Abstract CT122: Randomized assessment of cisplatin dose interval for ototoxicity in the treatment of locally advanced squamous cell carcinoma of the head and neck undergoing curative concurrent chemoradiotherapy (RADIO)
Authors: Winquist Eric , Meyers Brandon , Pond Greg , Hotte Sebastien , Black Morgan , Parker Christina , Nichols Anthony , Palma David , Kim Richard , Kuruvilla Sara 
Published: August 2019

Background: Recently reported randomized clinical trials (RCTs) have confirmed the importance of concurrent cisplatin in the curative treatment of HPV-related oropharynx cancer treated with definitive radiotherapy (RT) (Mehanna ESMO 2018, Trotti ASTRO 2018). However, the optimal cisplatin dose and schedule in this setting remain unclear. Concurrent high-dose cisplatin (HDC) given every 3 weeks is considered standard but associated with increased risks of infection, vomiting and nephrotoxicity (Szturz 2018). Cisplatin-associated hearing loss (CAHL) has been less well studied. Noronha et al (2018) reported less permanent deafness but inferior cancer outcomes with weekly cisplatin at a dose of 30 mg/m2 compared to HDC. However, meta-analysis of RCTs shows no difference in mortality with weekly compared to HDC (Szturz 2018). RCT results to date suggest a minimum total dose of 200 mg/m2 cisplatin be delivered at a minimum dose of 40 mg/m2 per week for optimal anticancer effect. Weekly cisplatin schedule, MATE1 polymorphisms (SNPs), absence of COMT SNPs and lower cochlear RT dose independently predict lower CAHL risk (Teft 2019). We hypothesize that if there is a small incremental antitumor benefit of HDC in oropharyngeal cancer patients who are expected to be cured, it is offset by the negative quality of life (QoL) impact of permanent hearing loss. This RCT was designed to confirm reduced ototoxicity with weekly compared to q3weekly cisplatin when combined with RT, quantitate effects on hearing-related QoL, and validate pharmacogenomic risk factors.

Methods: This randomized clinical trial will be conducted at two comprehensive cancer centres in Ontario, Canada and is open to enrollment. 100 patients will be stratified by tumor HPV status and randomized (1:1) to receive cisplatin either 100 mg/m2 IV q21days for 3 doses (control arm) or 40 mg/m2 IV weekly (experimental arm) during RT. Eligible patients will have squamous cell carcinoma of the oral cavity, oropharynx, larynx, nasal cavity, hypopharynx or unknown primary site planned for IMRT + cisplatin with curative intent after assessment by a multidisciplinary team, and must be deemed suitable for HDC by the treating medical oncologist. Patients with prior head or neck RT, baseline hearing impairment or known/suspected nasopharyngeal cancer are ineligible. RT will be once daily IMRT 5 days weekly to total dose of 70 Gy/35F (64 Gy/30F if postoperative). The trial is powered to evaluate co-primary endpoints of hearing-related QoL (by HHIA & HHIE) and CAHL grade 2 or greater (CTCAE 4.03) at 1 year. Secondary endpoints include: need for amplification, tinnitus, health-related QoL, and grade 3 or worse neuropathy and neuropathy all at 1 year. Overall and progression-free survival, locoregional control, and cost-effectiveness will also be assessed.

Citation Format: Eric Winquist, Brandon Meyers, Greg Pond, Sebastien Hotte, Morgan Black, Christina Parker, Anthony Nichols, David Palma, Richard Kim, Sara Kuruvilla. Randomized assessment of cisplatin dose interval for ototoxicity in the treatment of locally advanced squamous cell carcinoma of the head and neck undergoing curative concurrent chemoradiotherapy (RADIO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT122.