PLATINUM OTOTOXICITY
July 5, 2012 — Platinum-based chemotherapy is widely used in the treatment of adult and pediatric cancers, but cisplatin is responsible for hearing loss in at least 60% of children treated with it. Research is needed to reduce the incidence of platinum-induced hearing loss while optimizing cancer control, according to the authors of a review paper published in the July 1 issue of the Journal of Clinical Oncology.
The authors, led by Edward A. Neuwelt, MD, from Oregon Health & Science University in Portland, summarize the recommendations that were made at the Congress of the International Society of Paediatric Oncology (SIOP) in 2010.
They point out that mechanisms are needed to foster translation from basic science to clinical practice. In addition, more research is needed on the mechanisms of platinum ototoxicity and the trafficking of platinum to cochlear sensory cells.
"Collaboration between the pharmacogenomic community and basic scientists to investigate potential new pathways and biologic understanding could result in novel strategies," they write.
Dr. Neuwelt and his coauthors note that the advent of new technologies and reductions in cost "make relevant pharmacogenomic research possible." Such research includes identifying genotypes that are at high risk for ototoxicity and collecting DNA samples to study hearing loss.
Currently, Dr. Neuwelt recommends that clinicians continue to follow the standard of care, which is to continually monitor children who are being treated with cisplatin. "Many of these children get high-frequency hearing loss, which means they have difficulty hearing in a noisy classroom," he said in an interview with Medscape Medical News.
"Even though these effects may appear mild on an audiogram, they can have a profound effect on quality of life," he said.
In adults, sodium thiosulfate has been shown to be effective in preventing the ototoxic effects of carboplatin, Dr. Neuwelt explained. "There are good data for adults, but we don't know if that is going to be the case with children."
A phase 3 trial from the Children's Oncology Group is evaluating whether sodium thiosulfate can prevent hearing loss in children who receive cisplatin chemotherapy for newly diagnosed cancers. "The accrual has completed," said Dr. Neuwelt, and "we are waiting for the results."
Genetic Variants Identified
As previously reported by Medscape Medical News, researchers were able to identify genetic variants associated with ototoxicity that occurs in more than half of children treated with cisplatin. That study analyzed almost 2000 single-nucleotide polymorphisms to identify variants of 220 genes that influence the "absorption, distribution, metabolism, and elimination" of drugs and drug metabolites, and any association with cisplatin ototoxicity. Variants of the TPMT and COMT genes were found to be strongly associated with cisplatin-induced hearing loss.
Recommendations put forth in the review by Dr. Neuwelt and colleagues include developing novel clinical trial designs that increase the power of studies and decrease the sample size needed to demonstrate effect. Audiologic results are a key end point in studies of otoprotective agents; they can provide the phenotypes for pharmacogenomic ototoxicity research. Thus, Dr. Neuwelt and colleagues note, it is critical that high-quality reliable audiologic data be obtained.
It is also essential to develop international standards for grading and comparing ototoxicity; these are key to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss, according to the authors.
New SIOP Scale
In their review, the authors propose a new SIOP Boston scale to grade and classify ototoxicity, which is based on sensorineural hearing thresholds. This new scale "combines the best elements from all the assessment criteria."
"The SIOP Boston ototoxicity scale is being validated on existing data that include international multicenter audiologic results in very young children treated with cisplatin," the authors note, adding that the results will be compared directly with existing scales. This will help determine if the SIOP scale better correlates with functional outcomes and if it offers improved simplicity and interrater reliability.
The SIOP scale will be recommended only if the study outcomes are positive, they add.
The Proposed SIOP Boston Ototoxicity Scale
| Grade | Hearing Loss (HL) or Sensorineural HL (SNHL) Measurement Parameters |
| 0 | ≤20 dB for all frequencies |
| 1 | >20 dB HL SNHL above 4000 Hz |
| 2 | >20 dB HL SNHL at 4000 Hz and above |
| 3 | >20 dB HL SNHL at 2000 Hz or 3000 Hz and above |
| 4 | >40 dB HL SNHL at 2000 Hz and above |
The grading scale proposed by Dr. Neuwelt and colleagues is based on absolute hearing level, rather than change from baseline, note the authors of an accompanying editorial.
"It further refines and simplifies the characterization of hearing loss from that of the 1991 Brock et al and the 2010 Chang and Chinosornvatana scales," write James G. Gurney, PhD, and Johnnie K. Bass, AuD, CCC-A, both from St. Jude Children's Research Hospital in Memphis, Tennessee.
This new SIOP scale is simpler and potentially better than the previous ones, but it is "certainly not transformative," they note. Several of the problems related to use and application that existed in previous scales persist in this tool. This raises several questions, the editorialists explain.
One question is how grading should be coded for incomplete testing and/or objective measurements, such as otoacoustic emissions or auditory evoked potentials that are necessary for testing in some children. Also, it is unclear how the confounding impact of a conductive overlay or of cranial radiation exposure will affect grading.
Other issues, they point out, are how asymmetric hearing loss (worst ear vs best ear) should be coded to define an outcome measure, and what grade of hearing loss is clinically important as a cutoff point to define an adverse event in clinical trials.
"These concerns are not directly addressed in the SIOP or other hearing loss scales per se, but their impact can lead to erroneous grading, potentially affecting treatment decisions and clinical trial outcome measures to assess efficacy of otoprotective agents or to define dose-limiting adverse events," the editorialists write.
Finally, they point out that cranial radiation therapy and platinum-based chemotherapy are commonly used together in the pediatric setting, and from a grading perspective, radiation-induced hearing loss is more complicated than cisplatin-induced hearing loss. In addition, the risk of hearing loss increases when cranial radiation is combined with platinum-based chemotherapy, and it is generally considered to be a late-onset adverse effect, sometimes occurring several years after treatment.
The paper was supported by grants from National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH); the National Cancer Institute, NIH; and by funding from the Walter S. and Lucienne Driskill Foundation. The authors and editorialists have disclosed no relevant financial relationships.
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