Efficacy and safety of flunarizine in preventing ototoxicity associated with cisplatin-based concurrent chemoradiotherapy in head and neck cancer patients: a phase II single-arm study

Cisplatin-based concurrent chemoradiotherapy (CRT) is the standard of care for locally advanced head and neck cancer (HNC) as a definitive or adjuvant therapy. This approach has been associated with a 6.5% improvement in overall survival (OS) and enhanced locoregional control when compared to radiotherapy (RT) alone. However, Cisplatin and RT carry a significant risk of ototoxicity, with 53% developing grade two (G2) or higher hearing loss through audiometry. Pre-clinical studies have suggested that Flunarizine may offer otoprotective benefits. This is a unicentric, non-comparative, open-label, phase II clinical trial conducted to assess the otoprotective efficacy and safety of Flunarizine in patients undergoing Cisplatin-based CRT (100mg/m2 IV every 21 days), with the aim of reducing G2 or higher ototoxicity by 20%. Patients received Flunarizine for 21 days prior to CRT, continued throughout the course of CRT, and extended up to three months post-CRT. The primary endpoint was acute and late ototoxicity. Secondary endpoints included objective response rate, safety profile, quality of life and OS. Between October 2019 and December 2022, 91 patients were screened, and nine were enrolled. The high screening failure was due to the high prevalence of pre-existing hearing loss (36.3%): 17.6% symptomatic and 18.7% asymptomatic hearing loss (detectable only through audiometry). The median follow-up was 57.5 months. Flunarizine most frequent adverse events were weight loss (88.9% G1, 11.1% G2 e 22.2% G3), xerostomia (44.4% G1, 11,1% G2 e 11.1% G3), decreased appetite (33.3% G1, 33,3% G2 e 11,1% G3) and drowsiness (33.3% G1). At the three-month post-CRT assessment, audiometry was performed on five patients, all of them (5/5) exhibited G2 or higher hearing loss. One patient (14.3%) had G1 hearing loss and one patient (14.3%) had G1 tinnitus. At the six-month post-CRT assessment, seven patients underwent audiometry, and five patients (71%) had G2 or higher hearing loss. The objective response rate was 66.67%. All patients achieved complete response. Three patients (33%) had disease progression and died due to cancer. The median OS was not reached, and two year OS rate was 66.6%. Due to the lack of otoprotective effect observed in the interim analysis, the study was prematurely terminated for futility. This phase II trial demonstrated that Flunarizine did not confer any otoprotective benefit in patients undergoing Cisplatin-based concurrent CRT for locally advanced HNC.

Corresponding author: Katia Regina Marchetti (e-mail: katia.marchetti96@gmail.com).