Ototoxicity in Chinese Osteosarcoma Children Treated with Cisplatin
Objective: To evaluate the ototoxicity of cisplatin in Chinese children who were suffered from osteosarcoma. Patients & Methods: Restrospective case series of Chinese children who were treated in a tertiary referral centre of Hong Kong. Data was based on hospital records of children who were suffering from osteosarcoma between 1994 and 2001. They all have cisplatin treatment with pre- and post-chempotherapy pure tone audiometry results. Results: Sixteen patients fulfied the inclusion criterias were studied. Nineteen percent had grade I hearing impairment even at baseline evaluation. Sixty-nine percent showed worsening of the hearing after cisplatin treatment. The hearing threshold was increased at 2000Hz after cisplatin, which was more clearly shown at 4000Hz and 8000Hz. The results were statistically significant with the p-value 0.011, 0.003 and 0.002 respectively. Conclusion: Cisplatin would damage the hearing particularly at high frequency range (2000Hz, 4000Hz and 8000Hz). The hearing at low frequency range was relatively spare.
Keyword : Cisplatin; Osteosarcoma; Ototoxicity
Cisplatin, a DNA-damaging agent, is widely used as a chemotherapeutic agent for treatment of solid tumours such as neuroblastoma, medulloblastoma, hepatoblastoma, hepatocellar carcinoma (HCC) and osteosarcoma. On the other hand, cisplatin also induces a lot of side effects including nephrotoxicity, gastrointestinal toxicity, myelosuppression, and neurotoxicity such as ototoxicity.
For the mechanism of ototoxicity, cisplatin generates reactive oxygen species (ROS) and interferes with the antioxidant systems of cochlear sensory cells (inner and outer hair cells) and spiral ganglion cells, leading to the degeneration of the stria vascularis1-7 which result in sensorinerual hearing loss. The sensorineural hearing loss begins at high frequencies. The incidence of auditory hair cell damage and hearing loss can be as high as 90% with patients undergoing cisplatin chemotherapy.8 As mammalian hair cells do not regenerate so such hearing loss is permanent.
Method of Study
We performed a retrospective chart review on a cohort of osteosarcoma patients treated with cisplatin from 1994 to 2001 in the Children Cancer Centre ( CCC ) of Prince of Wales Hospital (PWH). We included all Chinese patients with osteosarcoma treated with cisplatin. The exclusion criteria were patients with no baseline pure tone audiometry (PTA) evaluation before cisplatin treatment, patients with no follow-up PTA after cisplatin treatment, and patients underwent cranial radiotherapy treatment on top of cisplatin (as confronting factor for hearing loss). Data were collected under standard data registration sheet with information including patient's particulars, diagnosis, age at diagnosis, duration of treatment, cumulative dose of cisplatin, PTA results before and after cisplatin treatment.
PTA was done by audiologists in Ear, Nose and Throat Department of Prince of Wales Hospital. The assessment included the changes of hearing threshold on both ears at different frequencies namely 250Hz, 500Hz, 1000Hz, 2000Hz, 4000Hz and 8000Hz. High frequency hearing loss in children was further categorised as Brock's classification, which classified hearing loss into 5 levels ranging from grade 0 to grade 4. At grade 0, the child was able to hear all frequencies at threshold less than 40 dB. At grades 1 and 2, the child could hear at 8000Hz at 40 dB or greater, higher than 4000Hz at the same 40 dB or greater respectively. At grades 3 and 4, the hearing impairment advanced to 40 dB loss in 2000Hz and above, 1000Hz and above respectively. The grade for the worse ear was counted to be the child's overall un-aided hearing score if hearing loss was asymmetrical.
There were a total of twenty-eight patients' records reviewed. One non-Chinese patient was excluded. Eleven patients (11/27, 40.74%) got either one PTA or no PTA performed. Only sixteen patients (16/27, 59.26%) got both pre-treatment and post-treatment PTA for comparison. And therefore, only these sixteen patients were included in this study. For the 12 patients who were not included in the study, 1 patient did not get any PTA result and 1 patient just got a baseline PTA. For the 10 patients with post-cisplatin PTA, 5 of them (50%) were male and female each. The median age at diagnosis was 11.74 years old with range from 7.51 to 16.45 years old. The median dose of cisplatin was 500 mg/m2 with range from 100 mg/m2 to 700 mg/m2. Three patients got grade I, 1 patient got grade II and 1 patient got grade III hearing impairment. Overall, 50% got hearing impairment after cisplatin treatment. The details were shown on Table 1.
For those sixteen patients with pre- and post-cisplatin PTA, seven of them (43.8%) were female and nine of them (56.3%) were male. The median age at diagnosis was 12.Eighteen years old with range between 3.30 to 14.23 years old. The median dose of cisplatin was 450 mg/m2 with range between 200 to 600 mg/m2. The basic data of patients were showed in Table 2. Three patients (18.7%) got Brock's grade 1 hearing impairment without obvious cause even before the treatment of cisplatin. Eleven patients (68.8%) showed worsening of the hearing after cisplatin treatment. Patient number 5 showed that even a dose of 200 mg/m2 could cause hearing impairment. Two patients (number 13 and 15) had followed up PTA even after termination of treatment for 65 months and 17 months respectively, which showed no further change of the PTA results. It signified that the damage of the hearing by cisplatin was permanent and irreversible, and appearing to be non-progressive.
Wilcoxon Signed Ranks Test p-value was used and p-value was regarded as statistically significant when it was less than 0.05. The results were shown in Table 3. The hearing threshold was not changed significantly with cisplatin treatment below 1000Hz. However, the hearing threshold was increased at 2000Hz level after cisplatin treatment. It was even more profound at 4000Hz and 8000Hz range respectively. The results were all statistically significant with the p-value of 0.011, 0.003 and 0.002 respectively. All of these results confirmed that cisplatin would damage the hearing at high frequency (2000Hz, 4000Hz and 8000Hz). The hearing at low frequency was relatively spare although patients number 13 showed severe hearing impairment of Brock's grade 4. However, the statistical analysis did not show a significant p-value may be due to the small sample size in this study.
In our study, only sixteen out of the twenty-seven patients (59.26%) got both pre- and post-treatment PTA for comparison. It was because in some cases, we had to start chemotherapy early even before the PTA appointment could be arranged. However, it is indeed very important to have a baseline PTA evaluation for we found that around 20% of our patients got Brock's grade 1 hearing impairment even prior to cisplatin treatment. Without the pre-treatment PTA evaluation, we could not conclude whether the hearing loss was purely induced by cisplatin or partly contributed by preexisting hearing impairment. As preexisting hearing abnormality was common so baseline PTA testing was mandatory if follow-up studies were to be adequately interpreted.9 In our study, we found that about 70% patients of our study showed worsening of the hearing after cisplatin treatment. As compared to other studies, the reported incidence of hearing loss ranges from 26% to 90%. Because of the variation of treatment and patient-related factors, it will be difficult to compare data from different clinical trials directly.
Our data clearly showed that cisplatin would cause high frequency hearing loss in Chinese children who suffered from osteosarcoma. As more and more patients treated with cisplatin would survive nowaday, the hearing problem should be properly addressed in order to improve patients' long term quality of life.
In the childhood period, children are in the pivotal phase of learning. They have to acquire the proper structure for speech and language development. Hearing impairment would definitely jeopardize their chances and ability of acquiring this intrinsic skill. Early intervention should be applied before the hearing problem further worsening. However, it is not easy to detect the hearing loss especially for the young infants because these patients could not cooperate well enough to perform a formal PTA. But cisplatin is also commonly used in these young infants such as in those patients suffering from neuroblastoma. Moreover, young age patient is more susceptible to the ototoxicity of cisplatin.
Theoretically, patient who are too young to be evaluated by PTA, hearing loss can be assessed by Brain Stem Auditory Evoked Potential (BAEP) at 8 kHz for threshold shift. But only 1 kHz stimulus is routinely used in our unit, 8 kHz stimulation is tried but without recognised waveform produced. BAEP has a low sensitivity in detecting early phase of ototoxicity at high frequency hearing range. On the contrary, abnormal BAEP results at 1 kHz already meant advanced hearing loss. Due to the low sensitivity of BAEP, early detection of high frequency hearing loss remains a big challenge in these patients.
Caring of these kinds of children should be conducted by a multi-disciplinary approach. The awareness of the problems by paediatric oncologists, neurologists and ENT specialists is just the beginning. ENT surgeons need to closely follow up the problems. Audiologists should be involved for the better care of these patients. Teachers in school should know how to handle these patients. Speech therapists should be aware of the articulation and language problems in young kids with hearing loss. With the cooperation of different disciplines and early intervention, the detrimental effects of hearing impairment resulted from cisplatin would be minimised.
In order to reduce the ototoxicity of cisplatin, possible specific protective agents (anti-oxidants) were studied. These included D-methionine,10-12 diethyldithiocarbamate acid (DDTC),13 and sodium thiosulfate14 but most of these were animal studies. All of them had the limitation of decreasing the efficacy of cisplatin against tumours. Some of them could even induce additional side effects. For example, DDTC can enhance the renal toxicity of cisplatin when comparing with cisplatin plus placebo.15-17 Natural antioxidants such as vitamin C and E were also studied. While there were no additional side effects documented but there were no significant protective effect noted.18 Salicylate is an agent with potential therapeutic benefit against cisplatin induced auditory threshold shift.19 Animal study showed that salicylate could protect against cisplatin-induced ototoxicity, nephrotoxicity and neurotoxicity without compromising its oncolytic action.20 However, salicylate may not be applicable in chemotherapy setting due to the commonly encountered severe thrombocytopenia and associated bleeding tendency. More studies are needed before salicylate can be used in reducing the side effects of cisplatin for human subjects.
Carboplatin is a second generation derivative of platinum. It has the similar mechanism of action as cisplatin but has less ototxicity and nephrotoxicity.21 However, carboplatin has more myelosuppresive effect and particularly, thrombocytopenia is one the typical dose-limiting factors.22,23 It can be used as a replacement of cisplatin when the patient showed significant toxicity induced by cisplatin. However, the efficacy of caboplatin in osteosarcoma patients is not well established.
In conclusion, the hearing threshold was found to be impaired starting at the 2000Hz range after cisplatin treatment. The impairment was more clearly showed at 4000Hz and 8000Hz range. The hearing at low frequency range was usually unaffected.
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