A
Newly Recognized Sequelae of Radiation Treatment
Authors: Joel W. Goldwein, M.D.*, Lawrence W.C. Tom, M.D.**,
Bruce Cohen, M.D., Beverly Lange, M.D., Georgio Perilongo, M.D.,
Leslie Sutton, M.D., Roger J. Packer, M.D.,
and Giulio J. D'Angio, M.D.
Affiliations: * Department of Radiation Oncology, The Hospital of the
University of Pennsylvania. ** Department of Pediatric Otolaryngology,
The Children's Hospital of Philadelphia. Copyright © 1994-1997, The
Trustees of the University of Pennsylvania
Mild ototoxicity is seen commonly in children after high dose radiation treatment involving the ear. Complete deafness that develops years after the completion of radiation given alone or in conjunction with non-ototoxic chemotherapeutic agents, is not a commonly recognized sequelae. We report on four patients who developed complete or partial deafness in both ears at least five years following radiation therapy for brain tumors. Three patients were treated for medulloblastoma, and one for a brainstem glioma. None of these patients received chemotherapeutic agents generally associated with ototoxicity and all received radiation doses lower than those generally associated with late ototoxicity. We speculate that late radiation-associated deafness (LRAD) may occur at relatively lower doses in children than adults, and may be a more common sequelae of therapy than had been previously recognized. Although only a small proportion of patients who receive high doses of radiation to the middle and inner ear are at risk for this complication, the syndrome is irreversible and its potential should be considered in the design of future studies where radiation and ototoxic chemotherapy is combined.
Key Words: Ototoxicity, Radiotherapy, Chemotherapy, Children
Although the ear is widely regarded to be resistant to the deleterious effects of therapeutic radiation, it is becoming more clear that it is subject to damage even from moderate doses when combined with ototoxic chemotherapy. These effects can be both short and long lived and have been recognized for at least 3 decades. The sequelae of radiation are generally more profound in children and are enhanced by ototoxic chemotherapy. Although these cytotoxic agents play a major role in causing ototoxicity, radiation alone can also inflict damage. We hereby report on a group of patients who have been cured of medulloblastoma with radiation alone and who developed complete or near-complete deafness in one or both ears at substantial intervals following the completion of radiation.
Between 1970 and 1985, 97 patients were treated with radiation for posterior fossa medulloblastomas and brain stem tumors at the Radiation Oncology Department of University of Pennsylvania. Patients who died before 5 years of follow-up and patients who received cis-diamminedichloroplatinum-based (CDDP) chemotherapy were excluded. The remaining 36 long-term survivors form the population upon which our study is based.
Amont these patients, there were 23 treated for medulloblastomas and 13 treated for brainstem tumors. The follow-up ranged from 5.5 to 21.4 years (mean = 11.5 yrs.).
Radiation doses in this group ranged between 2400 and 4200 cGy to the craniospinal axis (0 cGy for the brain stem patients) with boosts to the posterior fossa ranging between 5600 and 6200 cGy.
Among this group of survivors, 4 patients (11%) have presented with slowly progressive deafness at a median of 8.5 years following the completion of radiotherapy. Details of treatment in for patients are listed in Table 1 and a summary of the progression of their otologic abnormalities is summarized in Table 2.
The true incidence of radiation and chemotherapy induced ototoxicity in children is unknown. Certainly, it depends on a number of factors including the particular toxicity with which one is concerned, the doses of radiation and chemotherapy used, and the way in which the toxicity is measured. In adults treated for head and neck tumors with radiation alone, the incidence of hearing loss of 10dB or more has been estimated to be as high as 70% (Strohm, Moretti[1]). However, radiation doses in these patients generally exceed 7000 cGy whereas doses in children rarely exceed 5500 cGy. If the quantity of literature is any indication of the incidence in children, one would assume that it is not significant, as case reports are the rule.
When chemotherapy is added to radiation, or when radiation is added to chemotherapy, the associated ototoxicity can be both substantial in incidence and degree. With the use of CDDP, frequently utilized for the treatment of pediatric brain tumors, it is common to see significant sensorineural hearing loss in the high frequency range. In the study by Cohen et al, 97% of the patients who received up to 476 mg/m[2] of CDDP sustained hearing loss of between 10 and 20 dB in the >4000 Hz range. This compares to 88% found in the series by McHaney et al. who used doses above 450 mg/m[2]. Because most physicians withhold CDDP when hearing loss occurs in the range important for language perception (500 - 2000 Hz), it is difficult to make an estimate of the incidence of this problem. Cohen et al., who reported treatment of patients with brain tumors with CDDP (68 mg/m[2]/cycle) plus radiation found that 56% of their patients were unable to complete CDDP therapy due to this degree of ototoxicity. However, of a total of 34 patients, they were able to deliver 408 mg/m[2] to 29 and 476 mg/m[2 ]to 25. Eleven patients tolerated 544 mg.m[2] without hearing loss in the audible range.
Patients treated with CDDP alone experience similar ototoxicity although this damage occurs with higher CDDP doses.
There are three clinical syndromes associated with radiation treatments involving the ear. The first, acute radiation otitis can occur either during or shortly following the completion of a course of radiation. It is generally associated with middle ear doses above 3000 cGy and is characterized by erythema of the drum and external canal. Occasionally, a serous middle ear effusion is seen and is associated with tinnitus. At the University of Florida, this syndrome has been reported in 15 - 20 % of patients (Parsons) and it occurs in approximately 20 - 30% in pediatric patients who received middle ear doses in excess of 3000 cGy at the University of Pennsylvania. It is almost always self-limiting but may require therapy in more severe cases. It is not necessarily associated with the development of later ototoxicity.
Chronic radiation otitis is benign. It is characterized by dryness of cerumen, a thickening and grainy appearance of the tympanic membrane, and, occasionally, a slight conductive and sensorineural hearing loss. It usually begins several months following the completion of radiation and is the most commonly seen radiation ototoxicity. It is associated with moderate radiation doses (4500-6500 cGy) and has occurred in approximately 70% of pediatric patients at the University of Pennsylvania treated with doses in excess of 5000 cGy.
Late Radiation-Associated Deafness is the rarest syndrome associated with radiation to the brainstem and ear. It is characterized by profound hearing loss that is at first unilateral and may progress over a period of weeks to months. It may result in total unilateral deafness and then progress to involve the contralateral ear. It occurs from 3 to 10 years following the completion of radiotherapy and is irreversible. At the University of Pennsylvania, we are aware of 4 such patients all of whom had brain tumors treated with opposing lateral fields that, of necessity included the ears. The actual incidence of this syndrome remains unknown.
Physical examination is useful and should be performed as the first step in the evaluation of suspected radiation ototoxicity. Visual exam of the ear and canal should be performed to rule out perforation, infections, effusions and to characterize the appearance of the canal and tympanic membrane. During the acute phase, the ear canal may be erythematous and a serous effusion may be found behind the drum. Later, examination of the irradiated ear generally reveals a grainy appearing drum with dried cerumen in the canal. If the patient is being treated for a tumor involving the middle ear, the possibility of recurrence or progression should also be entertained.
If there is hearing loss, Weber's and Rinne's test should be used in an attempt to differentiate between conductive and sensorineural deficits.
A baseline audiogram should be performed in all patients with brainstem tumors as well as in patients with tumors that directly involve the ear and auditory pathways. In addition, they should be performed in any patient who will be receiving ototoxic chemotherapy or high dose radiation directed at the ear. Serial studies are mandatory to follow the hearing of children at risk for developing radiation ototoxicity. Findings depend on radiation doses and the use of ototoxic chemotherapy. When CDDP chemotherapy is used alone, high frequency hearing loss (4000-8000 Hz) is typical especially after cumulative doses above 200 mg/m[2]. When combined with radiation, CDDP associated high frequency hearing loss occurs at lower CDDP doses (Cohen).
Following radiation, tympanometry and tympanic impedance may become abnormal, particularly during the acute or the chronic phases of radiation otitis. In this case, the tympanic membrane becomes less compliant and, tympanometry may suggest the presence of an effusion. This is also important in ruling out perforation.
In patients with late radiation-associated deafness, early audiogram changes show both low and high frequency hearing loss which may eventually progresses to a total sensorineural loss.
Brainstem auditory evoked responses (BAER) are useful in separating conductive from sensorineural hearing loss (Sukowski) . In addition, they may help to differentiate auditory from brainstem sensorineural damage. In cases where hearing loss is profound, and where there is question as to its cause, BAERs should be performed.
To understand the mechanisms behind radiation ototoxicity it is important to recognize the anatomic relationships between the ear, skull and brain. In children, the cochlea is located approximately 1.5 - 2.5 cm beneath the scalp. The tympanic membrane lies approximately 1.5 - 2 cm below the skin surface and the ossicles are between the cochlea and the drum. Since some air lies between the surface and the cochlea, this results in an effective depth of tissue that is less than the actual depth. These facts are particularly important when radiation dosimetric factors are considered. It is also noteworthy that the ears lie directly lateral to the pontine brainstem. It is safe to say that any patient treated for a pontine lesion with opposing lateral radiation fields will receive a substantial portion of the dose to the ear.
Reports in which the relationship between radiation dose and ototoxicity is explored are rare. Those that do exist generally do not take into account the peculiarities of radiation dosimetry in that area. Briefly, when the brainstem or a midline brain target is treated, photons with an energy of 6 million electro-volts (MeV) are generally utilized, usually with opposing lateral portals. When delivered in this fashion, "hot spots" between 1 to 2 cm beneath the surface generally appear. Depending on the quality of the radiation used, the separation of the skull, and the particular radiation plan, the dose to the middle and inner ear may be from 10 to 20% higher than the dose delivered to the tumor. For instance, in treating brainstem tumors with doses of 7200 cGy in 100 cGy fractions, the ear may be receiving over 8000 cGy in fraction sizes up to 120 cGy. The high total dose and fraction size both contribute to toxicity. The clinical implication is that 1) these patients may develop otitis during radiation at a lower stated dose than other toxicity such as skin redness would be appreciated and 2) these same patients are at higher risk for long-term auditory effects relative to other organs due to the high total dose and fraction size delivered to the ear.
The exact mechanism whereby radiation induces hearing loss is unknown. There are a number of possibilities. First, damage to the tympanic membrane and the ossicles may result in fibrosis and conductive losses. Second, late radiation injury to small vessels is likely to cause hearing loss by virtue of hypoxia. Third, there may be direct damage to the cochlea both to the hair and to the oval and round window. Finally, there may be damage to the brainstem from RT that can indirectly contribute to hearing loss.
Only a few reports of pathologic confirmation of damage are currently available. In these cases, atrophy or absence of the organ of Corti has been noted along with loss of hair cells and atrophy of the spiral ganglion and cochlear nerve. (Leach, Schuknecht )
The effects of cochlear irradiation and CDDP have been studied in animals. After a single fraction of 3000 cGy to guinea pigs, cochlear hair cell loss developed along with damage to the stria vascularis and tectoral membrane (Gamble). Chinchilla treated with fractionated radiation showed similar changes (Bohne). Other studies have shown that CDDP induces cytoarchitectural changes in the outer hair cells of the organ of Corti ant the stria vascularis following cumulative doses around 10 mg/kg (Konishi, Komune, Nakai ).
Combined effects have also been examined. Chinchillas given unilateral radiation with and without CDDP (after RT) were found to have a significant shift of hearing thresholds with XRT or XRT/CDDP (Baranak).
It is clear that in children, radiation enhances the effects of ototoxic chemotherapy on hearing (Granowetter, Mahoney, Walker, Cohen, Wittes). And, it is likely that the reverse is also true. Granowetter et al. reported on 6 children treated with infusional CDDP chemotherapy in doses above 110 mg/m[2 ] for recurrent brain tumors. All had initial radiotherapy and all patients experienced more significant hearing loss than would have been expected with CDDP alone.
Other compelling evidence is established in a report by Cohen et al. where the threshold for high frequency hearing loss after CDDP chemotherapy was found to be lower in patients treated for brain tumors with radiation. Further evidence is also derived from some of our patients who received unilateral radiation for tumors located away from auditory centers but in whom substantial radiation doses were delivered to the ear. A surprising finding was the development of unilateral high frequency hearing loss at a lower CDDP dose than would have ordinarily been expected.
Little is known regarding the timing of radiation relative to chemotherapy with respect to ototoxicity. In a report from Walker et al., it was suggested that radiation administered less than 10 months prior to or along with CDDP chemotherapy seemed to confer the worst damage. Beyond that, information regarding the optimal sequence and timing is not available.
A number of potential factors might contribute to the development of acute and chronic radiation otitis.
Repeated infections are notorious for causing auditory damage. Though no specific data is available, these infections may contribute to the radiation effect. Pre-existing damage such as that from tumors which directly involve the ear or auditory pathways may also contribute to the toxicity.
In instance where radiation to the ear and the use of ototoxic agents are unavoidable, measures should be aimed at minimizing the intensity of the agents and at eliminating other potential risk factors. Where possible, higher energy linear accelerators (10 - 15 MeV) should be used (to avoid causing "hot spots" in the ear). The inner ear should be shielded from the radiation beam, particularly when high doses are to be delivered assuming the dose to critical target volumes is not compromised. Patients who develop effusions as an acute effect of radiation should be considered for tube placement, as there are data to support their use[2]Evans RA, Liu KC, Azhar T, Symonds RP: Assessment of permanent hearing impairment following radical megavoltage radiotherapy. J Laryngol Otol 102(7):588-9, 1988 (Chowdhury). At the very least, possible auditory damage should be an integral part of the informed consent for patients at risk.
Infections should be treated aggressively and factors which might contribute to infection such as repeated barotrauma (SCUBA, swimmer's ear) should be avoided. Antibiotic/steroid ear drops may relieve discomfort and should be used to treat external otitis caused by radiation. Decongestants can also be used in patients where a serous otitis is present.
Patients who develop chronic radiation ototoxicity generally do not require therapy. For those who develop profound radiation-associated hearing loss, there is no established therapy. However, when this occurs other treatable causes such as perforation, infection, primary ear tumors and even hyperviscosity states should be excluded. Certainly, the possibility of tumor relapse should also be ruled out.
Once other potential causes have been eliminated and appropriate diagnostic studies have been performed, it is reasonable to attempt a short course of steroid therapy. We have, in 1 case, attempted hyperbaric oxygen therapy but this was not effective. Finally, while investigational for patients with radiation induced damage, cochlear implant should be considered.
Radiation associated ototoxicity is a common sequelae of treatment which involves the ear in patients with brain, head and neck tumors. It is more common when doses to the middle and inner ear exceed 5000 cGy. The ototoxic effects of radiation and chemotherapy are enhanced by one-another. Evaluation should include visual inspection and routine audiograms in patients at risk. More elaborate tests aimed at defining the sites of damage should be performed in profound cases. Measures aimed at preventing contributory causes of ear damage should be taken. A very small proportion of patients who receive high doses of radiation to the middle and inner ear as well as the brainstem are at risk for an irreversible form of late radiation associated deafness.
| Table 1: Characteristics and treatment of four children with brain tumors who developed late radiation-associated deafness. | |||||
| Patient | Diagnosis | Age at Therapy | Chemo Used | Machine Energy | Cochlear Dose |
| 1 | Medulloblastoma | 8 yrs. | CCNU, VCR, PDN | 2.5 MeV | ? |
| 2 | Brain Stem Glioma | ||||
| 3 | Medulloblastoma | ||||
| 4 | ? | ||||
| Table 2: Development of late radiation-associated deafness in four children with brain tumors. | |||||
| Patient | Interval from radiation to onset of Hearing Loss |
Clinical Characteristics of hearing loss |
Interval over which hearing loss progressed |
Audiogram | BAER |
| 1 | |||||
| 2 | |||||
| 3 | |||||
| 4 | |||||
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[1]46/67 (68%) developed 10 db or more sensorineural hearing loss (Strohm) with RT for H&N tumors in adults. Moretti et al also reported /13 patients treated for nasopharyngeal cancer who suffered sensorineural hearing loss.
[2] The role of ventilatory tubes in relieving tinnitus
and conductive or sensorineural hearing loss was assessed in a randomized
trial of 115 patients who were treated with radiotherapy for nasopharyngeal
carcinoma . They found a significant decrease in sensorineural loss in
patients who received tubes, and therefor advocate their use in patients
who develop acute radiation ototoxicity.