Cisplatin Ototoxicity: Examination of the Impact of Dosing, Infusion Times, and Schedules In Pediatric Cancer Patients.

BACKGROUND: Sensorineural hearing loss is a well-known side effect of cisplatin (CDDP). There is limited research on the effect of dosing, infusion times, and schedules of cisplatin administration and their impact on hearing loss. METHODS: A retrospective review of 993 pediatric patients' medical and audiological charts from August 1990 to March 2015 was conducted using stringent inclusion criteria to characterize patients with hearing loss. 248 of these patients received CDDP. Of these, 216 patients had sufficient CDDP infusion data to assess for sensorineural hearing loss attributable to CDDP and its associated risk factors. Chart reviews were performed to extract clinical data including CDDP dosing information. Demographic and clinical characteristics were summarized by descriptive statistics, and univariate and multivariate logistic regressions were performed to examine the relationship between hearing loss and specific parameters of cisplatin administration (amount infused per dose, prescribed infusion time, total number of doses, number of doses per cycle, number of cycles, cumulative cisplatin exposure). Stepwise variable selection procedure was performed in the multivariate model building to extract the best subset of risk factors for the prediction of hearing loss and worsening ototoxicity grade using an established ototoxicity grading scale from the International Society of Pediatric Oncology (SIOP). RESULTS: A total of 153 patients with complete medical and audiologic data were evaluable for analysis. Hearing loss was identified in 72.6% of the patients. Multivariate analysis revealed that age [OR=0.90 (0.84-0.97), p-value=0.0086], radiation to any part of the body, [OR=3.20 (1.29-7.93), p-value=0.012], amount infused per dose (mg/m2) [OR=1.018 (1.002-1.033), p-value=0.029], and cumulative cisplatin exposure (mg/m 2) [OR=1.004 (1-1.008), p-value=0.027] were associated with hearing loss. Similar associations were also found between these risk factors and worsening SIOP grade. CONCLUSION: In one of the largest studies examining the influence of CDDP dosing and schedules on hearing loss, we found the amount of CDDP infused per dose is a significant risk factor. Considerations in designing regimens that reduce the amount of CDDP infused per dose may reduce the risk of hearing loss. Randomized prospective trials are needed.

Effect of sensorineural hearing loss on neurocognitive and adaptive functioning in survivors of pediatric embryonal brain tumor.

PURPOSE: Survivors of pediatric embryonal brain tumors (BT) are at high risk for sensorineural hearing loss (SNHL) associated with neurocognitive decline. However, previous studies have not assessed the relationship between SNHL and adaptive functioning. We examined neurocognitive and adaptive functioning in patients with and without SNHL. METHODS: Participants included 36 patients treated for an embryonal BT with craniospinal irradiation (CSI) and cisplatin chemotherapy who were assessed 6.7 years post-treatment on average. The impact of SNHL on neurocognitive performance and parent-rated adaptive functioning was assessed in univariate and multivariate analyses. RESULTS: There were 17 cases with SNHL (mean age at evaluation = 14.4) and 19 cases with NH (mean age at evaluation = 13.8). After accounting for age at diagnosis and additional covariates in multivariable analyses, SNHL was associated with worse overall intellectual functioning (p = 0.027) and perceptual reasoning (p = 0.016) performance. There was no effect of SNHL on adaptive functioning in multivariable models. Age at diagnosis and sex were associated with performance on neurocognitive measures. CONCLUSIONS: SNHL in pediatric embryonal BT is associated with increased risk for neurocognitive deficits in conjunction with other demographic and treatment-related factors.

Asymmetric sensorineural hearing loss is a risk factor for late-onset hearing loss in pediatric cancer survivors following cisplatin treatment.

BACKGROUND: Ototoxicity is a significant complication of cisplatin treatment. Hearing loss can be symmetric or asymmetric, and may decline after therapy. This study examined the risks of asymmetric and late-onset hearing loss (LOHL) in cisplatin-treated pediatric patients with cancer. METHODS: A retrospective review of 993 patients' medical and audiological charts from August 1990 to March 2015 was conducted using stringent criteria to characterize patients with asymmetric hearing loss (AHL) or LOHL. Audiologic data were reviewed for 248 patients that received cisplatin to assess cisplatin-induced sensorineural hearing loss and its associated risk factors. RESULTS: Of the patients evaluable for AHL, 26% exhibited this finding. Of those evaluable for LOHL, 42% of the patients' hearing worsened more than 6 months after therapy completion. Radiation and type of cancer diagnosis were major risk factors for both AHL and LOHL. Furthermore, LOHL was linked to age of diagnosis, noncranial radiation, and longer audiologic follow-up. AHL was strongly associated with LOHL-60% of patients with AHL also had LOHL. Logistic regression analysis revealed that patients with AHL (OR 6.3, 95% CI: 2.2-17.8, P = 0.0005) or those receiving radiation (OR 3.2, 95% CI: 1.2-8.6, P = 0.02) were at greatest risk for LOHL. CONCLUSION: Children receiving cisplatin therapy are at risk for developing AHL and LOHL. Those that have received radiation and/or with AHL are at increased risk for further hearing decline. Long-term monitoring of these patients is important for early intervention as hearing diminishes.

Determining the prevalence of vestibular screening failures in pediatric cancer patients whose therapies include radiation to the head/neck and platin-based therapies: A pilot study.

BACKGROUND: Sensorineural hearing loss due to ototoxic cancer therapy is well established; effects on the vestibular system are unknown. We examined the feasibility of implementing vestibular screens for pediatric cancer survivors exposed to ototoxic agents. The prevalence of screening failures is reported. METHODS: Cancer survivors who were 6-17 years, at least 1-month posttreatment, and received ototoxic therapy (radiation to the head/neck, cisplatin, carboplatin) were eligible. Screening measures included (1) Pediatric Vestibular Symptom Questionnaire, (2) Modified Clinical Test of Sensory Interaction on Balance, and (3) Dynamic Visual Acuity. RESULTS: Vestibular screening failures were observed in 30 participants (60%). Patients with a brain tumor diagnosis were at increased risk for failures compared to nonbrain tumor patients (74.2% vs. 36.8%, P = 0.009). Patients who underwent brain surgery were at increased risk for failures compared to patients without brain surgery (71% vs. 42%, P = 0.043). Patients with a longer duration between end of treatment and vestibular screening had a reduced risk of failures, with an almost 20% decrease for each year between the time points (odds ratio = 0.812; 95% confidence interval: 0.683-0.964, P = 0.018). Receiving carboplatin correlated with a decreased risk of failure (P = 0.016), due to a negative correlation with other clinical risk factors (diagnosis of a brain tumor, major brain surgery) that are associated with vestibular screening failure. CONCLUSION: Vestibular screening failures are highly prevalent in childhood cancer survivors who received ototoxic therapy. Broad screening of this population and further characterization of these patients are warranted.