Search

PURPOSE Hearing loss (HL) is a serious secondary effect of treatment for CNS and head-and-neck tumors in children. The goal of this study was to evaluate incidence and risk factors for HL in patients with multiple ototoxic exposures. PATIENTS AND METHODS We evaluated 340 ears from 171 patients with CNS or head-and-neck tumors treated with radiation, with or without chemotherapy, who had longitudinal audiologic evaluation. International Society of Pediatric Oncology-Boston grades were assigned to 2,420 hearing assessments. Multivariable weighted ordinal logistic regression was fitted to evaluate the effect of clinicopathologic features on HL. RESULTS Mean cochlea dose (odds ratio [OR] 1.04 per Gy, P < .001), time since radiotherapy (RT; OR 1.21 per year, P < .001), cisplatin dose (OR 1.48 per 100 mg/m2, P < .001), and carboplatin dose (OR 1.41 per 1,000 mg/m2, P = .002) were associated with increasing International Society of Pediatric Oncology-Boston grade of HL. There was no synergistic effect of RT and cisplatin (interaction term, P = .53) or RT and carboplatin (interaction term, P = .85). Cumulative incidence of high-frequency HL (> 4 kHz) was 50% or greater at 5 years after RT if mean cochlea dose was > 30 Gy, while incidence of HL across all frequencies continued to increase beyond 5 years after RT. CONCLUSION Children treated with radiation and chemotherapy experience a high incidence of HL over time, with associations found between more severe HL and cisplatin or carboplatin dose as well as mean cochlea dose. Mean cochlea dose of ≤ 30 Gy is proposed as a goal to reduce the risk of HL; a lower threshold (20-25 Gy) may be considered in patients receiving platinum chemotherapy to reduce cumulative HL burden.

10503 Background: RAS/MAPK pathway mutations have been identified as the major drivers of pediatric low-grade glioma (pLGG). The impact of these alterations on outcome and response to therapy is still unknown. Methods: We performed a large population based study of all pLGG diagnosed from 1985-2015. Detailed treatment and very long term outcome data was collected on all patients. Known pLGG-related alterations were detected using NanoString and QX200™Droplet Digital™PCR. Molecular data was correlated with outcome and response to chemotherapy. Results: In our cohort of 614 patients, BRAF was found to be altered in 57% and wild-type (WT) in 43% of patients without neurofibromatosis 1 (NF1). Among BRAF-WT we identified H3.3K27M, FGFR1-TACC1, MYBL1 and other alterations. Molecular alterations stratified pLGG into several risk groups. Ten-year progression free survival (PFS) was 72.3% for NF1, 69.5% for KIAA1549-BRAF, 53.5% for BRAF-WT, 30.3% for BRAF-V600E and 0% for H3.3K27M mutations (p < 0.0001). Similarly, overall survival (OS) at 10 years delineated difference between excellent survival of KIAA1549-BRAF and NF1 compared to BRAF-V600E and BRAF-WT (p = 0.0005). Interestingly, all patients with FGFR1-TACC1 and MYBL1 were alive despite observed progressions. Strikingly, response to chemotherapy determined by changes in tumor size at 6 months of therapy correlated with pLGG alteration. Objective response to first line chemotherapy was observed in 46% of patients with KIAA1549-BRAF and 35% of NF1. In contrast, only 15% BRAF-V600E and 18% BRAF-WT responded and 41% tumors grew after six months of chemotherapy. Moreover, 5-year PFS after chemotherapy was strikingly low for BRAF-V600E and BRAF-WT (25% and 31.9% respectively) compared to KIAA1549-BRAF (50%) and NF1 (76.7%) (p = 0.001). This translated to decreased OS for BRAFV600E and BRAF-WT patients (p = 0.042). Conclusions: Our study provides evidence that molecular alterations dictate the outcome of pLGG. KIAA1549-BRAF harbors excellent prognosis and choice of therapy should be made in favor of less toxic agents to minimize deleterious late effects. In contrast, poor prognosis is associated with lack of response to chemotherapy in BRAF-V600E and BRAF-WT tumors.

2029 Background: Neurological side effects associated with childhood brain tumors and their treatments contribute to long term neurocognitive morbidity. The aims of this study were to identify the incidence of sensorineural hearing loss (SNHL) in a large sample of children treated for malignant brain tumors, and to evaluate the potential relationship between SNHL and intellectual functioning following the completion of treatment. Methods: We conducted a prospective follow-up study at a single center with review of 119 patients treated for embryonal brain tumors at the Hospital for Sick Children, between 1996-2015, to analyze the impact of significant SNHL (Chang > 2b) on intellectual function. Hearing was assessed post-treatment (median age: 13.5y (+4.5)) and the median age for neurocognitive testing was 12.8y (+ 4.1). The median interval from time of diagnosis was 5.8y (+ 3.7). Results: Severe SNHL was identified in half the patients (50.4%, n = 60/119). We identified a subset of patients (n = 61) who had assessments of intellectual function. In this cohort, intellectual function was significantly poorer in the group with severe SNHL, even after controlling for the effect of craniospinal radiation (severe SNHL 22.4 Gy + 13.3, no or mild hearing loss 20.4 Gy +12.8) and boost dose and volume. Children experiencing severe SNHL had lower overall IQ (severe SNHL 72.4 + 16.6; no/mild hearing loss 92.0 + 20.5) p < 0.001 and in significantly lower verbal comprehension (severe SNHL 78.7 + 15.9; no/mild hearing loss 94.7 + 13.8) p < 0.001, and working memory (severe SNHL 78.2+ 17.6; no/mild hearing loss 94.8 + 16.4) p < 0.001, scores. Conclusions: Hearing loss is a much more significant complication in children with embryonal brain tumors than previously estimated. We show the profound impact of hearing loss on intellectual deficit in children. Namely, patients with severe SNHL have difficulty using and understanding verbal language, and they have a reduced ability to concentrate and manipulate information in short-term memory. Our results have implications on future trial designs and follow-up of children treated for embryonal brain tumors.

10509Background: Pediatric low-grade gliomas (PLGG) are the most common CNS neoplasm in children. PLGG are histologically and clinically diverse and molecular stratification is desperately needed. ...

10565Background: Re-irradiation (re-RT) is increasingly adopted in relapsed ependymoma. In the setting of local relapse without dissemination, there is variation in whether focal or craniospinal (C...

2069 Background: Chemotherapy is widely accepted as the first-line therapy for pediatric low-grade gliomas (PLGG). Treatment modalities for further progression are controversial. Radiation therapy ...