Cisplatin Ototoxicity in Children: Implications for Primary Care Providers

Jessica Helt-Cameron, MSN, MA, RN; Patricia Jackson Allen, MS, RN, PNP, FAAN

Disclosures

Pediatr Nurs. 2009;35(2):121-127. 

In This Article

Review of Literature

Mechanism of Action of Cisplatin

Cisplatin or cis-diamminedichloridoplatinum (CDDP) is an antineoplastic platinum compound. It was the first drug of its class, and as such, it is the most widely studied. Other platinum-containing compounds currently used to treat cancer include carboplatin and oxaliplatin. Platinum agents exert their effect by interfering with cell division or mitosis. They do so by forming platinum complexes within cells. The complexes cause cross-linking between and within strands of DNA (Lehne, 2007; Li, 2006). This damages the DNA of cells and prevents cell mitosis from occurring. It also activates apoptosis pathways to cause cell death.

Current Usages of Cisplatin

Cisplatin is currently utilized in many childhood cancer clinical trials overseen by the Children’s Oncology Group, which is the main research organization involved in developing pediatric oncology treatment protocols. Cisplatin and other platinum compounds are used in the treatment of cancers of the bone, connective tissue and muscles, brain and nerve tissues, head, neck, lungs, eyes, kidneys, adrenal glands, lymph tissues, liver, and reproductive organ tissues (see Figure 1) (CureSearch, National Childhood Cancer Foundation, & Children’s Oncology Group, 2008; Mayo Clinic, 2008). For these treatment regimens, cisplatin is administered intravenously, and the timing and dosage of cisplatin is dependent on the specific type and grading of the cancer metastasis.

Figure 1.

Childhood Cancers Treated with Cisplatin and Other Platinum Compounds

Side Effects of Cisplatin

Common side effects of cisplatin include nausea, vomiting, decreased appetite, metallic taste, alopecia, and tinnitus (Mayo Clinic, 2008). It can also cause electrolyte disturbances in children, including hypomagnesaemia, hypokalemia, and hypocalcaemia (CureSearch et al., 2008; Mayo Clinic, 2008). Other more serious adverse effects of cisplatin include nephrotoxicity, peripheral neuropathy, acute bone marrow suppression, and ototoxicity (CureSearch et al., 2008; Lehne, 2007; Li, 2006; Mayo Clinic, 2008). During cisplatin treatment, children are monitored for most of these toxicities. Kidney function tests, including glomerular filtration rate, blood urea nitrogen, and creatinine clearance, are measured to monitor for nephrotoxicity; physical assessments are conducted to detect any peripheral neuropathies; and complete blood counts with differentials are drawn to monitor for cisplatin-induced myelosupression. Although in the past children’s hearing was not monitored, today efforts are being made to routinely assess children’s hearing before, during, and after cisplatin treatment.

Cisplatin-Induced Sensorineural Hearing Loss

Normal hearing physiology. Human ear anatomy is divided into outer, middle, and inner ear segments. The outer ear includes the pinna and external auditory canal; the middle ear consists of the tympanic membrane and the boney ossicles (malleus, incus, and stapes); and the inner ear consists of the oval window, the cochlea (which houses the organ responsible for hearing), the semicircular canals, and vestibule (which are responsible for balance and equilibrium) (Fontana & Porth, 2005).

Once a sound wave travels through the external auditory canal and into the middle ear, it causes the tympanic membrane to vibrate. The vibration of the tympanic membrane causes the ossicles to vibrate in turn, with the stapes eventually pressing upon the oval window of the inner ear. When the oval window begins to vibrate, it causes the fluid in the cochlea to oscillate along the Organ of Corti, which is lined with hair cells that serve as our hearing receptors. When the hair cells are stimulated by this fluid movement, they transmit nerve impulses through the cochlear nerve to cranial nerve VIII, the vestibulocochlear nerve. From there, the nerve impulses travel to the temporal lobe auditory processing centers of the brain, and audition is perceived (Fontana & Porth, 2005; Huether & Defriez, 2006).

Conductive vs. sensorineural hearing loss. Hearing loss is divided into two classifications: conductive or sensorineural. Conductive hearing loss occurs when there is a malfunction somewhere in the auditory pathway of the outer or middle ear sections, often a blockage in the outer canal due to excessive cerumen or fluid buildup in the middle ear space as a result of otitis media. Sensorineural hearing loss occurs when there is a malfunction in the auditory pathway in the inner ear. Research suggests that cisplatin causes damage to the hair cells that line the Organ of Corti in the inner ear, resulting in a sensorineural hearing loss (Garcia-Berrocal et al., 2007).

Mechanism of cisplatin-induced sensorineural hearing loss. Although scientists are still trying to elucidate the precise mechanism(s) of cisplatin-induced sensorineural ototoxicity in humans, animal models provide some insight into the underlying pathophysiology of cisplatin’s ototoxicity. Researchers are using animal studies to determine if cisplatin activates apoptosis (or programmed cell death) in hair cells that line the Organ of Corti (Devarajan et al., 2002; Garcia-Berrocal et al., 2007; Husain, Scott, Whitworth, Somani, & Rybak, 2001). Garcia-Berrocal and colleagues (2007) examined the effect of cisplatin on 36 rats’ inner ear hair cells and found that cisplatin increased the activity of a specific enzyme called capase-3/7. Capase-3/7 is an apoptotic enzyme that upon activation initiates a cascade of events that results in cell death in the cochlea.

Other researchers are using animal studies to establish the role reactive oxygen species (or oxygen free radicals) produced by cisplatin have in generating damage in the cochlea (Clerici, DiMartino, & Prasad, 1995; Lee et al., 2004; Rybak, 2007). They hypothesize that cisplatin produces oxygen free radicals in the cochlea. These reactive oxygen species decrease the endogenous antioxidant enzymes found in the cochlea, further increasing its susceptibility to damage caused by cisplatin-derived free radicals. Lee and colleagues (2004) found elevated levels of two potent oxygen free radicals, 4-hydoxynonel and nitrotyrosine, in mice following the administration of cisplatin; autopsies showed the radicals extensively damaged the cochlear hair cells of the mice.

The study of cisplatin-induced sensorineural hearing loss in animals is important. If researchers can isolate the mechanism(s) involved in cisplatin-induced cochlear damage in animal models, they can extrapolate the information to humans to determine how cisplatin exerts its ototoxic effects in children and hopefully develop a management technique to block or minimize these ototoxic effects. More research in this area is needed.

Prevalence of cisplatin-induced sensorineural hearing loss in childhood cancer survivors. Studies have shown that cisplatin causes irreversible ototoxicity in children (Bertolini et al., 2004; Coradini, Cigana, Selistre, Rosito, & Brunetto, 2007; Gilmer-Knight, Kraemer, & Neuwelt, 2005; Kushner, Budnick, Kramer, Modak, & Cheung, 2006; Lackner et al., 2000; Simon, Hero, Dupuis, Selle, & Berthold, 2002; Stohr et al., 2005). The prevalence rate or occurrence of cisplatin-induced sensorineural hearing loss varies in each of these studies, ranging from 10% to 85% of children studied.

One late effects study by Lackner and colleagues (2000) examined 223 children who were treated for childhood cancer with a median age at diagnosis of 7.2 years. The median time from treatment was 5 years. Twenty-two of the study’s participants had received cisplatin, with a mean cumulative dosage of 367mg/m2. Pure tone audiometry testing for late effects showed that 18 of the 22 children (81%) had bilateral sensorineural hearing loss, with 5 using hearing aids. The study’s results are limited by its small sample size.

Gilmer-Knight and colleagues (2005) looked at the incidence of hearing loss in children and young adults treated with cisplatin chemotherapy. They used pure tone audiometry to measure the hearing abilities of 67 children treated with cisplatin. The researchers were able to perform a baseline audiogram on these children prior to the beginning of their cisplatin chemotherapy. The children and young adults ranged in age from 8 months to 23 years of age. Serial audiological evaluations were performed throughout their treatment and up to 800 days after the initial administration of cisplatin. They found 41 of the 67 treated children (61%) experienced sensorineural hearing loss, and the median time to development of the hearing loss was 135 days. The progressive hearing loss was observed for up to 26 months after children completed their cancer treatments.

These occurrence rates may actually underestimate the prevalence of hearing loss in childhood cancer survivors. Coradini et al. (2007) found that using pure tone audiometry testing as a single measure is not as sensitive as using otoacoustic emissions testing, which identified hearing losses in 71% of the children, whereas pure tone audiometry only indicated hearing losses in 52% of the children. Further research using otoacoustic emissions testing is needed to examine the incidence of cisplatin-induced sensorineural hearing loss in childhood cancer survivors.

Characteristics of Cisplatin-Induced Ototoxicity In Childhood Cancer Survivors

High-frequency hearing loss. Cisplatin-induced ototoxicity results in high frequency hearing loss in children. Hearing loss is categorized by a grading system that ranges from Grade 1 to Grade 4 (Brock, Bellman, Yeomans, Pinkerton, & Pritchard, 1991). Grade 1 characterizes the least severe hearing loss where children have difficulty hearing only high frequency sounds, including those at 40 dB and greater than 8000 Hertz (Hz). Grade 4 characterizes the most severe hearing loss, where children have difficulty hearing both high and low frequency sounds, including those at 40 db between 1000 to 8000 Hz. Studies demonstrate that while children who receive cisplatin can develop varying degrees of hearing loss, most children develop Grade 1 ototoxicity or high frequency hearing loss (Bertolini et al., 2004; Gilmer-Knight et al., 2005; Kushner et al., 2006; Simon et al., 2002). Bertolini and colleagues (2004) found that of 52 children, 33 (63%) developed Grade 1 ototoxicity, 13 (25%) developed Grade 2 ototoxicity, and only 6 (12%) developed Grade 3 or 4 ototoxicity.

Dose-dependent ototoxicity related to cisplatin. Late effects studies have examined cisplatin ototoxicity and its relationship to different total cumulative dosages of the platinum agent (Allen et al., 1998; Li, Womer, & Silber, 2004; Simon et al., 2002). Simon and associates (2002) reviewed medical records of 1,170 children successfully treated for neuroblastoma and found 146 had documented hearing losses. They discovered that the presence of cisplatin-induced hearing impairments was associated with the stage at diagnosis of the neuroblastoma; children with more advanced disease received higher total cumulative dosages of cisplatin in comparison to children with less advanced disease. Children with non-metastatic neuroblastoma stage 1 disease received a total dose of 320mg/m2. Children with metastatic stage 4 disease received a total dose of 640mg/m2, a significantly higher amount than children with stage 1 disease. The study’s results indicated that only 1% of children who received 320mg/m2 of cisplatin developed hearing impairments, as compared to 26.9% who received 640mg/m2 of cisplatin. These results support the hypothesis that cisplatin-induced sensorineural hearing loss is dose dependent with lower cumulative dosages having less ototoxic effects.

Other late effects studies confirmed these findings (Coradini et al., 2007; Kushner et al., 2006; Stohr et al., 2005). Stohr and colleagues (2005) used pure tone audiometry to examine 74 individuals who were diagnosed with osteosarcoma and treated in childhood. Although no specific demographic information about the sample was provided, people currently above the age of 40 were excluded from the sample so that age-related hearing loss would not affect the results. The total cumulative dose of cisplatin in the study’s sample ranged from 120 to 600mg/m2. Individuals who received a cumulative cisplatin dose of less than 240mg/m2 displayed no significant hearing loss. However, people who received a cumulative cisplatin dose of greater than 360mg/m2 demonstrated significant hearing impairments. Kushner and colleagues (2006) also studied the ototoxic effects of different cumulative doses of cisplatin. They used a more comprehensive assessment to evaluate the hearing abilities of 173 children with neuroblastoma treated with cisplatin therapy, including audiometry, visual reinforcement, and otoacoustic emissions testing. They found similar results to the aforementioned studies; higher dosages of cisplatin were associated with increased incidence of acquired sensorineural hearing loss. Hearing losses occurred more frequently once the total cumulative dose reached 300 to 400mg/m2.

Clearly, the total cumulative dosage of cisplatin is a mediating factor in the child’s development of ototoxicity. More research is needed to determine the exact total dosage amount that separates minimal hearing losses from severe hearing impairments.

Age-dependent ototoxicity related to cisplatin. It is hypothesized that administration of cisplatin to children at younger ages results in increased sensorineural hearing loss. In a landmark study examining cisplatin ototoxicity in 153 children treated with cisplatin, Li and colleagues (2004) found that even when the statistical analysis controlled for total cumulative dosages of cisplatin, the age at which the child received the cisplatin had a significant affect on whether or not the child developed sensorineural hearing loss. Specifically, they found that children younger than 5 years of age when they received cisplatin were 21 times more likely to develop moderate to severe hearing loss compared to children 15 to 20 years of age when they received cisplatin.

Kushner and colleagues (2004) divided the childhood cancer survivors successfully treated for neuroblastoma into three age group categories: those who received cisplatin before age 5, between the ages of 5 and 12, and after age 12. Children who received cisplatin before age 5 were significantly more likely than other children to have moderate to severe hearing loss. Children who received cisplatin before age 5 lost the ability to hear both high and low frequencies, even those in the normal speech frequency range (between 1000 to 2000 Hz). Being of an older age at the time of diagnosis and cisplatin administration appeared to be a protective factor against severe ototoxicity.

One study revealed results that contradicted these findings. Bertolini and associates (2004) examined 120 children who had been treated for neuroblastoma, osteosarcoma, hepatoblastoma, or germ cell tumors. The median age of diagnosis was 2.6 years, and the median age of follow up was 7 years post-treatment. The results showed that only 25% of children who were diagnosed and treated with cisplatin before the age of 36 months had significant hearing losses compared with 42% of children who were diagnosed and treated after 3 years of age. These results suggest that younger age (less than 3 years) could be a protective factor against cisplatin-induced ototoxicity. A possible explanation for this could be children less than 3 years of age still have plasticity to their neurons and cerebral cortex, allowing for recovery from the cellular effects of cisplatin. Further research is needed to elucidate the role that age has in mediating the ototoxic effects of cisplatin chemotherapy treatment.

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