New International Society of Pediatric Oncology Boston Ototoxicity Grading Scale for Pediatric Oncology: Still Room for Improvement

Best known for its remarkable effectiveness in successfully treating testicular cancer in adults, cisplatin is a platinum-based chemotherapeutic agent used in many multimodal pediatric cancer treatment regimens. Children with neuroblastoma, hepatoblastoma, retinoblastoma, germ cell tumors, osteosarcoma, medulloblastoma, and other brain tumors are routinely treated with cisplatin, and/or its newer and less toxic analog, carboplatin. The mechanism of action of these drugs involves covalent binding to purine DNA bases, leading to cellular apoptosis. The dose-limiting factors in the administration of platinum-based drugs are generally nephrotoxicity (cisplatin) or myelosuppression (carboplatin), but cisplatin in therapeutic doses is highly ototoxic. Carboplatin, although with substantially less ototoxic potential than cisplatin, is associated with a high risk for hearing loss when used in combination with cisplatin and when used in myeloablative doses as conditioning for hematopoietic stem-cell transplantation in children. Ototoxicity from cisplatin manifests initially as bilateral high frequency sensorineural hearing loss, progressing in severity to the speech ranges with increasing cumulative doses. The hearing loss is caused by sensory hair cell destruction that begins at the base of the cochlea, where high frequency sounds are processed, and continues toward the cochlear apex, where lower frequency sounds are affected. Hearing loss from cisplatin or carboplatin is permanent and may have a delayed onset, with progressive loss occurring many years after completion of therapy. Young children are particularly sensitive to this unfortunate adverse effect. Children treated for high-risk neuroblastoma, for example, are likely to sustain moderate to severe therapy-related hearing loss, with high potential for difficulties in speech discrimination and language acquisition, diminished academic achievement compared with peers with normal hearing, the potential for lifelong impairment of language and academic skills, and diminished quality of life. Although often underappreciated, even hearing loss restricted to high frequency ranges (4,000-8,000 Hz) can have a significant impact on language development, verbal abilities, and reasoning skills in young children. This is of particular concern with patients treated in early childhood for embryonal malignancies because the ototoxic effects are concurrent with the developmental period in which the process of acquiring speech and language skills is so critical. As described by Brock et al in this issue of Journal of Clinical Oncology, efforts to find a method to prevent or mitigate the ototoxic effect of therapeutic doses of platinum drugs in children without diminishing its effectiveness in killing cancer cells is ongoing but has yet to be realized in the clinical setting. One of the key issues in designing a clinical research study to evaluate preventative interventions is having a valid and reliable outcome measure that is standardized, practical, and widely accepted. Such a hearing loss measure needs to reflect the unique aspects of testing children of different ages and capabilities. Although in 1991 Brock et al published a pediatricspecific hearing loss scale for cisplatin exposure, the measure used to monitor and categorize severity of hearing loss in therapeutic trials has been the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 3.0, which requires a baseline evaluation before treatment initiation and then measures change in hearing level as treatment progresses. The NCI-CTCAE v3.0 scale was not specialized to children and has many inherent problems for clinical research purposes, including the fact that baseline measurements are often difficult to obtain in pediatric patients, particularly in very ill patients. In addition, obtaining true auditory thresholds (response to lowest intensity level) can be challenging in pediatric patients. Instead, only minimal response levels are often obtainable, which makes calculating a true decrease in hearing sensitivity difficult and potentially inaccurate. The NCI-CTCAE v3.0 also does not specify test frequencies. Greater emphasis should be placed on the higher frequencies than the lower frequencies when determining cisplatin-induced ototoxicity in children. NCI-CTCAE v3.0 toxicity grades 3 and 4, usually dose-limiting in clinical trials, are defined by subjective measures that are left to interpretation and may differ among audiologists. Although the most recent version of the NCICTCAE, version 4.03, significantly improves on the previous 3.0 version by identifying specific test frequencies for pediatric patients and defining more objective measures, problems with measuring change in hearing compared with baseline measurements and the somewhat subjective nature of defining grades 3 and 4 still remain. Several other hearing loss grading scales have been introduced over the years, as shown in Table 1, including a modification of the 1991 Brock et al scale by Chang and Chinosornvatana in 2010. In the new measure presented by Brock et al, a grading scale based on JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 19 JULY 1 2012