Definitive or postoperative radiation therapy (RT) is commonly used for the management of intracranial and extracranial head and neck tumors. Because of the variability of tumor location and dimensions, sparing of nontarget normal tissue and organs may not be possible. Treatment modalities that deliver the highest doses of radiation to the auditory system include stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for the treatment of vestibular schwannomas (VS), and fractionated radiotherapy (FRT) or intensity-modulated radiation therapy (IMRT) for the treatment of head and neck malignancies. Radiation therapy for VS is unique because of its involvement of the inner ear and preexisting auditory and vestibular dysfunction. Auditory and vestibular dysfunction following RT for VS may be limited by limiting the total dose of cranial nerve VIII irradiation and by fractionation.
Definitive or postoperative radiation therapy (RT) is commonly used for the management of intracranial and extracranial head and neck tumors. Because of the variability of tumor location and dimensions, sparing of nontarget normal tissue and organs may not be always possible. Parts of the auditory and vestibular systems often receive high doses of radiation and exhibit radiation-induced morbidity. Treatment modalities that deliver the highest doses of radiation to the auditory system include stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for the treatment of vestibular schwannomas (VS), and fractionated radiotherapy (FRT) or intensity-modulated radiation therapy (IMRT) for the treatment of head and neck malignancies. Radiation therapy for VS is unique because of its involvement of the inner ear and pre-existing auditory and vestibular dysfunction. Direct otologic involvement is rarely observed in other neoplasms that are routinely treated with RT. The assessment of postirradiation effects thus differs in these two situations and is more complex in the treatment of VS.
Radiation biology
A comprehensive discussion of the tissue effects of radiation is beyond the scope of this article. However, a brief overview of this topic is necessary to fully understand radiation effects on the auditory and vestibular systems.
Tissue effects of radiation are dependent on a number of factors. Megavoltage X rays in the therapeutic range interact with tissue primarily by way of the Compton effect. The Compton mass attenuation coefficient is independent of the atomic number and depends only on the number of the electrons per gram of the interacting material. The attenuation of beam is related to density thickness (density of material multiplied by the thickness) expressed as g/cm 2 , thus a relative decrease in attenuation leads to increased penetration in air-filled spaces or air cavities, such as the lungs and temporal bones.
Deposition of radiation energy in tissue results in cell injury and death. Most of radiation’s tissue effect is thought to be a result of the damage to DNA. This occurs both directly and indirectly. The latter, the predominant mechanism, involves ionization of surrounding water molecules to form free radicals, which, in turn, result in double-strand breaks in DNA. This injury may result in cell death during mitosis, induction of apoptosis (ie, programmed cell death), recovery, and cell cycle arrest or terminal differentiation through activation of repair pathways that may also play a role in tumor suppression (eg, activation of p53).
The radio-response of a tissue depends on the inherent sensitivity of the cells, the kinetics of cell population, total dose, dose per fraction, and time-dose fractionation. Cells with fast turnover rate or higher mitotic activity exhibit more sensitivity to radiation, subjecting to cell death in attempting subsequent mitosis. This is the basis for therapeutic RT (ie, relatively greater damage to highly reproductive tumor cells). Further, RT fractionation offers the potential for greater differential sparing of normal tissues and killing of tumor cells.
These factors also determine the unwanted manifestations of RT. Skin and mucosa, which cycle quickly, manifest more significant early, transient, and inflammatory changes. Organ dysfunction are often manifest by cell lines with slow turnover (eg, radionecrosis of bone). In some tissues, such as inner-ear hair cells, functional progenitor cells may be lacking, resulting in greater organ system dysfunction. It is unclear how RT leads to long-term dysfunction in cells, such as neurons and inner-ear hair cells, which lose mitotic activity after differentiation. Such cells are dependent on supporting cells (eg, glia) and small blood vessels. Though a wide range of morphologic changes in neural tissue in response to RT have been observed, the effect of RT on neurons cannot be distinguished from the effect on the supporting cells and the vasculature.
Finally, radiation dose to the target and surrounding tissues is controlled by the choice of modality (eg, conventional external beam, IMRT, or SRS) and treatment plan. In SRS, doses are prescribed to the tumor margin. The maximal dose within the target area may vary tremendously, depending on the specifics of the treatment plan. For example, single or multiple isocenters may be used.
For further information, please see the Treatment Planning/Radiation Delivery Section in the Gamma Knife Radiosurgery for Vestibular Schwannoma chapter of this publication.
Radiation and the ear
The entire auditory-vestibular system is vulnerable to RT injury. Nearly half of all patients that have undergone RT for head and neck tumors demonstrate evidence of auditory or vestibular system pathology. RT-induced injury may be manifest as chronic otitis externa, stenosis of the external auditory canal, chronic otitis media with effusion, tympanic membrane perforation, osteonecrosis, chronic suppurative otitis media, middle ear fibrosis, conductive, mixed, or sensorineural hearing loss, labyrinthitis, vestibular paresis, and vertigo. The focus of this discussion will be on the inner ear and central pathways rather than the middle and external ear.
Measurement or scoring of ototoxicity after fractionated RT for head and neck tumors has historically been qualitative and descriptive. Comparing results from such assessments has been difficult. Newer scoring systems have been developed, but none have been widely used and validated. The Radiation Therapy Oncology Group criteria are applicable for retrospective analyses of acute toxicity, but not late complications. Detailed prospective assessment of delayed RT-induced ototoxicity has been addressed by the Late Management of Normal Tissue/Somatic Objective Management Analytic (LENT/SOMA) scoring system ( Table 1 ). This system does not distinguish between external, middle, and inner ear toxicity and has a narrow categorization of hearing loss. The National Cancer Institute Common Toxicity Criteria (NCI CTC) includes auditory side effects, but only gross changes in hearing are addressed ( Table 2 ). The NCI CTC system has been mainly applied to chemotherapeutic studies. Note that these classification systems correspond to RT of nonacoustic tumors. These classification systems have not been used for SRS or FSRT of VS. The evaluations of post-RT hearing status of patients with VS have consistently been presented according to the Gardner-Robertson scale.
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| Subjective | ||||
| 1. Pain | Occasional and minimal | Intermittent and tolerable | Persistent and intense | Refractory and excruciating |
| 2. Tinnitus | Occasional | Intermittent | Persistent | Refractory |
| 3. Hearing | Minor loss, no impairment in daily activities | Frequent difficulties with faint speech | Frequent difficulties with loud speech | Complete deafness |
| Objective | ||||
| 4. Skin | Dry desquamation | Otitis externa | Superficial ulceration | Deep ulceration, necrosis |
| 5. Hearing | <10 dB loss in one or more frequencies | 10–15 dB loss in one or more frequencies | >15–20 dB loss in one or more frequencies | >20 dB loss in one or more frequencies |
| Management | ||||
| 6. Pain | Occasional non-narcotic | Regular non-narcotic | Regular narcotic | Parenteral narcotics |
| 7. Skin | Occasional lubrication/ointments | Regular eardrops or antibiotics | Eardrums | Surgical intervention |
| 8. Hearing | Hearing aid | |||
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| External auditory canal | External otitis with moist or dry desquamation | External otitis with moist desquamation | External otitis with discharge, mastoiditis | Necrosis of canal, soft tissue or bone |
| Inner ear/hearing (including conductive hearing loss) | Hearing loss on audiometry only | Tinnitus or hearing loss not requiring hearing aid or treatment | Tinnitus or hearing loss, correctable with hearing aid or treatment | Severe unilateral or bilateral hearing loss(deafness), not correctable |
| Middle ear/hearing | Serous otitis without subjective decrease in hearing | Serous otitis or infection requiring medical intervention;subjective decrease in hearing; rupture of tympanic membrane with discharge | Otitis with discharge, mastoiditis or conductive hearing loss | Necrosis of the canal, soft tissue or bone |
The unique nature of the inner ear cell lines leads to unique manifestations of RT injury. Acute dysfunction after RT is a result of transient alterations in the homeostasis of endolymph and perilymph, whereas delayed sensorineural hearing loss (SNHL) most commonly exhibits a chronic, progressive, and irreversible evolution. Hair cells and the stria vascularis have been implicated as the two major sites of inner ear radiation toxicity.
In animal studies, the earliest post-RT changes with lower doses were observed in the stria vascularis. With increasing dose, shriveling of hair cells and distention of Reissner’s membrane were observed. Experimental fractionated radiation of chinchillas led to loss of myelinated nerve fibers in the osseous spiral lamina, inner and outer hair cells, and supporting cells. Hair cell damage and compound action potential changes have been linked to stria vascularis degeneration, but direct damage to hair cells is feasible at high- radiation doses. Similar findings have been reported for the vestibular system.
Post-mortem observations of human temporal bones after RT have included loss of inner and outer hair cells and spiral ganglion cells in the basal turn of the cochlea, atrophy of the stria vascularis, and changes in vessels of the facial nerve. Further histologic studies have shown that the greatest damage to inner ear is the result of injury to the vessels of stria vascularis. Vestibular damage has also been observed in cases manifesting with vestibular complaints. An autopsy study after a high dose of radiation demonstrated absence of the organ of Corti, macula of the utricle and the cristae of the semicircular canals. Overall, however, the vestibular apparatus is more resistant to effects of radiation than the cochlea.
Sensorineural hearing loss following fractionated RT may begin early or may be delayed. Transient SNHL begins early. Recovery usually occurs in 6 to 12 months, but may be delayed. This delay has been attributed to an inner ear vasculitis, and has been associated with auditory recruitment. Permanent post-RT SNHL may occur in up to 54% of patients receiving high doses to the inner ear. A review by Jerekczeck-Fossa and colleagues suggested that post-RT SNHL occurs in one third of the patients treated with definitive RT with the inner ear receiving high radiation doses. Raaijmakers and Engelen’s review reported a pure tone average loss of greater than 10 dB occurred in 18 (± 2%) of patients and a 4 kHz loss occurred in one of three patients receiving a dose of 70 Gy at 2 Gy per fraction to the inner ear. The pooled incidence of post-RT SNHL is 44% and 36% for treatment of the nasopharynx and parotid, respectively.
Ho and colleagues prospectively studied the latency for SNHL after fractionated RT and found it to be 1.5 to 2.0 years after RT. Kwong and colleagues also reported the progression of SNHL to plateau within 2 years of treatment. Most other studies are in agreement with these observations. Onset of hearing deterioration has been reported to be as early as 3 months after completing RT. In one study, the stability of postlatency SNHL was followed up for a period of 13 years. Though cumulative risk of persistent SNHL (>15 dB) has been reported to stabilize at 2 years, the cumulative risk for severe SNHL (>30 dB) continues to increase through the third and fourth year after RT.
Vestibular dysfunction occurs in roughly 25% to 30% of patients treated with RT to the temporal bone. Caloric weakness has been reported in 9% to 36%. Young and colleagues attributed post-RT vertigo mainly to a peripheral labyrinthine disorder(69%), followed by central vestibular lesions (31%). The authors proposed two mechanisms that contribute to the peripheral labyrinthine dysfunction: (1) direct injury to the inner ear, or (2) RT-induced otitis media with effusion (OME) with a secondary labyrinthitis. In the study by Young and colleagues, the mean interval from completion of RT to occurrence of vertigo was 10 years. The relationship between OME and vertigo, however, has not been supported in other studies. RT-induced degenerative changes in the vestibular sensory epithelia has been observed in experimental animal studies and human temporal bones.
Radiation and the ear
The entire auditory-vestibular system is vulnerable to RT injury. Nearly half of all patients that have undergone RT for head and neck tumors demonstrate evidence of auditory or vestibular system pathology. RT-induced injury may be manifest as chronic otitis externa, stenosis of the external auditory canal, chronic otitis media with effusion, tympanic membrane perforation, osteonecrosis, chronic suppurative otitis media, middle ear fibrosis, conductive, mixed, or sensorineural hearing loss, labyrinthitis, vestibular paresis, and vertigo. The focus of this discussion will be on the inner ear and central pathways rather than the middle and external ear.
Measurement or scoring of ototoxicity after fractionated RT for head and neck tumors has historically been qualitative and descriptive. Comparing results from such assessments has been difficult. Newer scoring systems have been developed, but none have been widely used and validated. The Radiation Therapy Oncology Group criteria are applicable for retrospective analyses of acute toxicity, but not late complications. Detailed prospective assessment of delayed RT-induced ototoxicity has been addressed by the Late Management of Normal Tissue/Somatic Objective Management Analytic (LENT/SOMA) scoring system ( Table 1 ). This system does not distinguish between external, middle, and inner ear toxicity and has a narrow categorization of hearing loss. The National Cancer Institute Common Toxicity Criteria (NCI CTC) includes auditory side effects, but only gross changes in hearing are addressed ( Table 2 ). The NCI CTC system has been mainly applied to chemotherapeutic studies. Note that these classification systems correspond to RT of nonacoustic tumors. These classification systems have not been used for SRS or FSRT of VS. The evaluations of post-RT hearing status of patients with VS have consistently been presented according to the Gardner-Robertson scale.
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| Subjective | ||||
| 1. Pain | Occasional and minimal | Intermittent and tolerable | Persistent and intense | Refractory and excruciating |
| 2. Tinnitus | Occasional | Intermittent | Persistent | Refractory |
| 3. Hearing | Minor loss, no impairment in daily activities | Frequent difficulties with faint speech | Frequent difficulties with loud speech | Complete deafness |
| Objective | ||||
| 4. Skin | Dry desquamation | Otitis externa | Superficial ulceration | Deep ulceration, necrosis |
| 5. Hearing | <10 dB loss in one or more frequencies | 10–15 dB loss in one or more frequencies | >15–20 dB loss in one or more frequencies | >20 dB loss in one or more frequencies |
| Management | ||||
| 6. Pain | Occasional non-narcotic | Regular non-narcotic | Regular narcotic | Parenteral narcotics |
| 7. Skin | Occasional lubrication/ointments | Regular eardrops or antibiotics | Eardrums | Surgical intervention |
| 8. Hearing | Hearing aid | |||
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| External auditory canal | External otitis with moist or dry desquamation | External otitis with moist desquamation | External otitis with discharge, mastoiditis | Necrosis of canal, soft tissue or bone |
| Inner ear/hearing (including conductive hearing loss) | Hearing loss on audiometry only | Tinnitus or hearing loss not requiring hearing aid or treatment | Tinnitus or hearing loss, correctable with hearing aid or treatment | Severe unilateral or bilateral hearing loss(deafness), not correctable |
| Middle ear/hearing | Serous otitis without subjective decrease in hearing | Serous otitis or infection requiring medical intervention;subjective decrease in hearing; rupture of tympanic membrane with discharge | Otitis with discharge, mastoiditis or conductive hearing loss | Necrosis of the canal, soft tissue or bone |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
