Radiotherapy-induced ear toxicity

CANCER TREATMENT REVIEWS 2003; 29: 417–430 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; Medelec and Hearing Sciences Department, University of Antwerp, Belgium; 3Faculty of Medicine of the University of Milan, Italy

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Despite their particular functional consequences, radiotherapy-induced ear injuries remain under-evaluated and under-reported. These reactions may have acute or late character, may affect all structures of the hearing organ, and result in conductive, 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 impairment. Thus, reduction in radiation dose to the auditory structures should be attempted whenever possible. New radiotherapy 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 approach. 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 idiopathic 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.

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.: 39-0257489607. Fax: +39-02-57489036; E-mail: [email protected] 0305-7372/$ - see front matter

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irradiation (for example in parotid tumours, highgrade brain tumours or paranasal sinus malignancies), 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 complications 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

2003 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED.

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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 evaluation, 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 malignancies. 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., orthovoltage 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). References 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 management of numerous benign and malignant human disorders, including chronic ear infections, hearing loss or aerotitis media (2). During the 1920s, a technique 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 placement of the radium near the eustachian tube opening for 8 to 12 min. This therapy was also used to treat sinusitis, tonsillitis, asthma, bronchitis, and repeated viral and bacterial infections. Because it was effective in treating otitis media, military physicians used it to treat aerotitis media in submariners, aviators 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 development of head and neck cancers (especially in children) (4–6). Moreover, the post-radiation inner ear damage was soon recognized and then intensively studied in animal and human series (7). In 1905,

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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 studies 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 hypofractionated orthovoltage X-rays or electron irradiation for epithelial tumours of the pinna (10–12) and seems to be lower in case of brachytherapy (13,14) or irradiation for skin cancer at other sites (15–18). 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

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structures. The most common reaction is otitis media due to transient oedema and dysfunction of the eustachian 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 together with compromise of the active mechanism of pressure equilibration during swallowing or yawning lead to formation of reduced pressure in the middle ear cavity (fullness), retraction of the tympanic membrane (pain) and increased tension in the ossicular chain resulting in compromised conduction of sound (hearing loss). If the function of the eustachian tube does not normalize, and the middle ear negative pressure becomes 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, columnar, 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 proliferation of fibrovascular granulation tissue and the formation of inflammatory polyps can be observed leading to perforation of the tympanic membrane and persistent otorrhea. Permanent changes of the tympanic 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 effusion 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 approximately 60 dB of conductive hearing loss). Conductive 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) (24–26). 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).

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SNHL can have sudden or progressive character. The following definitions of the SNHL are applicable. 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 performed with at least three month intervals (28). According 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 (1,24,29,30,32–34). Unlike otitis media, which usually occurs soon after the radiation therapy is started, SNHL typically appears several months or years after completion of treatment. However, depending on the mechanism, SNHL can also occur soon after irradiation (acute reaction) and in some of these cases may be reversible 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 cumulative 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 (36,39–41). Within weeks or months after irradiation, vascular insult to the inner ear structures can cause progressive degeneration and atrophy of the inner ear sensory 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 endotheliocytes in vessels, and atrophy of the spiral ganglion

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cells and the cochlear nerve (34,39–42). Both inflammation and oedema can damage the cochlear nerve in the narrow internal auditory bony canal (43). Studies on the human temporal bones in patients 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 fibrosis 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 degeneration 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 abnormalities 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 subjective vertigo or dizziness). Experimental animal data have shown degenerative changes in the vestibular 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 osteonecrosis of the tympanic ring, where an area of exposed dead bone, usually in the floor of the external meatus, becomes evident. When a bone sequestrum forms and gradually separates, the bony dehiscence can heal (although the healing process may take years) (9). The more severe pattern includes 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-induced tumours of the external auditory canal in patients irradiated for nasopharyngeal cancer (51).

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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 neuropathy) can also be observed. In cases of diffuse white matter injury, the most apparent symptom would be progressive cognitive neurological impairment and hearing loss, whereas vestibular or gait disorders could be concomitant findings.

SCORING SYSTEMS Radiation-induced ear toxicity has remained underevaluated and under-reported and its assessment usually has included descriptive methods. In recent decades however, this issue has been given its importance and various scoring systems have been developed. There are several systems of ear toxicity classification. The Radiation Therapy Oncology Group (RTOG) criteria include acute but not late ear morbidity 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 prospective 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, several 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 1

No change over baseline Mild external otitis with erythema, pruritus, secondary to dry desquamation not requiring medication. Audiogram unchanged from baseline Moderate external otitis requiring topical medication, serous otitis media, hypoacusis on testing only Severe external otitis with discharge or moist desquamation, symptomatic hypoacusis, tinnitus, not drug-related Deafness

2

3

4

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

Subjective 1. Pain 2. Tinnitus 3. Hearing

Objective 4. Skin

5. Hearing

Management 6. Pain 7. Skin

Grade 1

Grade 2

Grade 3

Grade 4

Occasional and minimal Occasional Minor loss, no impairment in daily activities

Intermittent and tolerable Intermittent Frequent difficulties with faint speech

Persistent and intense Persistent Frequent difficulties with loud speech

Refractory and excruciating Refractory Complete deafness

Dry desquamation

Otitis externa

Superficial ulceration

< 10 dB loss in one or more frequencies

10 to 15 dB loss in one or more frequencies

< 15 to 20 dB loss in one or more frequencies

Deep ulceration, necrosis, osteochondritis > 20 dB loss in one or more frequencies

Occasional non-narcotic Occasional lubrication/ ointments

Regular non-narcotic Regular eardrops or antibiotics

Regular narcotic Eardrums

8. Hearing loss

Parenteral narcotics Surgical intervention

Hearing aid

Scoring: score the 8 SOM parameters with 0 to 4 (0 ¼ 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)

External auditory canal Inner ear/hearing (including conductive hearing loss) Middle ear/hearing

Grade 1

Grade 2

Grade 3

Grade 4

External otitis with erythema or dry desquamation Hearing loss on audiometry only

Extenal otitis with moist desquamation

External otitis with discharge, mastoiditis Tinnitus or hearing loss, correctable with hearing aid or treatment Otitits with discharge, mastoiditis or conductive hearing loss

Necrosis of the canal, soft tissue or bone

Serous otitis without subjective decrease in hearing

Tinnitus or hearing loss, not requiring hearing aid or treatment Serous otitis or infection requiring medical intervention; subjective decrease in hearing; rupture of tympanic membrane with discharge

Cancer Institute (NCI CTC) include auditory/hearing side effects (conductive hearing loss is graded as Middle ear/Hearing in the Auditory/Hearing category). In this system, changes associated with radiation to the external ear are graded under radiation 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 rather insensitive to the small changes in hearing that may be clinically significant (53). Gardner and Robertson’s classification (54) is commonly used in the assessment of hearing preservation after surgery or stereotactic irradiation (55–63).

Severe unilateral or bilateral hearing loss (deafness), not correctable Necrosis of the canal, soft tissue or bone

RISK FACTORS Numerous clinical and physical factors associated with the risk of hearing loss after irradiation have been reported (Table 4).

Concomitant disorders and treatments In the recommendations for trials using potentially ototoxic agents particular attention should be paid to the patient’s history (53). High risk subjects are those

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TA B L E 4 Factors associated with the high risk of post-irradiation hearing impairment Factors Treatment-related variables Total radiotherapy dose Marginal doseb Cisplatin-based chemotherapy Fraction dose > 2 Gy Radiosurgery vs. fractionated stereotactic RTb Dose rateb Stereotactic RT based on MRI datab Number of isocenters useda Conventional RT (vs. IMRT) Follow-up time Patient-related variables Neurofibromatosis type 2b Older age (>50 years at higher risk) Hearing deficit before RT Threshold at <60 dB at 4 kHz Reduction in static compliance of the tympanic membrane before RT Secretory otitis media after RT Male sex Tumour-related variables Site of tumour (nasopharynx, parotid at high risk) Involvement of the upper cervical lymph nodes Tumour sizeb Cystic vs. solid type of tumourb

Associated (references)

Not associated (references)

(29), (31)a , (33), (92), (95), (96) (55), (79–81), (121) (44), (91), (122–124) (75) (36), (78), (79), (82), (83) (35), (78) (125)

(24), (59), (63)b , (91) (59) (1), (24), (33)

(63) (92) (31) (1), (35–37), (126) (1), (24), (31), (109), (126) (1), (31), (78) (1) (29)

(29), (33), (95), (123)c

(24), (34), (126) (24) (64) (64) (80), (83)

(36), (59), (61), (63) (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, Meniere’s disease, otosclerosis, diabetes mellitus, acoustic nerve tumours, paraneoplastic syndroms, otomastoiditis, surgical damage, microvascular disease, otologic insults with delayed effects (e.g., previous irradiation, syphilis) and genetic anomalies (e.g., Cogan’s syndrome, Usher’s syndrome) 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 nasopharyngeal carcinoma. High doses, large fields, relatively young patient age and good prognosis explain the well documented frequent occurrence of radiationinduced 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 significant SNHL in up to 50% of nasopharyngeal cancer patients treated with radiotherapy (1,24,29,30). Importantly, more than 50% of the nasopharyngeal cancer patients can present with conductive hearing loss (due to otitis media with effusion) as the first symptom (65–68). These patients show hearing loss before radiotherapy is started. More than 20% of patients develop middle ear effusion after radiotherapy (67). However, the predictive role of a preradiotherapy tumour pattern (presence of middle ear effusion with regard to eustachian tube invasion or displacement) on the outcome of middle ear effusion 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

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survivors. However the correlation between radiation dose and the risk of this late effect remains unknown (71). Uncommon otological manifestations of nasopharyngeal carcinoma include hemotympanum, barotrauma, and sudden SNHL (72). There are also reports of subclinical brainstem damage in nasopharyngeal 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 tumours, yet the chance for development of retrocochlear 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 developed hearing impairment and 10% of the patients showed dysfunction of the vestibular part of the inner ear. The authors recommended long-term follow-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-containing chemotherapy (76).

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unilateral, non-syndromic vestibular schwannomas (this however is also valid for traditional surgical excision) (35–37). Due to continuous improvement in the radiotherapy 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 reduction of the peripheral dose (55,79–81). 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 stereotactic radiotherapy as compared to the those treated with radiosurgery) (36,78,79,82,83). The studies of Sakamoto et al. (57) suggest that fractionated stereotactic radiotherapy is effective in lowering the rate of hearing loss as compared to hearing loss resulting from the natural tumour growth (the mean annual hearing loss is greater before treatment than after, and the rate of hearing loss slows after stereotactic 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 schwannomas 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 radiation approach may decrease the risk of cranial neuropathies (including hearing loss) (89). Eustachian tube dysfunction can be observed in patients treated with radiosurgery for lower cranial nerve schwannomas (90). Paediatric tumours

Vestibular schwannoma Stereotactic radiosurgery (single fraction) or stereotactic radiotherapy (multiple fractions) is a viable alternative to surgical excision in selected cases of vestibular schwannoma of the cerebello-pontine angle (63). However, these treatment modalities carry a substantial risk for hearing loss due to a high probability 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 neurofibromatosis type 2 run a higher risk for the hearing loss after stereotactic irradiation as compared to patients with

Several paediatric malignancies (central nervous system tumours, leukemia, head and neck sarcomas) are treated with definite or adjuvant irradiation including 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 radiotherapy has become feasible as more effective chemotherapy has been developed over recent decades. Importantly, the association of irradiation and chemotherapy (particularly including cisplatin) must be used with particular caution. Indeed, high frequency hearing loss was more frequent in children treated

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for intracranial tumours, when cisplatin was combined 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 radiotherapy 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 dose–response relationship 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 patient’s age has been recently proposed 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 (29,95–97). 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 series, wider dose ranges and a prospective assessment 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

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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 receive 35 to 75% of the prescribed dose and eustachian 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 medulloblastoma 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 incidence 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 distribution in the inner and middle ear structures in parotid cancer patients receiving postoperative radiotherapy. Importantly, high quality computer tomography 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 necessary 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

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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, baseline audiological data are missing or are incomplete in many cases. It should be stressed that before radiation 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 functional tests, such as pure tone audiometry (PTA), tympanometry (TM) and stapedial reflexes (SR). Air and bone conduction PTA allows for assessment of the patient’s subjective hearing thresholds and enables detection of conductive/sensorineural/mixed hearing loss. PTA measurements are usually performed at frequencies at which most speech is recognized (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) complements tympanometric measurements and provides important additional information on the status of the neural reflex loop (acoustic-facial nerves). In small children, where obtaining reliable audiometrical data can be difficult, PTA should be replaced by objective tests such as the transient evoked otoacoustic 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 external, middle and inner ear is normal or close to normal. The above mentioned tests are the reasonable minimum, in patients with age-adjusted normal values (102). If the results show any abnormalities, a full specialist otological assessment should be performed (this includes patients with known retrocochlear 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 radiotherapy an extended otological assessment is warranted. External and middle ear side effects are best diagnosed by micro-otoscopy and TM. Micro-otoscopy can reveal different forms of external and middle ear inflammation and, together with TM,

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helps evaluate the middle ear aeration (and exclude/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 diagnosis 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 responses (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/progression of the hearing thresholds should be controlled 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 evaluation 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 implantation, 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-pontine angle tumours. In this group the risk for total electrical nerve dysfunction is relatively high, which may preclude cochlear implantation.

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Electronystagmography (ENG) or videonystagmography (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 secretion. 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 conservative therapy is ineffective, by early paracenthesis (incision of the ear-drum) with insertion of a ventilation tube ( ¼ grommet) in the tympanic membrane. This approach can relieve the pain and improve hearing (in one randomized trial, hearing improvement 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 dysfunction 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 (9,67–69,94,105). Therefore, according to some authors (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-irradiation middle ear effusion and/or external otitis and/ or otorrhea can be effectively alleviated by application of bone conduction hearing aids, such as, e.g., the bone anchored hearing aid (BAHA). The advantage 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 stimulates the inner ear, bypassing the dysfunctional

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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 lumen 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 progressive SNHL’s. All ENT departments have their own schemes of management of these cases, including a combination of corticosteroid, and rheologic therapies. Corticosteroid intake may improve inflammation and oedema in the inner ear after radiotherapy-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 radiotherapy 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 concentrations (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 radiationinduced 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 (114–116). 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 tumour which progressed after radiosurgery) (117).

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In patients with deafness caused by a vascular insult to the inner ear (by irradiation or microsurgery), fibrosis of the inner ear fluid spaces may develop 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 active vestibular rehabilitation. It is based on compensational 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 osteoradionecrosis, whereas corticosteroids, HBO and sometimes surgery are used in management of the brain necrosis (10,104, 119,120).

CONCLUSIONS Radiotherapy for the head and neck area is associated with an increased risk of considerable acute and late radiation-related ear toxicity. The post-irradiation 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 potential 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, fractionated stereotactic irradiation) are of paramount importance, since they allow for a better dose distribution 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.

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