Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium.

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.

Treatment burden and long-term health deficits of patients with low-grade gliomas or glioneuronal tumors diagnosed during the first year of life.

BACKGROUND: Low-grade gliomas (LGGs) and low-grade glioneuronal tumors (LGGNTs) diagnosed during the first year of life carry unique clinical characteristics and challenges in management. However, data on the treatment burden, outcomes, and morbidities are lacking. METHODS: A retrospective study of LGGs and LGGNTs diagnosed in patients younger than 12 months at St. Jude Children's Research Hospital (1986-2015) was conducted. RESULTS: For the 51 patients (including 31 males), the mean age at diagnosis was 6.47 months (range, 0.17-11.76 months), and the mean follow-up period was 11.8 years (range, 0.21-29.19 years). Tumor locations were hypothalamic/optic pathway (61%), hemispheric (12%), brainstem (12%), cerebellar (8%), and spinal (8%). There were 41 patients with histological diagnoses: 28 had World Health Organization grade 1 tumors, 6 had grade 2 tumors, and 7 had an LGG/LGGNT not definitively graded. Forty-one patients required an active intervention at diagnosis. Throughout their treatment course, 41 patients eventually underwent tumor-directed surgeries (median, 2 surgeries; range, 1-6), 39 received chemotherapy (median, 2 regimens; range, 1-13), and 21 received radiotherapy. Forty patients experienced disease progression (median, 2 progressions; range, 1-18). Ten patients died of progression (n = 5), malignant transformation (n = 2), a second cancer (n = 2), or a shunt infection (n = 1). The 10-year overall survival, progression-free survival, and radiation-free survival rates were 85% ± 5.3%, 16.9% ± 5.3%, and 51.2% ± 7.5%, respectively. Forty-nine patients experienced health deficits (eg, endocrinopathies, obesity, seizures, visual/hearing impairments, neurocognitive impairments, and cerebrovascular disease). Predictors of progression and toxicities were defined. CONCLUSIONS: Infantile LGG/LGGNT is a chronic, progressive disease universally associated with long-term morbidities and requires multidisciplinary intervention.

Neuropsychological outcomes of patients with low-grade glioma diagnosed during the first year of life.

PURPOSE: Low-grade gliomas (LGG) are a heterogeneous group of brain tumors, which are often assumed to have a benign course. Yet, children diagnosed and treated for LGG in infancy are at increased risk for neurodevelopmental disruption. We sought to investigate neuropsychological outcomes of infants diagnosed with LGG. METHODS: Between 1986 and 2013, 51 patients were diagnosed with LGG before 12 months of age and managed at St. Jude Children's Research Hospital. Twenty-five of the 51 patients received a cognitive assessment (68% male; 6.8 ± 3.3 months at diagnosis; 10.5 ± 4.8 years at latest assessment). Approximately half the patients received radiation therapy (n = 12; aged 4.0 ± 3.0 years at radiation therapy), with a median of 2 chemotherapy regimens (range = 0-5) and 1 tumor directed surgery (range = 0-5). RESULTS: The analyses revealed performance below age expectations on measures of IQ, memory, reading, mathematics, and fine motor functioning as well as parent-report of attention, executive, and adaptive functioning. Following correction for multiple comparisons, a greater number of chemotherapy regimens was associated with lower scores on measures of IQ and mathematics. More tumor directed surgeries and presence of visual field loss were associated with poorer dominant hand fine motor control. Radiation therapy exposure was not associated with decline in neuropsychological performance. CONCLUSIONS: Children diagnosed with LGG in infancy experience substantial neuropsychological deficits. Treatment factors, including number of chemotherapy regimens and tumor directed surgeries, may increase risk for neurodevelopmental disruption and need to be considered in treatment planning.

Evaluation and Management of Hearing Loss in Survivors of Childhood and Adolescent Cancers: A Report From the Children's Oncology Group.

Hearing loss (HL) is common in childhood cancer survivors exposed to platinum chemotherapy and/or cranial radiation and can severely impact quality of life. Early detection and appropriate management can mitigate academic, speech, language, social, and psychological morbidity resulting from hearing deficits. This review is targeted as a resource for providers involved in aftercare of childhood cancers. The goal is to promote early identification of survivors at-risk for HL, appropriate evaluation and interpretation of diagnostic tests, timely referral to an audiologist when indicated, and to increase knowledge of current therapeutic options.

Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study.

BACKGROUND: Survivors of childhood cancer who are treated with platinum-based chemotherapy and/or cranial radiation are at risk of treatment-induced hearing loss. However, the effects of such hearing loss on adult social attainment have not been well elucidated. METHODS: Adult survivors of pediatric central nervous system (CNS) solid tumors (180 survivors) and non-CNS solid tumors (226 survivors) who were treated with potentially ototoxic cancer therapy completed audiologic evaluations and questionnaires assessing their perception of social functioning and social attainment (ie, independent living, marriage, and employment). Audiograms were graded with the Chang ototoxicity grading scale. Analyses were stratified by tumor type (ie, CNS vs non-CNS). Multivariable logistic regression models were conducted with adjustment for age; sex; chronic health conditions; and, for the CNS group, IQ. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported. RESULTS: Serious hearing loss (that requiring a hearing aid or deafness) was detected in 36% of survivors of CNS tumors and 39% of survivors of non-CNS tumors. Serious hearing loss was associated with an increased risk of perceived negative impact in ≥1 areas of social functioning (survivors of non-CNS tumors: OR, 1.83 [95% CI, 1.00-3.34]). Among survivors of non-CNS tumors, serious hearing loss was associated with 2-fold increased risk of nonindependent living (OR, 2.19; 95% CI, 1.19-4.04) and unemployment or not graduating from high school (OR, 1.85; 95% CI, 1.00-3.34). CONCLUSIONS: A substantial proportion of adult survivors of childhood cancer treated with potentially ototoxic therapy have serious hearing loss. Treatment-induced hearing loss was found to be associated with reduced social attainment, both perceived and actual, in this study sample.

Concordance between the chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma.

BACKGROUND: Reporting ototoxicity is frequently complicated by use of various ototoxicity criteria. The International Society of Pediatric Oncology (SIOP) ototoxicity grading scale was recently proposed for standardized use in reporting hearing loss outcomes across institutions. The aim of this study was to evaluate the concordance between the Chang and SIOP ototoxicity grading scales. Differences between the two scales were identified and the implications these differences may have in the clinical setting were discussed. PROCEDURES: Audiological evaluations were reviewed for 379 patients with newly diagnosed medulloblastoma (ages 3-21 years). Each patient was enrolled on one of two St. Jude clinical protocols that included craniospinal radiation therapy and four courses of 75 mg/m(2) cisplatin chemotherapy. The latest audiogram conducted 5.5-24.5 months post-protocol treatment initiation was graded using the Chang and SIOP ototoxicity criteria. Clinically significant hearing loss was defined as Chang grade ≥2a and SIOP ≥2. Hearing loss was considered serious (requiring a hearing aid) at the level of Chang grade ≥2b and SIOP ≥3. RESULTS: A strong concordance was observed between the Chang and SIOP ototoxicity scales (Stuart's tau-c statistic = 0.89, 95% CI: 0.86, 0.91). Among those patients diagnosed with serious hearing loss, the two scales were in good agreement. However, the scales deviated from one another in classifying patients with less serious or no hearing loss. CONCLUSIONS: Although discrepancies between the Chang and SIOP ototoxicity scales exist primarily for patients with no or minimal hearing loss, the scales share a strong concordance overall.

Association of hearing loss with patient-reported functional outcomes in adult survivors of childhood cancer.

BACKGROUND: Hearing loss is prevalent following ototoxic therapy for childhood cancer. Associations between hearing loss, self-perceived hearing handicap, and functional outcomes have not been examined in survivors. METHODS: Adult survivors treated with platinum or head and neck radiotherapy with hearing loss were recruited. A total of 237 survivors (median age at survey = 37.0 years [range = 30.0-45.0 years]; median = 29.1 years [range = 22.4-35.0 years] since diagnosis; median = 4.0 years [range = 2.9-7.7 years] from last audiogram to survey) completed the Hearing Handicap Inventory for Adults and questionnaires on social and emotional functioning and hearing aid use. Hearing loss severity was defined according to Chang criteria. Multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between hearing loss, hearing handicap, functional outcomes, and hearing aid use with adjustment for sex, race, age at hearing loss diagnosis, and age at survey. RESULTS: Two-thirds of survivors had severe hearing loss, which was associated with increased likelihood of hearing handicap (mild-moderate handicap: OR = 2.72, 95% CI = 1.35 to 5.47; severe handicap: OR = 5.99, 95% CI = 2.72 to 13.18). Survivors with severe hearing handicap had an increased likelihood of social isolation (OR = 8.76, 95% CI = 3.62 to 21.20), depression (OR = 9.11, 95% CI = 3.46 to 24.02), anxiety (OR = 17.57, 95% CI = 3.77 to 81.84), reduced personal income (OR = 2.82, 95% CI = 1.46 to 5.43), and less than full-time employment (OR = 2.47, 95% CI = 1.30 to 4.70). Survivors who did not use a recommended hearing aid were twice as likely to have less than full-time employment (OR = 2.26, 95% CI = 1.10 to 4.61) and reduced personal income (OR = 2.24, 95% CI = 1.08 to 4.63) compared with survivors who wore a hearing aid. CONCLUSION: Self-perceived hearing handicap beyond measured hearing loss is associated with reduced functional outcomes. Assessment of hearing handicap may facilitate targeted interventions in adult survivors with hearing loss.

Modeling the Risk of Hearing Loss From Radiation Therapy in Childhood Cancer Survivors: A PENTEC Comprehensive Review.

PURPOSE: The Pediatric Normal Tissue Effects in the Clinic (PENTEC) hearing loss (HL) task force reviewed investigations on cochlear radiation dose-response relationships and risk factors for developing HL. Evidence-based dose-response data are quantified to guide treatment planning. METHODS AND MATERIALS: A systematic review of the literature was performed to correlate HL with cochlear dosimetry. HL was considered present if a threshold exceeded 20 dB at any frequency. Radiation dose, ototoxic chemotherapy exposure, hearing profile including frequency spectra, interval to HL, and age at radiation therapy (RT) were analyzed. RESULTS: Literature was systematically reviewed from 1970 to 2021. This resulted in 739 abstracts; 19 met inclusion for meta-analysis, and 4 included data amenable to statistical modeling. These 4 studies included 457 cochleas at risk in patients treated with RT without chemotherapy, and 398 cochlea treated with chemotherapy. The incidence and severity of cochlear HL from RT exposure alone is related to dose and age. Risk of HL was <5% in cochlea receiving a mean dose ≤35 Gy but increased to 30% at 50 Gy. HL risk ranged from 25% to 40% in children under the age of 5 years at diagnosis, declining to 10% in older children for any radiation dose. Probability of similar severe HL occurred at doses 18.3 Gy higher for children <3 versus >3 years of age. High-frequency HL was most common, with average onset occurring 3.6 years (range, 0.4-13.2 years) after RT. Exposure to platinum-based chemotherapies added to the rates of HL at a given cochlear dose level, with 300 mg/m2 shifting the dose response by 7 Gy. CONCLUSIONS: In children treated with RT alone, risk of HL was low for cochlear dose <35 Gy and rose when dose exceeded 35 Gy without clear RT dose dependence. High-frequency HL was most prevalent, but all frequencies were affected. Children younger than 5 years were at highest risk of developing HL, although independent effects of dose and age were not fully elucidated. Future reports with more granular data are needed to better delineate time to onset of HL and the effects of chemoradiotherapy.

Validation of Male Talker Recordings of the Spanish Pediatric Speech Recognition Threshold Test and the Spanish Pediatric Picture Identification Test.

PURPOSE: The purpose of this study was to validate recordings of the Spanish Pediatric Speech Recognition Threshold (SPSRT) test and Spanish Pediatric Picture Identification Test (SPPIT) for Spanish-speaking children using a native, bilingual Spanish-English male talker of Castilian peninsular dialect from Spain. METHOD: Seventy native Spanish-speaking children from a variety of countries participated. Fifty-eight participants had normal hearing, and the remaining 12 had mild hearing loss in at least one ear. Male talker recordings of the SPSRT and SPPIT were administered to obtain baseline validation data. Participants listened to the stimuli and pointed to the appropriate item on the picture boards that represented the word they heard. RESULTS: Mean SRTs were within 5 dB of mean pure-tone averages resulting in a positive correlation. Performance-intensity functions for the SPPIT showed minimal significant differences across the three test lists, and performance increased as the sensation level increased. CONCLUSIONS: The male talker recordings of the SPSRT and SPPIT are valid speech perception picture-pointing assessments that can be used with Spanish-speaking children. The recordings present the Spanish target word while simultaneously presenting the English interpretation for ease of scoring.

Outcome and molecular analysis of young children with choroid plexus carcinoma treated with non-myeloablative therapy: results from the SJYC07 trial.

BACKGROUND: Choroid plexus carcinoma (CPC) is a rare and aggressive tumor of infancy without a clear treatment strategy. This study describes the outcomes of children with CPC treated on the multi-institutional phase 2 SJYC07 trial and reports on the significance of clinical and molecular characteristics. METHODS: Eligible children <3 years-old with CPC were postoperatively stratified to intermediate-risk (IR) stratum if disease was localized or high-risk (HR) stratum, if metastatic. All received high-dose methotrexate-containing induction chemotherapy. IR-stratum patients received focal irradiation as consolidation whereas HR-stratum patients received additional chemotherapy. Consolidation was followed by oral antiangiogenic maintenance regimen. Survival rates and potential prognostic factors were analyzed. RESULTS: Thirteen patients (median age: 1.41 years, range: 0.21-2.93) were enrolled; 5 IR, 8 HR. Gross-total resection or near-total resection was achieved in ten patients and subtotal resection in 3. Seven patients had TP53-mutant tumors, including 4 who were germline carriers. Five patients experienced progression and died of disease; 8 (including 5 HR) are alive without progression. The 5-year progression-free survival (PFS) and overall survival rates were 61.5 ± 13.5% and 68.4 ± 13.1%. Patients with TP53-wild-type tumors had a 5-year PFS of 100% as compared to 28.6 ± 17.1% for TP53-mutant tumors (P = .012). Extent of resection, metastatic status, and use of radiation therapy were not significantly associated with survival. CONCLUSIONS: Non-myeloablative high-dose methotrexate-containing therapy with maximal surgical resection resulted in long-term PFS in more than half of patients with CPC. TP53-mutational status was the only significant prognostic variable and should form the basis of risk-stratification in future trials.

Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.

PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.

Spanish Pediatric Picture Identification Test.

Purpose The purpose of this study was to construct and validate a recorded word recognition test for monolingual Spanish-speaking children utilizing a picture board and a picture-pointing task. Design The Spanish Pediatric Picture Identification Test was developed and validated in this study. Test construction steps included (a) producing new digital recordings of word lists created by Comstock and Martin (1984) using a bilingual Spanish-English female, (b) obtaining list equivalency, (c) creating digitally illustrated pictures representing the word lists, (d) validating the pictures using monolingual Spanish-speaking and bilingual Spanish-English children, and (e) re-establishing list equivalency and obtaining performance-intensity functions using a picture-pointing task with monolingual Spanish-speaking children and bilingual Spanish-English adults. Results Normative data for three Spanish word recognition lists were established. Performance-intensity functions at sensation levels from 0 to 40 dB SL in 8-dB steps were obtained, establishing list equivalency for Lists 1, 2, and 3. Conclusions The Spanish Pediatric Picture Identification Test was developed and validated as a picture-pointing task for word recognition with monolingual Spanish-speaking children. The two validated channel recordings include an English translation for ease of testing by clinicians lacking Spanish language skills. Future validation will be conducted with bilingual Spanish-English children with normal hearing and with hearing loss.

Association of Hearing Impairment With Neurocognition in Survivors of Childhood Cancer.

Importance: Despite advancements in cancer therapy and supportive care, childhood cancer survivors remain at risk for chronic morbidities associated with disease and treatment, such as hearing impairment (HI) and neurocognitive deficits. This study, to our knowledge, is the first to objectively measure hearing and neurocognitive function in a large cohort of long-term survivors of childhood cancer stratified by treatment exposures. Objective: To assess the association of HI with neurocognitive function and the factors in HI that mediate neurocognitive outcomes in survivors of childhood cancer. Design, Setting, and Participants: Data analyzed in this cross-sectional study were collected for the period April 25, 2007, to June 30, 2017, from participants in the St. Jude Lifetime Cohort Study (SJLIFE), an ongoing study that quantifies the long-term health outcomes of survivors of childhood cancer. Participants included those treated at St. Jude Children's Research Hospital (Memphis, Tennessee) for childhood cancer who survived 5 or more years after their original diagnosis and who were eligible for audiologic and neurocognitive testing. Hearing outcomes were coded using the Chang Ototoxicity Grading Scale. Data analysis was performed from March 22, 2019, to March 5, 2020. Main Outcomes and Measures: Hearing and neurocognitive function. Survivors were grouped by hearing sensitivity (normal hearing [Chang grade 0], mild HI [Chang grades 1a, 1b, and 2a], or severe HI [Chang grade ≥2b]) and stratified by treatment exposure (platinum-only exposure group [treated with cisplatin and/or carboplatin chemotherapy], cochlear radiotherapy [RT] exposure group [treated with cochlear RT with or without platinum-based chemotherapy], or no exposure group [no platinum-based chemotherapy or cochlear RT]). Multivariable log-binomial models were adjusted for age at diagnosis, time since diagnosis, sex, and relevant treatment exposures. Results: A total of 1520 survivors of childhood cancer were analyzed, among whom 814 were male survivors (53.6%), the median (interquartile range [IQR]) age was 29.4 (7.4-64.7) years, and the median (IQR) time since diagnosis was 20.4 (6.1-53.8) years. Prevalence and risk of severe HI among survivors were higher in survivors in the platinum-only (n = 107 [34.9%]; relative risk [RR], 1.68 [95% CI, 1.20-2.37]) or cochlear RT (n = 181 [38.3%]; RR, 2.69 [95% CI, 2.02-3.57) exposure group compared with those in the no exposure group (n = 65 [8.8%]). Severe HI was associated with deficits in verbal reasoning skills (no exposure group RR, 1.11 [95% CI, 0.50-2.43]; platinum-only exposure group RR, 1.93 [95% CI, 1.21-3.08]; cochlear RT exposure group RR, 2.00 [95% CI, 1.46-2.75]), verbal fluency (no exposure group RR, 1.86 [95% CI, 1.19-2.91]; platinum-only exposure group RR, 1.83 [95% CI, 1.24-2.71]; cochlear RT exposure group RR, 1.45 [95% CI, 1.09-1.94]), visuomotor speed (no exposure group RR, 1.87 [95% CI, 1.07-3.25]; platinum-only exposure group RR, 3.10 [95% CI, 1.92-4.99]; cochlear RT exposure group RR, 1.40 [95% CI, 1.11-1.78]), and mathematics skills (no exposure group RR, 1.90 [95% CI, 1.18-3.04]; platinum-only exposure group RR, 1.63 [95% CI, 1.05-2.53]; cochlear RT exposure group RR, 1.58 [95% CI, 1.15-2.18]), compared with survivors with normal hearing or with mild HI. Conclusions and Relevance: Results of this study suggest that severe HI in childhood cancer survivors is associated with neurocognitive deficits independent of the neurotoxic treatment received. Early screening and intervention for HI may facilitate the development and maintenance of neurocognitive function and identify individuals at risk for impairment.

Spanish Pediatric Speech Recognition Threshold Test.

Purpose The purpose of this study was to construct a recorded speech recognition threshold (SRT) test for Spanish-speaking children utilizing a picture board and a picture-pointing task. Design The Spanish Pediatric Speech Recognition Threshold (SPSRT) test was developed and validated in this study. Test construction steps included (a) stimulus selection, (b) assessment of familiarity, (c) digital recording, (d) creation of pictures that accurately depicted the target word from the stimulus set, and (e) validation of the test and recordings. SRTs were obtained from 24 Spanish-speaking children whose 1st language was Spanish. Results Normative data are presented that validate the SPSRT and establish the baseline relationship between the pure-tone average and the SRT obtained with the SPSRT. Results indicated that the SPSRT obtained using this test should be within 2-12 dB of an individual's pure-tone average for Spanish-speaking children with normal hearing and minimal hearing loss. Conclusions The SPSRT was developed and validated as a picture-pointing Spanish SRT test to be used with Spanish-speaking children. The 2-channel recording contains an English translation track, making this test easy to administer and interpret for clinicians without knowledge of Spanish.

Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

PURPOSE: Sensorineural hearing loss (SNHL) is associated with intellectual and academic declines in children treated for embryonal brain tumors. This study expands upon existing research by examining core neurocognitive processes that may result in reading difficulties in children with treatment-related ototoxicity. PATIENTS AND METHODS: Prospectively gathered, serial, neuropsychological and audiology data for 260 children and young adults age 3 to 21 years (mean, 9.15 years) enrolled in a multisite research and treatment protocol, which included surgery, risk-adapted craniospinal irradiation (average risk, n = 186; high risk, n = 74), and chemotherapy, were analyzed using linear mixed models. Participants were assessed at baseline and up to 5 years after diagnosis and grouped according to degree of SNHL. Included were 196 children with intact hearing or mild to moderate SNHL (Chang grade 0, 1a, 1b, or 2a) and 64 children with severe SNHL (Chang grade 2b or greater). Performance on eight neurocognitive variables targeting reading outcomes (eg, phonemics, fluency, comprehension) and contributory cognitive processes (eg, working memory, processing speed) was analyzed. RESULTS: Participants with severe SNHL performed significantly worse on all variables compared with children with normal or mild to moderate SNHL (P ≤ .05), except for tasks assessing awareness of sounds and working memory. Controlling for age at diagnosis and risk-adapted craniospinal irradiation dose, performance on the following four variables remained significantly lower for children with severe SNHL: phonemic skills, phonetic decoding, reading comprehension, and speed of information processing (P ≤ .05). CONCLUSION: Children with severe SNHL exhibit greater reading difficulties over time. Specifically, they seem to struggle most with phonological skills and processing speed, which affect higher level skills such as reading comprehension.

Profound hearing loss following surgery in pediatric patients with posterior fossa low-grade glioma.

BACKGROUND: Hearing loss may occur in patients with posterior fossa low-grade glioma who undergo surgery. METHODS: We retrospectively reviewed 217 patients with posterior fossa low-grade glioma, including 115 for whom results of hearing tests performed after surgery and before chemotherapy or radiation therapy were available. We explored the association of UHL with age at diagnosis, sex, race, tumor location, extent of resection, posterior fossa syndrome, ventriculoperitoneal shunt placement, and histology. RESULTS: Of the 115 patients, 15 (13.0%: 11 male, 6 black, 8 white, 1 multiracial; median age 7 years [range, 1.3-17.2 years]) had profound UHL after surgery alone or before receiving ototoxic therapy. Median age at tumor diagnosis was 6.8 years (range, 0.7-14.1 years), and median age at surgery was 6.8 years (range, 0.7-14.1 years). Patients with UHL had pathology characteristic of pilocytic astrocytoma (n = 10), ganglioglioma (n = 4), or low-grade astrocytoma (n = 1). Of these 15 patients, 4 underwent biopsy, 1 underwent gross total resection, 1 underwent near-total resection, and 9 underwent subtotal resection. UHL was more frequent in black patients than in white patients (OR 7.3, P = .007) and less frequent in patients who underwent gross total resection or near-total resection than in those who underwent subtotal resection (OR 0.11, P = .02). CONCLUSIONS: Children undergoing surgery for posterior fossa low-grade glioma are at risk for UHL, which may be related to race or extent of resection. These patients should receive postoperative audiologic testing, as earlier intervention may improve outcomes.

Auditory Outcomes in Patients Who Received Proton Radiotherapy for Craniopharyngioma.

PURPOSE: Compared to photon-based radiotherapy, protons deliver less radiation to healthy tissue resulting in the potential reduction of late complications such as sensorineural hearing loss (SNHL). We report early auditory outcomes in children treated with proton radiotherapy (PRT) for craniopharyngioma. METHOD: Conventional frequency (CF = 0.25-8.0 kHz) audiometry, extended high-frequency (EHF = 9.0-16.0 kHz) audiometry, distortion product otoacoustic emission (DPOAE) testing, and speech-in-noise (SIN) assessments were prospectively and longitudinally conducted on 74 children with a median of 2 post-PRT evaluations (range, 1-5) per patient. The median age at PRT initiation was 10 years, and median follow-up time was 2 years. Ototoxicity was classified using the Chang Ototoxicity Grading Scale (Chang & Chinosornvatana, 2010) and the American Speech-Language-Hearing Association (ASHA) criteria (ASHA, 1994). Comparisons were made between baseline and most recent DPOAE levels, with evidence of ototoxicity based on criterion reductions of ≥ 6 dB. The critical difference values for comparing SIN scores between two conditions (i.e., pre- and post-PRT) were used to determine a significant change between test scores. RESULTS: At last evaluation, no patients had SNHL in the CF range, and 2 patients had SNHL (Chang Grade 1a) in the EHF range. Based on the ASHA criteria, a decrease in hearing was observed in 0 patients in the CF range alone, in 9 patients in the EHF range alone, and in 15 patients in both the CF and EHF ranges. DPOAE levels decreased at a faster rate at higher versus lower frequencies. For 41 evaluable patients, SIN perception did not decline over time (p = .6463). CONCLUSION: At a median follow-up time of 2 years post-PRT, normal hearing was maintained within the CF range. However, subclinical decreases in hearing were observed, particularly in the EHF range and in the DPOAE level; thus, long-term follow-up is recommended to monitor for potential auditory late effects from PRT.

Approach for Classification and Severity Grading of Long-term and Late-Onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort.

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666-74. ©2016 AACR.

Hearing Loss in Patients Who Received Cranial Radiation Therapy for Childhood Cancer.

PURPOSE: Patients treated with cranial radiation therapy (RT) are at risk for sensorineural hearing loss (SNHL). Although SNHL is often characterized as a delayed consequence of anticancer therapy, longitudinal reports of SNHL in childhood cancer survivors treated with contemporary RT are limited. We report the incidence, onset, severity, and long-term trajectory of SNHL among children receiving RT. Potential risk factors for SNHL were also identified. PATIENTS AND METHODS: Serial audiologic testing was conducted on 235 pediatric patients who were treated with conformal or intensity-modulated RT as part of an institutional phase II trial for localized primary brain tumors, including craniopharyngioma, ependymoma, and juvenile pilocytic astrocytoma. All but one patient had measurable cochlear radiation dose (CRD) greater than 0 Gy. The median follow-up from RT initiation to latest audiogram was 9 years with a median of 11 post-RT audiograms per patient. Audiograms were classified by the Chang Ototoxicity Grading Scale. Progression was defined by an increase in Chang grade from SNHL onset to the most recent evaluation. RESULTS: At last evaluation, SNHL was prevalent in 14% of patients: 2.1% had mild and 11.9% had significant SNHL requiring hearing aids. Median time from RT to SNHL onset was 3.6 years (range, 0.4 to 13.2 years). Among 29 patients with follow-up evaluations after SNHL onset, 65.5% experienced continued decline in hearing sensitivity in either ear and 34.5% had no change. Younger age at RT initiation (hazard ratio [HR], 2.32; 95% CI, 1.21 to 4.46), higher CRD (HR, 1.07; 95% CI, 1.03 to 1.11), and cerebrospinal fluid shunting (HR, 2.02; 95% CI, 1.07 to 3.78) were associated with SNHL. CONCLUSION: SNHL is a late effect of RT that likely worsens over time. Long-term audiologic follow-up for a minimum of 10 years post-RT is recommended.

Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss.

Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10(-8), hazard ratio = 4.5) in 238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents.