Research Labs
The Evaluation, Management, and Prevention of Cisplatin Ototoxicity in Pediatric Patients.
Cisplatin is a commonly administered chemotherapeutic agent in multiple pediatric neoplasms. The ototoxicity of this agent is well-documented, though poorly characterized. Reports of ototoxicity rates in children vary from 1% to 82%. This disparity is due to extreme variability between institutions in the audiologic assessment of sick pediatric patients, as well as the lack of a well established and clinically validated classification for degrees of ototoxicity. The Common Terminology Criteria for Adverse Events (CTCAE v3.0) widely used by oncologists, fails to classify ototoxicity in a clinically consistent, or relevant manner.
Due to a lack of a robust grading system for ototoxicity, it is difficult to design ototoxicity studies in patients that can be easily compared to other studies. I have developed a more clinically useful grading system for pediatric ototoxicity and have validated it to a large 5-year cohort of children treated by the Lucile Packard Children’s Hospital (LPCH) at Stanford Pediatric Oncology department. By examining details such as dose delivery schedule and co-administered drugs, a number of interesting revelations regarding optimal methods of reducing ototoxicity in children have been discovered, and will be presented at the next ASCO meeting.
As an active member of the Children’s Oncology Group (COG), a national organization involved in improving the oncologic care of children, I have been intimately involved in the ototoxicity assessment of multiple large multi-institutional studies administered by COG (including the Intergroup Hepatoblastoma Study P9645 and the ARAR0331 Nasopharyngeal Carcinoma Study). This grading system has been a valuable tool and has helped to improve methodologies for accurately assessing and characterizing ototoxic effects. This is particularly important since children seem to be much more susceptible to ototoxicity than adults. Furthermore, while the effects of ototoxicity may be quite limited in adults who have mastered speech and language, in pre-lingual young children, ototoxicity may result in severe speech delay and the inability to ever assume a normal role in society. So while the children may be cured of their cancer, they really never fully recover from their treatment to live normal unhindered lives.
While accurately monitoring cisplatin ototoxicity may provide some insights into improved dosing strategies for reducing adverse effects in children, a more exciting approach is actual prevention of ototoxicity by administering various “otoprotective” agents. In the course of investigating the protective effect of the anti-oxidant N-acetylcysteine in the guinea pig cochlea, my laboratory discovered a novel otoprotective effect induced by the transtympanic administration of lactate to the middle ear. In this experiment, guinea pigs treated with cisplatin that were administered either lactated Ringer’s solution or N-acetylcysteine had significantly improved cochlear function, as measured by DPOAE, compared to the normal saline and negative control groups (see figure). Currently, with the collaboration the LPCH Pediatric Oncology department, standardized protocols utilizing my grading scale are being developed to investigate these as well as other otoprotective agents, including EPO and several gene therapy agents. Our goal is with these efforts is to eliminate this most devastating late-effect of chemotherapy in young children.
Figure Legend:
Mean post-treatment DPOAE data. Stimulus parameters were L 2 = 55 dB and F 2 ranging from 2 to 16 kHz. Error bars represent one SEM, and are plotted for the Control and LR groups; however they were comparable across all 4 groups (average SEM across frequencies measured 2.88, 3.27, 2.93, and 2.78 for the 4 groups). The light dotted line at the bottom of the graph represents the average noise floor during emission recording.
