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Ototoxicity in a Randomized Phase III Trial of Intra-Arterial Compared With Intravenous Cisplatin Chemoradiation in Patients With Locally Advanced Head and Neck Cancer

Charlotte L. Zuur, Yvonne J. Simis, Pauline E. Lansdaal, Augustinus A. Hart, Jan H. Schornagel, Wouter A. Dreschler, Coen R. Rasch, Alfons J. Balm

From the Department of Otorhinolaryngology and Department of Audiology, Academical Medical Centre; and the Department of Head and Neck Oncology and Surgery, Department of Radiation Therapy, and Department of Medical Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands

Address reprint requests to Charlotte L. Zuur, MD, Department of Otorhinolaryngology, 1D-116, VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands; email: cl.zuur{at}vumc.nl

Purpose Cisplatin concomitantly administered with radiotherapy is increasingly used in locally advanced head and neck squamous cell carcinoma. We aimed to compare the incidence of hearing loss between patients treated with intra-arterial high-dose cisplatin chemoradiation with sodium thiosulfate (CRT-IA) and intravenous high-dose cisplatin chemoradiation without sodium thiosulfate (CRT-IV).

Patients and Methods We conducted a prospective analysis of hearing thresholds at low and (ultra-) high frequencies obtained before, during, and after treatment in 158 patients. Patients were randomly assigned for either CRT-IA (150 mg/m², four courses) with sodium thiosulfate cisplatin neutralization or CRT-IV (100 mg/m², three courses) without rescue. All patients received concomitant radiation therapy (RT; 70 Gy).

Results CRT-IA resulted in approximately 10% less hearing loss at frequencies vital for speech perception, compared with CRT-IV (P < .001). In CRT-IA, fewer ears qualified for hearing aids (36% v 49%; P = .03). However, in both treatment arms, the incidence expressed in National Cancer Institute Common Terminology Criteria of Adverse Events (version 3) did not deviate (P > .14). Age, cumulative cisplatin dose, cumulative RT dose, and the considered frequency area determine the degree of hearing loss (P < .001). Cisplatin induced increasing hearing loss of 24% to 60% with increasing frequencies. RT induced hearing loss at speech frequencies of 9% to 12%.

Conclusion Depending on the criteria used to assess hearing loss due to treatment, differences in ototoxicity between CRT-IA and CRT-IV were found in favor of CRT-IA. It is desirable to specify hearing loss criteria toward frequencies vital for speech perception, and to refine grading scales to reveal subtle and clinically relevant dissimilarities in ototoxicity between different treatment protocols.

Presented in part at the International Workshop on Intra-Arterial Chemotherapy for Head and Neck Cancer, August 20-22, 2006, Springfield, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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