A Prospective Analysis of Ototoxicity in Modern Radiation Therapy Treatments for Head and Neck Squamous Cell Carcinoma (HNSCC) Patients Receiving Concomitant Chemo-Radiation (CRT) with Weekly or Tri-weekly Cisplatin (Cis)

Abstract

Radiation therapy can be ototoxic and dose constraints to the cochlea – mean <45Gy will give ∼<30% sensory-neural hearing loss. Cis is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Little is known about the incidence of hearing loss when using different cisplatin regimens in patients receiving concomitant CRT with modern day radiation therapy techniques. Therefore, we assessed prospectively the incidence of ototoxicity in patients receiving weekly or tri-weekly Cis concomitantly with volumetric modulated arc radiotherapy (VMAT). HNSCC patients receiving definitive or adjuvant cis-based CRT were included. Cis was administered weekly (40 mg/m2 weekly, total 7 cycles) or tri-weekly (100 mg/m2 every three weeks, total 3 cycles). Radiation was administered to a total dose of 70 Gy for definitive treatment or 66 Gy for adjuvant treatment (2 Gy/fraction). Intensity-modulated radiation therapy was used in all cases. Pure-tone air-conduction audiometry was performed in all patients before and after completion of CRT. The primary endpoint of the analysis was Common Terminology Criteria for Adverse Event (CTCAE v4.0) hearing change ≥3 at the completion of CRT. The cochlea was contoured by one dosimetrist and assessed by two physicians for accuracy. A total of 96 patients (M:77/F:19) were included (56 oropharynx patients and 40 non-oropharynx HNSCC)). The median age was 55 years (range 26-78) 68 patients received weekly cis and 28 received the tri-weekly regimen. 58 patients received definitive treatment and 38 adjuvant treatment. Nine patients (13%) receiving weekly cis experienced G3 ototoxicity vs 14 patients (50%) who received tri-weekly cis (p<0.001, OR=6.4, 95% CI= 2.1-20.7). Risk of ototoxicity was not associated with age, cis cumulative dose, sex, tumor primary site, or CRT modality (definitive vs. adjuvant). After adjusting for these factors in a multivariable model cis schedule remained significant (OR=8.7, 95% CI 2.31-32.75, p=0.001). With a minimum follow-up of three months, the complete response rate after treatment was 84% for weekly CRT and 86% for tri-weekly CRT (p=NS). Cochlear mean dose of 13.76 Gy +/- 8.5 Gy to bilateral cochlea was achieved. With mean cochlear doses of ≤ 22Gy bilaterally, tri-weekly Cis-based CRT increased the risk of grade 3 irreversible severe ototoxicity compared to weekly Cis. This risk of ototoxicity should be discussed with patients that are candidates for cis-based CRT.