The efficacy and safety of ulinastatin in the prevention and treatment of radiotherapy-induced oral mucositis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC): A multicenter, open-label, randomized controlled clinical trial.
Authors: Wang Lin , Wang Xu-Guang , Wu Haijun , Lei Feng , Liu Zhigang , Shen GuanZhu , Ye YiJing , Zhu Manyi , Huang Huageng , Huang RunDa , Chen Boyu , Zhao Chong , Miao Jingjing 
Published: July 2024

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Background: Severe oral mucositis is a common radiation-induced toxicity in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients treated with concurrent chemo-radiotherapy (CCRT). Ulinastatin (UTI) can reduce the inflammatory response by inhibiting the release of inflammatory factors, but its role in radiotherapy-induced oral mucositis (RTOM) is unclear. Therefore, we conducted a multicenter, open-label, randomized controlled clinical trial to investigate the efficacy and safety of UTI in the prevention and treatment of RTOM in LA-NPC patients. Methods: Patients with histologically confirmed LA-NPC who met the eligibility criteria were randomly assigned to UTI group and control group. All patients received radical intensity modulated radiation therapy (IMRT) and concurrent chemotherapy (cisplatin 100 mg/m2/3 weeks for 2 or 3 cycles). UTI of 100,000 units three times daily (5 days/week) was intravenously administrated from day 1 to the end of radiotherapy for UTI Group. The primary endpoint was the incidence of grade ≥ 3 acute RTOM during CCRT (Radiation Therapy Oncology Group, RTOG grading). The secondary endpoints included the cumulative incidence of RTOM, recovery rate (proportion of patients with grade ≥ 3 RTOM who recovered to grade ≤ 2 during CCRT), the onset time and duration of grade ≥ 3 RTOM, oral pain (Numerical rating scale, NRS), safety and survival outcomes. Results: From January, 2018, to December, 2021, 182 patients from 5 hospitals were enrolled. 179 patients were included for efficacy, safety and survival analysis (89 in the UTI group and 90 in the control group). All UTI group patients completed UTI treatment as planned, and both groups completed scheduled CCRT. The incidence of grade ≥ 3 RTOM was significantly lower in UTI group compared with control group (25.8% vs. 41.1%; P = 0.030). The recovery rate in UTI group was higher than that in control group (39.1% vs. 10.8%; P = 0.023). However, the onset time and the duration of grade ≥ 3 RTOM were similar between the two groups (Median [IQR] 26.00 [19.00, 33.00] days vs. 32.00 [20.50, 36.00] days; P= 0.621 and 12.00 [7.00, 18.00] days vs. 15.00 [8.00, 25.50] days; P= 0.209). The incidence of severe oral pain ( NRS score≥ 7 ) was significantly reduced in UTI group compared with the control group (22.5% vs. 36.7; P = 0.038). No UTI related adverse events were observed during treatment. With a median follow-up time of 41.6 months (IQR, 38.2 - 45.0 months), The 3-year OS, LRRFS, DMFS and PFS in UTI group and Control group were 96.5% vs. 94.3%, 91.2% vs. 87.2%, 95.2% vs. 92.1% and 89.9% vs. 85.1%, respectively (all P > 0.05). Conclusions: Our study revealed that UTI can effectively reduce the incidence of graded ≥ 3 RTOM and severe oral pain without increasing adverse events and compromising survivals. Clinical trial information: NCT03387774 .