Contents
24.1 Incidence . . . 375 24.2 Prevention and Treatment . . . 378 References . . . 381
Higher doses of chemotherapy and radiation in- crease the occurrence of side effects, especially sen- sorineural hearing loss (SNHL) (Huang et al., 2002).
SNHL results from damage to the inner ear or audi- tory nerve. At some point during most children’s can- cer treatment, they will receive an agent or a combi- nation of agents that will put them at risk of develop- ing ototoxicity (Landier, 1998). Hearing loss affects a child’s total quality of life; high-frequency hearing loss can result in difficulties with communication, in- cluding acquisition and development of speech and language, as well as emotional and social difficulties (Schweitzer, 1993).
24.1 Incidence
Ototoxic agents used for pediatric oncology patients include platinum-based chemotherapeutic agents, radiation therapy, aminoglycosides, and loop diuret- ics (Brookhouser, 2002).
Cisplatin and carboplatin are platinum-based chemotherapeutic agents. In one study, Brookhouser (2002) cites an 84–100% incidence of cisplatin- induced ototoxicity in the pediatric population. Cis- platin produces a high-frequency SNHL (i.e., 6000–
8000-Hertz [Hz] range) (Michaud et al., 2002). This generally irreversible hearing loss is caused by damage to the inner ear, specifically to hair cells of the organ of Corti, and possibly by damage to the stria vascularis (Michaud et al., 2002). Less common is vestibular toxicity with ataxia, vertigo, and nystag- mus (Meyer, 2001). Damage to the inner ear hair cells should be considered permanent, as hair cells do not regenerate (Landier, 1998). The hearing loss may first
Ototoxicity
Colleen Nixon
be noticed 3–4 days after the initial dose of cisplatin.
Ototoxicity caused by cisplatin is dose-related, cumu- lative, and inversely related to age (Schweitzer, 1993).
The dose of cisplatin at which SNHL occurs is around 400 mg/m2(Brookhouser, 2002). Continued exposure to cisplatin will ultimately affect the lower frequen- cies used in speech (i.e., 1,000–2,000 Hz) (Huang, 2002). Ototoxicity remains an irreversible, dose-lim- iting side effect of cisplatin, despite vigorous prehy- dration and in combination with mannitol diuresis (Schweitzer, 1993). Carboplatin, an analog of cis- platin, introduced in the early 1980s, can also cause a high-frequency hearing loss but without the loss of hair cells (Michaud et al., 2002).
Hearing loss is not typically associated with cra- nial irradiation alone (Halperin et al., 1999). Ototoxi- city becomes increasingly of concern when radio- therapy is used in combination with cisplatin. The administration of cisplatin after cranial radiation ap- pears to enhance the ototoxic effects of cisplatin (Halperin et al., 1999).
Aminoglycoside antibiotics are used mainly to treat infections caused by aerobic gram-negative bac- teria. Ototoxicity, a known side effect of these drugs, is often irreversible. Aminoglycosides initially injure outer hair cell membranes, followed by inner hair cell destruction, with damage most often occurring dur- ing prolonged elevated serum trough levels (Matz, 1993).
A synergism exists between aminoglycosides and loop diuretics (frusemide). Studies have shown that giving a loop diuretic and then an aminoglycoside antibiotic does not affect hearing more than giving either drug alone. But when the aminoglycoside is given first, and then the loop diuretic, the organ of Corti is damaged, causing synergistic hearing loss (Brookhouser, 2002). Ototoxicity caused by a loop di- uretic is often due to fluid changes within the inner ear, resulting in problems with nerve transmission.
This type of hearing loss typically develops quickly and is reversible (Brookhouser, 2002). Ototoxicity most often occurs after rapid intravenous infusion of frusemide (Landier, 1998).
The incidence of ototoxicity in the pediatric on- cology population is well documented in the litera- ture (Table 24.1). Many factors are associated with
the development of hearing loss in this group: age (3 years or younger), platinum-based chemotherapy or other ototoxic agents, rapid infusion of ototoxic medications, cranial irradiation, presence of a central nervous system tumor, surgery involving the 8th cra- nial nerve, excessive noise exposure, and prior oto- toxic therapy (Schell et al., 1989). Patients with poor renal function, associated with chemotherapeutic drugs, are at increased risk of hearing loss (Landier, 1998). Berg et al. (1999) noted studies that suggest that other factors such as nutrition, iris color, and skin pigmentation play a role in the development of cisplatin ototoxicity.
Despite known toxicities, many of the ototoxic drugs play a critical role in the treatment of the child with cancer. Often, when early hearing loss develops after treatment initiation, treatment protocols – par- ticularly ones containing platinum-based agents – may be altered (Landier, 1998).
Other children at high risk for hearing loss include those who had perinatal anoxia or hypoxia, low Ap- gar scores (<1 at 5 minutes), hyperbilirubinemia re- quiring an exchange transfusion, or mechanical ven- tilation for more than 10 days. Children with a histo- ry of bacterial meningitis, birth weight <1500 g, maternal infection (e.g., toxoplasmosis, rubella, cy- tomegalovirus, or herpes) while in utero, recurrent or persistent otitis media with effusion for at least 3 months, prior treatment with ototoxic drugs, or a family history of SNHL (presumably congenital) are also at risk (Cunningham & Cox, 2003). Clinical man- ifestations during infancy and early toddlerhood that may signify a hearing deficit include lack of a startle, failure to be awakened by loud environmental noises, absence of well-formed syllables (“da,” “na,” “ya”) by 11 months, and monotone and difficult to understand speech (Kline and Bloom, 2003).
The three main types of hearing loss, conductive, sensorineural, and mixed, are described according to the site of damage (Fig. 24.1). A conductive hearing loss occurs in the outer or middle ear and results in the prevention of sound waves progressing to the in- ner ear. This is often temporary, due to fluid in the middle ear or to otitis media, and reversible. Sen- sorineural loss results from damage to the inner ear or auditory nerve. For a child with SNHL, sounds are
Table 24.1. Studies of ototoxic agents in pediatric oncology
Author Ototoxic agent Results Recommendations
Berg et al. Cisplatin 26 % of children Audiologic assessment should be incorporated into (1999) 60–120 mg/m2/ developed bilateral regular medical examination because the onset of
course treatment symmetrical high- hearing loss can be delayed. Hearing aids may be useful frequency sensori- for patients with hearing loss affecting low or middle neural hearing loss frequencies. Assessment, evaluation, and intervention
by a speech pathologist to address possible communi- cation issues.
Schell, et al. Cisplatin, >50 % of patients had Obtain audiogram at least 3 weeks after cisplatin to (1983) medium cumula- substantial hearing monitor for delayed appearance of hearing loss.
tive dose loss (50 dB or greater) Serial audiograms for younger patients, patients 360 mg/m2 at higher frequencies receiving cranial irradiation, patients with CNS neoplasm,
(4,000–8,000 Hz), and any patient receiving cisplatin >360 mg/m2 and 11 % had hearing
loss at speech frequency level (500–3,000 Hz).
Hearing loss was related to cumulative dose of cisplatin
Huang et al. Comparing Compared with con- Larger sample size (2002) ototoxicity ventional radiothera- Further studies
in patients with py, IMRT delivered Longer follow-ups medulloblastoma 68 % of the radiation
receiving conven- dose to the auditory tional radiotherapy apparatus (cochlea vs. intensity-modu- and 8th cranial lated radiation nerve) while still therapy (IMRT) delivering full doses
to the desired target volume; 13 % of the IMRT group had a Grade 3 or 4 hearing loss vs. 64 % of the conventional RT group
Parsons et al. Carboplatin, 82 % of children with Continued efforts to monitor and evaluate hearing loss (1998) high-dose, 2 g/m2 neuroblastoma treated in patients treated with platinum-based agents as well
with autologous bone as other ototoxic agents.
marrow transplant Prepare patients and parents for this difficult side effect developed speech of treatment
frequency hearing loss requiring hearing aids
indistinct, and it is often difficult to perceive speech accurately. A mixed conductive-sensorineural hear- ing loss results from disruption of the transmission of sound along the auditory nerve (Kline and Bloom, 2003).
24.2 Prevention and Treatment
Early detection, with possible prevention, of hearing loss is an important consideration for a patient’s primary care team. Baseline audiologic testing is rec- ommended before a patient receives any platinum- based therapy or other potential ototoxic agents (Schweitzer, 1993). Serial audiologic testing should
continue throughout the entire treatment course, with close attention paid to the delayed effects of cis- platin ototoxicity. The testing is typically done before starting each cycle of cisplatin therapy (Landier, 1998).
Multiple audiologic tests exist for infants and chil- dren (Table 24.2). The method for evaluation can vary depending on the child’s age, state of health, and ability to cooperate (Parsons et al., 1998).
Pure tone audiometry remains the standard as well as the most common test for hearing evaluation (Cunningham and Cox, 2003). This test includes air and bone conduction testing to establish hearing sensitivity. Tones heard through earphones are pre- sented at different frequencies (pitch) ranging from 125–8,000 Hz. Hearing impairment or sensitivity is measured in decibels (dB), a measurement of loud- ness or intensity (Fig. 24.2) (Landier, 1998).
Normal hearing is considered to be in the 0–20 dB range for all frequencies tested in the 125–8,000 Hz (Fig. 24.3). A mild hearing loss for a child (20–40 dB) results in the inability to hear soft sounds or a whis- pered conversation in a quiet room. The child with a moderate hearing loss (40–60 dB) will have great difficulty understanding a typical conversation even in a quiet room. A child with a severe hearing loss (60–90 dB) will be able to have a conversation only if the speaker is within 6–12 inches of the child. A child with a profound loss of 90 dB or more may hear only loud sounds and will typically experience sound as a vibration (Landier, 1998)
Children’s ability to accurately understand what is being spoken is crucial. Many of the consonants are high-frequency sounds, such as “s,”“sh,”“f,” and “th.”
Most of the consonants are pitched higher than vow- els and are more difficult to identify, especially in a noisy environment (Berg et al., 1999).As the pediatric cancer survival rates continue to climb; the effect of hearing loss on a child’s life must be closely evaluat- ed. New promising treatments may help with the in- cidence of ototoxicity. Eloxatin (oxaliplatin) is a cell- cycle nonspecific platinum-based chemotherapeutic agent; its main side effects are nausea, neuropathy, and dyspnea, without the ototoxicity of cisplatin. As of this writing, Eloxatin has not been approved for the pediatric population but has shown promise in
Figure 24.1
Sound waves are funneled through the external audi- tory canal and hit the tympanic membrane (eardrum).
The sound waves hitting the tympanic membrane cause the ossicles of the middle ear to vibrate, setting the oval window (beginning point of the inner ear) in motion.The organ of Corti, located inside the fluid-filled cochlea, is the sensory receptor, which holds the hair cells, or the nerve receptors for hearing.The vibration of the ossicles causes fluid in the cochlea to move, stimu- lating the hair cells. Specific hair cells react to specific sound frequencies (pitch).Depending on the pitch, spe- cific hair cells are stimulated. Signals from the cochlear hair cells are transmitted into nerve impulses and sent to the brain via the acoustic nerve (Children’s Oncology Group, 2003)
the adult population (National Cancer Institute).Am- ifostine has been approved to prevent neurotoxicity from alkylating agents, platinum analogues, and ra- diation therapy while preserving the antineoplastic effect on tumors. It has shown efficacy in decreasing cisplatin neurotoxicity; however, its otoprotective ef- fect is uncertain. One study showed a 7% incidence of ototoxicity with amifostine and chemotherapy com- pared with 22% with chemotherapy alone (Meyer, 2001). In another study using cisplatin and amifos-
tine, neither a tumor-protective effect nor reduced toxicity was noted (Gradishar et al., 2001). The latest technology in radiotherapy is intensity-modulated radiotherapy (IMRT). IMRT is a complex type of three-dimensional conformal radiotherapy. The ben- efit of IMRT is its capability to deliver radiation to the intended site while avoiding surrounding tissues, such as the cochlea and auditory apparatus. This al- lows for less irradiation of normal tissue and de- creased side effects (Huang et al., 2002).
Table 24.2. Audiologic tests for infants and children (Cunningham and Cox, 2003)
Developmental Auditory test Type of Test procedures What the test
age of child measurement reveals
Birth to 9 months Brainstem Electrophysiologic meas- Placement of electrodes Patient’s hearing auditory evoked urement that evaluates on child’s head that is evaluated by response (BAER). function in auditory nerve record electrical respon- studying the size
15-minute test pathways ses to sound stimuli. of the peaks and
The child must be the time to form
asleep or sedated them
9 months Visual reinforce- Behavioral test obtained Requires a sound-treated Assesses hearing to 2.5 years ment audiogram in a sound-treated room. room. Condition the child of better ear (if
(VRA). 30-minute The child is seated on the to associate speech or earphones not test parent’s lap between two specific sound with a rein- worn). Used to
speakers or wearing ear- forcement stimulus evaluate frequen-
phones. When a sound is cies in the
presented at a specific 500–4000 Hz
frequency, the infant’s range
head-turn response is rein- forced with a lighted toy
2.5–4 years Play audiometry. Behavioral test assessing Child is instructed to Ear-specific 30-minute test auditory thresholds in perform a repetitive task, results if the child
response to speech and such as placing a peg in a does not wear specific tones delivered pegboard, each time the earphones. Assess through earphones child hears a sound. If the auditory percep-
child refuses to wear the tion of the child earphones, the test can
be administered in a sound field
All ages Evokes otoa- Physiologic test measuring Small microphone placed Otoacoustic emis- coustic emissions cochlear response to an in ear canal; signals are sions cannot be (OAE). 10-minute auditory stimulus generated by the cochlear picked up with
test hair cells in response >40 dB hearing
loss
Extended Measures frequencies in Important in
high-frequency the 8,000–20,000 Hz range monitoring early
audiometry hearing loss
(Landier, 1998)
Figure 24.2 aIllustration of normal audiogram (air conduction, right ear) bIllustration of audiogram showing sensorineural hearing loss (air conduction, right ear)
a b
Figure 24.3 Degree of hearing loss and effect on speech and language (Kline and Bloom, 2003)
Primary prevention and early detection are im- portant in the care and management of the child with a sensorineural hearing loss. Studies show that the in- cidence of hearing loss due to ototoxic agents ranges from minimal loss to greater than 80%. A multidisci- plinary team needs to be involved to manage the acute and long-term needs of the child with a hearing loss. Serial monitoring is recommended so that if ototoxicity develops, treatments can be changed or services added. The onset of ototoxicity cannot be predicted or delayed, making regular audiology ex- ams of the utmost importance (Berg et al., 1999). The Children’s Oncology Group has developed guidelines for monitoring hearing loss (Children’s Oncology Group, 2003).Any child who received any dose of car- boplatin or cisplatin should be tested at least once 2 years post-treatment, and if problems develop, then yearly until stable.Any child who received any dose of aminoglycoside or loop diuretics should be tested once post-treatment and if any other problems arise.
A child receiving doses of 30 Gy (3,000 cGy) or high- er to the ear, brain, or nasopharyngeal or infratempo- ral area should be screened yearly for 5 years after completion of treatment and then every 5 years as long as no problems arise.
Hearing loss affects a child’s total quality of life.
Strategies to reach dose intensification and to maxi- mize antineoplastic effects require interventions to minimize the associated side effects. This is particu- larly important as higher doses of cisplatin and car- boplatin continue to be used in attempt for cure. The future holds new developments of chemotherapeutic agents, chemoprotectants, and radiologic technology.
It is hoped that these new innovative treatments will greatly decrease the incidence of ototoxicity associat- ed with childhood cancer.
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