CLINICAL INVESTIGATION Head and Neck RELATIVE CONTRIBUTIONS OF RADIATIONAND CISPLATIN-BASED CHEMOTHERAPY TO SENSORINEURAL HEARING LOSS IN HEAD-AND-NECK CANCER PATIENTS YING J. HITCHCOCK, M.D.,* JONATHAN D. TWARD, M.D., PH.D.,* ANIKO SZABO,PH.D., y BRANDON G. BENTZ, M.D., z AND DENNIS C. SHRIEVE, M.D., PH.D.* Departments of *Radiation Oncology, y Biostatistics, and z Otolaryngology–Head and Neck, Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT Purpose: To investigate the risk of sensorineural hearing loss (SNHL) in patients with head-and-neck cancer and treated with radiation therapy (RT) or concomitant cisplatin-based chemoradiation, the relationship among SNHL and radiation dose to the cochlea, the use of two common cisplatin dose regimens. Methods and Materials: A total of 62 head-and-neck cancer patients treated with curative intent were included in this prospective study. Of the patients, 21 received RTalone, 27 received 40 mg/m 2 weekly cisplatin, 13 received 100 mg/m 2 every 3 weeks during RT, and 1 received RTwith weekly epidermal growth factor receptor inhibitor anti- body. The effect of chemotherapy and RT dose on hearing was determined using a model that accounted for the age and variability between each ear for each patient. Results: We constructed a model to predict dose-dependent hearing loss for RTor cisplatin-based chemotherapy either alone or in combination. For patients only receiving RT, no significant hearing loss was found at doses to the cochlea of less than 40 Gy. Patients receiving 100 mg/m 2 or 40 mg/m 2 of cisplatin chemotherapy had an estimated +21.5 dB and +9.5 dB hearing loss at 8,000 Hz with low radiation doses (10 Gy), which rose to +38.4 dB and +18.9 dB for high radiation doses (40 Gy). Conclusions: Use of RT alone with doses of less than 40 Gy did not result in clinically significant hearing loss. High- frequency SNHL was profoundly damaged in patients who received concomitant cisplatin when doses of 100 mg/m 2 were used. The threshold cochlear dose for hearing loss with cisplatin-based chemotherapy and RT was predicted to be 10 Gy. The inner ear radiation dose constraints and cisplatin dose intensity should be considered in the treat- ment of advanced head-and-neck cancer. Published by Elsevier Inc. Head and neck cancer, Radiation therapy, Chemotherapy, Sensorineural hearing loss. INTRODUCTION Radiation therapy (RT) or combined chemoradiation therapy has demonstrated improvement of locoregional control and organ preservation in locally advanced head-and-neck cancer (1–4). Long-term survivors of cancers of the head and neck can experience sensorineural hearing loss (SNHL) induced by radiation, chemotherapy, or a combination of both. The cochleae typically reside within the high–RT dose–vol- ume region of conformal RT plans when treating high-neck or base-of-skull malignancies, such as those in the nasopharynx, parotid, paranasal sinus, brain, or the area covering the para- pharyngeal space and pterygo-palatine fossa. The RT dose to the cochleae can be reduced by specifically excluding this region from three-dimensional conformal treatment plans or by the placement of dose constraints for intensity-modulated RT (IMRT) plans. Permanent SNHL resulting from treatment effects has resulted in worsening of the quality of life and is correlated with cognitive impairment (5–7). Using an animal model, the threshold of the severity of impairment was shown to be between 40 and 90 Gy (22). The severity of damage in- creased with increasing dose of radiation. The degree of dam- age found in many of these ears was of sufficient magnitude to produce a permanent SNHL. Prospective or retrospective reports from patients with head-and-neck cancer have also demonstrated SNHL associated with cumulative radiation dose to the cochlea (7–17). Although long recognized as an important side effect, the relative contribution to SNHL from RT alone, chemoradia- tion, and the dose–effect relationship for radiation with or without cisplatin-based chemotherapy remain undefined. This study was undertaken to quantify the magnitude of SNHL in a group of patients receiving these therapies. Reprint requests to: Ying J. Hitchcock, M.D., Department of Ra- diation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle of Hope, Salt Lake City, UT 84112. Tel: (801)581- 2396; Fax: (801) 585-3202; E-mail: Ying.hitchcock@hci.utah.edu Conflict of interest: none. Received Oct 2, 2007, and in revised form May 6, 2008. Accepted for publication May 7, 2008. 779 Int. J. Radiation Oncology Biol. Phys., Vol. 73, No. 3, pp. 779–788, 2009 Published by Elsevier Inc. Printed in the USA. 0360-3016/09/$–see front matter doi:10.1016/j.ijrobp.2008.05.040