Critical need for international consensus on ototoxicity assessment criteria.

With advances in the treatment of pediatric cancers, it is possible to focus on increasing long-term survival as well as reducing the toxicities associated with treatment. Cisplatin chemotherapy is effective in the treatment of several types of pediatric cancers, but is among the most ototoxic drugs known. Permanent, typically highfrequency, bilateral hearing loss occurs in 20% to 90% of children who receive cisplatin chemotherapy. The clinical study of cisplatin ototoxicity has been confounded by variability in the assessment and evaluation of ototoxic hearing loss, as pointed out by Chang and Chinosornvatana. Young children are at the greatest risk for acquiring hearing loss from cisplatin. Infants and young children are at a critical stage of development in which hearing loss can negatively impact speech and language development and literacy. In older children and adolescents, high-frequency hearing loss impacts educational achievement, social-emotional development, and quality of life. Hearing aids and other assistive technology are extremely helpful after hearing loss occurs, but hearing aids do not completely correct hearing loss. In a study of survivors of childhood neuroblastoma, children with hearing loss had twice the rate of parent-reported difficulties with reading skills, math skills, and/or attention. Hearing loss was also associated with poorer scores in child-reported quality of life in the area of school functioning. Ototoxicity reduces the utility of cisplatin therapy by limiting dose escalation and even causing dose reduction or discontinuation of therapy. Additionally, novel strategies to enhance cisplatin cytotoxicity, such as lowering glutathione in tumor cells, cannot be implemented in patients if such approaches concomitantly exacerbate cisplatin ototoxicity. A strategy for effective otoprotection would be a significant advance, not only for maintaining patients’ quality of life but also for improving treatment efficacy and possibly chemo-enhancement treatment strategies. Protection against platinum-induced hearing loss has been achieved in animal models and patients, with sodium thiosulfate (STS). These results provided key information for two recently activated phase III randomized clinical trials evaluating STS for the prevention of cisplatin-induced hearing loss in children with a variety of malignancies: one by the Children’s Oncology Group (study ACCL0431), and one by the International Tumor Strategy Group SIOPEL (study CCLG-LT-2007-03). Both of these studies are ongoing and currently enrolling patients; further information can be found at the NCI PDQ Clinical Trials Web site (http://www.cancer .gov/search/ResultsClinicalTrials.aspx? protocolsearchid 7215792). Several other thiol-based agents, including N-acetylcysteine and d-methionine, have shown otoprotection in animal models. In contrast, amifostine failed to prevent hearing loss in multiple clinical trials, with one exception that showed some otoprotection with a higher dose of amifostine. There are important challenges that must be addressed as otoprotective agents are studied in patients. In this issue of Journal of Clinical Oncology, Chang and Chinosornvatana illustrate the limitations of existing ototoxicity grading systems and their application to pediatric patients. The authors present new ototoxicity criteria that correlate well with functional outcomes. Several different ototoxicity criteria have been developed over the years. Cancer treatment studies in the United States typically evaluate ototoxicity as an adverse event based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). By tradition, published clinical studies usually report only grade 3 and 4 CTCAE toxicities, yet this underestimates the incidence of communicatively and developmentally significant hearing loss in children. The CTCAE version 3.0 definition of grade 3 pediatric ototoxicity is: “hearing loss sufficient to indicate therapeutic intervention, including hearing aids and requiring additional speech-language related services. ” This definition is not adequately objective. Indication for hearing aid amplification and related services does not depend solely on the audiogram. The child’s age, speech and language development, presence of other conditions, and educational functioning are important factors. When amplification is indicated, the recommendation for hearing aids may be delayed until therapy is completed, when the hearing loss has stabilized and when the family and child can focus on managing the hearing loss. This may introduce variability in reported CTCAE grades depending on who is responsible for assigning and reporting institutional ototoxicity grades and what information is available. The CTCAE version 4.0 definitions of grade 2 and 3 pediatric ototoxicity have been revised for greater objectivity. The American Speech-Language Hearing Association Ototoxicity Criteria (ASHA) were developed as a sensitive index of measurable change in hearing due to ototoxic therapy, and these can be applied to the extended high frequencies ( 8,000 Hz). Hearing thresholds during treatment are monitored and compared with the patient’s baseline evaluation. However, it is not always possible to obtain a complete baseline assessment in children who are young, sick, or who require immediate treatment. The most significant limitation of the ASHA criteria is the lack of a grading scale to indicate severity of acquired hearing loss. Change in hearing by ASHA criteria does not necessarily indicate communicatively significant hearing loss. The Brock criteria were specifically designed to evaluate platinum-induced hearing loss in children to compare ototoxicity in clinical trials. They have been widely used prospectively in pediatric trials both in Europe and internationally to measure platinum ototoxicity. A baseline evaluation is not required. Hearing loss grades 0 to 4 are assigned based on the standard pure-tone audiologic frequencies Editorials