhalation air conduction threshold was 74.69±27.03 dB. At week
12, the lowest air conduction threshold was 66.88±20.88 dB.
Pre-inhalation bone conduction threshold was 45.70±21.58 dB. At
week 12, the lowest bone conduction threshold was 40.94±18.93
dB. | In a real-world
evidence investigation examining voluntary hydrogen inhalation as a
rehabilitation method among patients with cancer, a 63-year-old
male with nasopharyngeal carcinoma experienced hearing loss
post-radiotherapy and relied on a hearing aid. Starting daily
hydrogen inhalation in January 2019, the patient achieved notable
hearing improvement after 3 months and no longer required the
hearing aid. | (56) |
| Shen et al,
2024 | Acupuncture.
therapy | Regulates
inflammatory responses, improves local blood circulation and
promotes blood flow in the ears. | Acupuncture was
performed by inserting sterile needles into predefined anatomical
sites. Patients diagnosed with NPC who received at least six
acupuncture treatments were identified as ‘acupuncture users’,
while the remaining cases were considered ‘non-acupuncture
users’. | Cohort study formed
of 811 patients with SSHL and 1,452 patients with NPC without SSHL.
It had a 10-year study period. | Acupuncture notably
reduced the risk of SSHL in patients with NPC, with an adjusted OR
of 0.39 (95% CI, 0.25-0.60). The longer the duration of acupuncture
use, the greater the reduction in SSHL risk in a dose-dependent
manner. | None. | (57) |
| Chen et al,
2016s | Methylpredni-solone
intravenous pulse therapy | Mitigates early
sensorineural hearing loss caused by radiotherapy and protects
outer hair cells. | Methylprednisolone
intravenous pulse therapy for 14 days compared with radiotherapy
alone. | Prospective,
controlled clinical study. Treatment group was formed of 25
patients, and the control group was formed of 28 patients. The
follow-up duration was 1 year. | Following 1 year
after radiotherapy, the control group showed increased air and bone
conduction pure tone hearing thresholds and decreased DPOAE levels.
No differences were observed in ABR wave I, III and V latencies and
I-V interwave latencies before and after radiotherapy. The
treatment group had decreased air conduction thresholds and
increased DPOAE levels compared with the control group. | None. | (58) |
| Lyu et al,
2021 | Intratympanic
methylpredni-solone injection | Downregulates
inflammatory responses, promotes cochlear blood flow, inhibits
inner ear cell apoptosis, improves stria vascularis function and
maintains ionic homeostasis. | Group one:
Treatment was initiated on day 1 with intravenous dexamethasone (10
mg/day for 5 days, followed by 5 mg/day for 7 days) and
intratympanic methylprednisolone (40 mg), which was administered
every other day for a total of four doses. Group two: Intravenous
dexamethasone (10 mg/day for 5 days, followed by 5 mg/dayfor 7
days) and intratympanic methylprednisolone (40 mg) every other day
for 4 times starting on day 6. | Retrospective study
with a total number of 61 patients. The follow-up duration was 6
months. | Both groups showed
comparable PTA gains with notable improvement compared with
pre-treatment. The long-term hearing threshold data (follow-up at 6
months) showed no notable changes between 3 months and 6 months
post-treatment for both groups (at 6 months: Group one, 40.50±21.76
dB and group two, 38.79±20.04 dB; and at 3 months: Group one,
39.27±22.28 dB and group two, 37.61±20.57 dB), indicating that
patients achieved maximum benefit from short-term treatment. | In group one, 5
patients (16.67%) were classified as ineffective, 13 patients
(43.33%) as effective and 12 patients (40.00%) as notably
effective. In group two, 2 patients (6.45%) were classified as
ineffective, 10 patients (32.26%) as effective and 19 patients
(61.29%) as notably effective. | (59) |
Inhalation of a high concentration of
hydrogen-oxygen mixture
Inhalation of a high concentration of
hydrogen-oxygen mixture (containing 2.0 l/min hydrogen and 1.0
l/min oxygen, equivalent to ~66.7% hydrogen and 33.3% oxygen by
flow) may enhance the immune function of patients with low levels
of immunity, such as individuals aged ≥65 years or those with
chronic lung diseases or malignant tumors. This method aims to
increase the quantity and activity of functional helper T
lymphocytes, cytotoxic T lymphocytes and natural killer cells
(63,64). Inhalation of small doses (typically
1-4%) of hydrogen gas may selectively reduce cytotoxic reactive
oxygen species, particularly hydroxyl radicals, by reacting with
them rather than by preventing their release. This antioxidant
action is novel and effective, and it helps to protect hair cells
in the auditory system and improve hearing (65). During this process, patients are
administered continuous once-daily treatment for 4-12 weeks, with
each session lasting 3-4 h. Patients are required to inhale a
mixture of hydrogen-oxygen gas through a nasal cannula, at a rate
of 2 liters/min hydrogen gas and 1 liter/min oxygen (~66.7%
hydrogen and 33.3% oxygen by flow). The results of a previous study
demonstrate that, after 4 weeks of hydrogen inhalation, the
Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) score, as well
as air conduction and bone conduction thresholds, were markedly
reduced, indicating alleviation of Eustachian tube
dysfunction-related symptoms. Furthermore, in patients receiving
radiotherapy or radiochemotherapy, air conduction thresholds were
notably reduced. In total, 5 patients (10 ears) underwent hearing
examinations 6-9 months after discontinuing hydrogen inhalation.
Hearing remained stable or continued to improve in 3 of the 10
ears, although overall hearing thresholds increased during
follow-up (Table V) (56).
Acupuncture
Acupuncture, a distinct therapeutic modality of
Traditional Chinese Medicine, is used for the management of diverse
health conditions and symptoms, including improvements in maximum
heart rate, pain, swelling, explosive force production and joint
mobility. Acupuncture requires the insertion of sterile needles
into specific areas of the body to regulate blood flow (66). Acupuncture may increase local blood
circulation, optimize metabolism and facilitate blood flow in the
ears through modulating inflammatory responses (67). A systematic review demonstrates
that a combination of acupuncture with pharmacotherapy leads to
improvements in the treatment of SSHL, compared with
pharmacotherapy alone (68).
Therefore, acupuncture may exhibit potential as an adjunctive
treatment option for SSHL (69).
To evaluate the role of acupuncture in reducing SSHL risk among
patients with NPC, a nested case-control study was conducted. Among
811 patients with initial-onset SSHL, 27 individuals received
acupuncture treatment (57). The
results of the aforementioned study reveal that patients receiving
acupuncture exhibit a reduced likelihood of developing SSHL,
compared with the 784 individuals who did not receive such
intervention [adjusted odds ratio, 0.39; 95% confidence interval,
0.25-0.60]. Therefore, incorporating acupuncture into routine care
for patients with NPC resulted in a 61% decrease in their
susceptibility to developing SSHL. Moreover, the observed effect is
considered dose-dependent, as an increased frequency of acupuncture
treatments corresponded to reduced incidence rates of SSHL
(Table V) (57).
Methylprednisolone use
A study by Chen et al (58) investigates the efficacy of
methylprednisolone in treating radiation-induced hearing loss in
patients with NPC undergoing radiotherapy. In the aforementioned
study, a total of 25 patients receive a 14-day course of
intravenous pulse therapy with methylprednisolone, in combination
with radiotherapy. This group is compared with 28 patients who
receive radiotherapy alone. Pure tone audiometry, distortion
product otoacoustic emission (DPOAE) and auditory brainstem
responses were evaluated prior to treatment, and 1 year after the
completion of radiotherapy. The results of the aforementioned study
reveal that the control group, who received radiotherapy alone,
exhibit increased air-bone gap thresholds and decreased DPOAE
levels at the 1-year follow-up assessment. By contrast, the
treatment group demonstrate reduced pure tone air conduction
thresholds and increased DPOAE levels, compared with the control
group. Therefore, administration of methylprednisolone during
radiotherapy may alleviate early SNHL caused by radiation exposure
(Table V) (58).
In a further randomized study, 99 patients were
administered either systemic infusion of methylprednisolone alone,
or a combined treatment involving intratympanic dexamethasone and
systemic methylprednisolone. The results of the aforementioned
study indicate that both treatment groups achieve improvements in
hearing over a 3-month follow-up period (Table V) (59).
6. Discussion
The present review provides a comprehensive overview
of the classification, assessment tools and intervention measures
for hearing loss following radiotherapy for NPC, offering valuable
insights for clinical practice (Fig.
1). Based on the underlying pathological mechanisms, hearing
loss is categorized into three types, namely: CHL, SNHL and MHL.
Each type of hearing loss exhibits distinct pathological and
physiological processes as well as clinical manifestations. Hearing
loss not only diminishes the quality of life of patients, but also
exerts profound impacts on their cognitive function and emotional
well-being. Hearing loss may increase the risk of cognitive
impairments, including mild cognitive impairment, cognitive decline
and dementia, and is associated with mental disorders, such as
anxiety and depression. A study by Ho et al (26) investigates the association between
the incidence of hearing loss and radiation dose-toxicity in
patients with NPC. The results of the aforementioned study reveal
numerous strategies that may mitigate the risk of SNHL in patients
who have been previously treated for NPC. These strategies include
constraining the radiation dose cochlear D-mean to <44-50 Gy,
response-adaptive reduction of radiotherapy volume and dose,
individualized cochlear constraints according to tumor stage, using
specific radiotherapy planning techniques, and reducing systemic
therapy. One such planning approach involves stratifying the
anatomical structures adjacent to the nasopharynx into different
layers while considering patterns of tumor spread. Target volumes
are then delineated based on the extent of the primary tumor, using
a combination of geometric expansion and inclusion of structures at
risk of tumor involvement (26).
The present review aimed to summarize the
characteristics of two other types of hearing loss, namely: CHL and
MHL. The present study evaluated assessment tools, such as HHIA-S,
ETDQ-7 and PRO-CTCAE. In addition, the present study aimed to
investigate a range of treatment modalities, such as Eustachian
tube insufflation, hydrogen-oxygen mixed gas inhalation therapy,
acupuncture and methylprednisolone use, which may demonstrate
therapeutic potential in preserving auditory function.
The multidisciplinary team (MDT) treatment model for
radiation-induced hearing loss requires the integration of
multidisciplinary resources and the development of individualized
treatment plans, according to levels of damage and individual
patient differences. Close collaboration between departments of
otolaryngology, radiation oncology, radiology and rehabilitation is
required. The department of otolaryngology, in conjunction with the
department of imaging, should complete the classification of
hearing damage and identify the cause, such as middle ear effusion
or nerve damage. The department of radiation oncology should then
review radiation records to analyze the spatiotemporal association
between dose distribution and damage. Subsequently, the department
of rehabilitation should guide the fitting of hearing aids and
auditory rehabilitation training to improve the quality of life of
the patient. Treatment of CHL involves medical intervention, such
as ototoxic ear drops. If ineffective, tympanocentesis or tube
placement may be used. The early use of steroid pulse therapy
combined with neurotrophic drugs, such as mecobalamin, is
recommended for SHL, and hearing aids should be fitted for patients
with moderate to severe levels of the condition. Regular MDT
assessments should be conducted according to a risk-adapted
schedule, typically every 3-6 months during the first 3 years after
treatment, every 6-12 months during years 4-5 and annually
thereafter, to monitor treatment outcomes and complications and to
allow timely adjustment of the management plan.
Further studies are required to investigate more
effective and safe intervention measures for the treatment of NPC.
Emphasis should be placed on interdisciplinary integration and
comprehensive research on hearing protection. Moreover, with
advancements in artificial intelligence and the analysis of large
datasets, future developments should focus on creating personalized
systems to monitor the hearing status of patients in real-time,
which may lead to precise treatment interventions. Additionally,
enhancing healthcare professional-patient communication and
educating patients on the importance of hearing protection are
important for improving post-radiotherapy quality of life for
patients with NPC. In conclusion, addressing the complexities of
hearing loss following radiotherapy for NPC necessitates
collaborative efforts from both the medical community and society
as a whole, to promote further research development, and provide
comprehensive and effective treatment options.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
LL and LZ analyzed the data and wrote the first
draft of the manuscript. JD and YL screened the literature. YK and
YZ revised the manuscript. LL and LZ supervised the project. All
authors read and approved the final version of the manuscript. Data
authentication is not applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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