Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale

Abstract

Purpose: The platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important.

Patients and methods: This review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection.

Results: Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally involves antioxidant thiol agents. Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects. Route of administration and optimal timing relative to platinum therapy are critical issues. In addition, international standards for grading and comparing ototoxicity are essential to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss.

Conclusion: Collaborative prospective basic and clinical trial research is needed to reduce the incidence of irreversible platinum-induced hearing loss, and optimize cancer control. Wide use of the new internationally agreed-on SIOP Boston ototoxicity scale in current and future otoprotection trials should help facilitate this goal.

Fig 1.

Model of the cochlea and cisplatin (Pt) trafficking routes. Potential pathways for systemic Pt to cross the blood-labyrinth barrier and enter hair cells include (1) a trans-strial trafficking route from strial capillaries to marginal cells, followed by clearance into endolymph; (2,3) traversing the blood-labyrinth barrier into perilymph and subsequently into endolymph via transcytosis across the epithelial perilymph/endolymph barrier. (4) Once in endolymph, Pt enters hair cells across their apical membranes. (5) Pt in the scala tympani could also pass through the basilar membrane into extracellular fluids within the organ of Corti and enter hair cells across their basolateral membranes. S, stria vascularis; F, fibrocytes in spiral ligament (data adapted).

Fig 2.

Kaplan-Meier graph of cisplatin ototoxicity and number of thiopurine S-methyltransferase (TMPT) and catechol-O-methyltransferase (COMT) risk alleles. An increasing number of TPMT rs12201199 and COMT rs9332377 risk alleles is associated with earlier onset of cisplatin-induced hearing loss (P < .001) and with more severe cisplatin-induced hearing loss (P < .001; adapted by permission from Macmillan Publishers: Nature Genetic, 2009).

Fig 3.

Chemoprotection studies. (A) Effect of sodium thiosulfate (STS) and cisplatin on subcutaneous human neuroblastoma xenograft growth. Nude mice were inoculated subcutaneously with 3.2 × 10⁷ SMS-SAN neuroblastoma cells and were treated with no treatment (blue circles; n = 5), cisplatin 4 mg/kg intraperitoneally (IP) × 4 days (gold squares; n = 6), cisplatin 4 mg/kg per day × 4 days plus STS 3.5 g/kg per day IP × 4 days immediately (0 hours) after cisplatin (gray squares; n = 6), or cisplatin 4 mg/kg per day IP × 4 days plus STS 3.5 g/kg per day IP × 4 days at 6 hours after cisplatin (red triangles; n = 6). Tumor volumes were measured twice per week (data adapted). (B) Time to tumor progression (tumor volume of > 600 μL or last measurement taken) was determined. The probability of progression-free survival for the four treatment groups was determined by using the permutated log-rank test. STS given 6 hours after cisplatin daily for 4 days did not significantly (P = .9) affect cisplatin antitumor activity in SMS-SAN xenografts in athymic nu/nu mice compared with cisplatin alone. However, STS given simultaneously with cisplatin daily for 4 days did significantly (P = .03) protect tumors from cisplatin (data adapted). (C) Cisplatin induced changes in auditory brainstem response (ABR) threshold when STS was given at 4, 8, or 12 hours after cisplatin in a rat model. As illustrated, delay of 4 or 8 hours was highly otoprotective, whereas delay of 12 hours was not otoprotective (data adapted). (D) Comparison of threshold shift against carboplatin treatment number (at 4,000 Hz) in historical comparison patients who received carboplatin without STS and in patients treated with STS delayed 2 hours or 4 hours after carboplatin. There was a significant difference between the STS treatment groups and the historical comparison control group (P = .0075; Adapted and reprinted by permission from the American Association for Cancer Research). BBBD, blood-brain barrier disruption.