Ulinastatin in the treatment of radiotherapy-induced oral mucositis in locoregionally advanced nasopharyngeal carcinoma: a phase 3 randomized clinical trial

Abstract

Radiotherapy-induced oral mucositis (RTOM) is a common side effect of radiotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) receiving concurrent chemoradiotherapy (CCRT). In this phase 3 trial, we aim to evaluate the efficacy and safety of Ulinastatin (UTI) for the prevention and treatment of RTOM in LA-NPC patients (NCT03387774). The primary endpoint is the incidence of grade ≥3 acute RTOM during radiotherapy. Secondary endpoints include cumulative incidence of RTOM, recovery rate, the onset time and duration of grade ≥3 RTOM, oral pain (severe), safety and survival outcomes. 179 eligible patients are randomly assigned to UTI Group (n = 89) or Control group (n = 90). All UTI group patients complete UTI treatment as planned, and both groups complete scheduled CCRT. The incidence of grade 3 RTOM is significantly lower in UTI group compared with control group (25.8% vs 41.1%, P = 0.030). The trial meet its prespecified primary endpoint. No Ulinastatin related adverse events are observed during treatment. The 3-year overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) in UTI group and control group are similar between two groups. In this work, Ulinastatin can effectively reduce the severity of RTOM and oral pain without increasing toxicity and compromising survivals.

Fig. 1. Trial profile.

UTI Ulinastatin, CCRT concurrent chemoradiotherapy, AEs adverse events.

Fig. 2. Acute oral mucosities by treatment groups.

A Incidence of acute oral mucosities for 179 evaluable patients. The difference in incidence of grade 3 RTOM during CCRT between groups was statistically significant (P = 0.030, two-sided Fisher’s exact test). Statistical note: no adjustments for multiple comparisons were applied, as the analysis focused on pre-specified differences in grade 3 RTOM. B Cumulative rate of grade ≥3 mucositis during treatment in UTI group (89 patients, at 7 weeks 23 at risk), Control Group (90 patients, at 7 weeks 37 at risk). Source data are provided as a Source Data file. *: Significant difference between groups (two-sided Fisher’s exact test; P < 0.05). UTI Ulinastatin.

Fig. 3. Oral pain by treatment groups.

A Incidence of oral pain for 179 evaluable patients. The difference in the incidence of severe oral pain during CCRT between groups was statistically significant (P = 0.038, two-sided Fisher’s exact test). Statistical note: no adjustments for multiple comparisons were applied, as the analysis focused on pre-specified differences in severe oral pain. B Cumulative rate of severe oral pain during treatment in UTI group (89 patients, at 7 weeks 20 at risk), Control group (90 patients, at 7 weeks 33 at risk). Source data are provided as a Source Data file. *: Significant difference between groups (two-sided Fisher’s exact test; P < 0.05). UTI Ulinastatin.