Acute Toxicity Results from the Randomized Assessment of Cisplatin Dosing Interval for Ototoxicity (RADIO) Trial Comparing Chemoradiation (CRT) with Cisplatin Q3weekly to Weekly for Locally Advanced Squamous Cell Carcinoma of the Head and neck (LASCCHN)

Purpose/Objective(s) The acute toxicities of CRT for LASCCHN patients (pts) remain challenging and may be influenced by the type and schedule of radiosensitizer. We report adverse effects (AEs) observed during CRT with different cisplatin schedules on the RADIO trial. Materials/Methods Adult pts ECOG 0-2 eligible for RADIO had histologically confirmed LASCCHN of oral cavity, oropharynx, nasal cavity, hypopharynx, larynx or PUK; were planned for primary curative CRT; had adequate baseline hearing and were suitable for q3weekly cisplatin. Pts received RT 70 Gy/35 fractions to gross disease and were randomized (stratified by tumor p16 status) to concurrent cisplatin either 100 mg/m2 days 1, 22 and 43 or 40 mg/m2 weekly x 7 weeks. Co-primary outcomes for RADIO were incidence of hearing loss determined by audiogram and hearing-related QoL both measured 1-year from start of treatment. Secondary outcomes included need for amplification, HRQoL and incidence of tinnitus, neuropathy and nephropathy. AEs were recorded prospectively using CTCAE v4.03 grading criteria. All pts provided informed consent for this REB approved trial. Results 99 eligible pts (85 males/14 females) median age 61 years (40-75) were enrolled at 3 centers in Ontario, Canada between Feb 2019 to June 2023. Baseline pt characteristics were well balanced between treatment arms. Most pts had oropharyngeal cancer (87%) and most tumors were p16-positive (93%). 50 pts received cisplatin q3weekly for 3 (74%), 2 (22%) or 1 cycle (4%); mean total dose 251.2 mg. 49 pts received weekly cisplatin for a median of 6 cycles (range, 3-7); mean total dose 247.3 mg. There were no treatment-related deaths. 87 pts had currently available AE data and most had multiple typical Grade 1-2 AEs. 7 pts (8%) reported only Grade 1 AEs. 33 pts (37.9%) reported 72 AEs ≥Grade 3: 32/15 pts treated q3weekly, and 40/18 pts treated weekly. More pts receiving q3weekly cisplatin had Grade 3 neutropenia (5 vs 2 pts) and AKI (2 vs 0 pts). More pts receiving weekly cisplatin had Grade 3/4 AEs (18 vs 15), Grade 3 dysphagia/mucositis (8 vs 4 pts) and anemia (2 vs 0 pts). One pt each on the weekly cisplatin arm had Grade 3 pulmonary embolism, Grade 4 acute psychosis and Grade 4 thrombocytopenia. Similar rates of acute Grade 3 dehydration, electrolyte disturbances, and weight loss were observed; as well as pt-reported ≥Grade 2 hearing impairment (8 vs 6 pts) and peripheral neuropathy (2 vs 2 pts). Conclusion RADIO participants had similar total cisplatin exposure by treatment arm. There were some differences in acute toxicity patterns related to cisplatin schedule. Severe neutropenia and AKI appeared to be more frequent with q3weekly cisplatin, and total severe AEs including dysphagia/mucositis and anemia appeared higher with weekly cisplatin. AE data continue to be collected and will be reported. Precise conclusions about ototoxicity differences will be made based on the definitive 1-year primary audiometric and QoL endpoints of RADIO which will be analyzed and reported in 2024. (NCT03649048)