Pirfenidone in the Treatment of Radiation-Induced Lung Injury: A Randomized, Controlled, Multicenter Clinical Trial

Abstract

Purpose/Objective(s)

Radiation-induced lung injury (RILI) can reduce survival time and lowering the quality of life of patients. However, the current standard therapy does not target its pathophysiologic process. Pirfenidone is indicated for idiopathic pulmonary fibrosis, and our experiments have shown that it ameliorates alveolar inflammation and fibrosis in mice after radiation, and its mechanism of action is similar to the pathophysiological process of RILI. Therefore, the aim of this trial was to investigate the efficacy and safety of pirfenidone in combination with standard therapy versus standard therapy alone for the treatment of grade 2 or 3 RILI.

Materials/Methods

This randomized, controlled, open-label phase II clinical trial enrolled patients diagnosed with grade 2 or 3 RILI at 10 centers who were randomly assigned in a 1:1 ratio to the pirfenidone group (pirfenidone plus standard therapy) and the control group (standard therapy). They were followed up once each at weeks 4, 8, 16, and 24 after randomization. Primary endpoint was change from baseline in DLCO% at week 24. Secondary endpoints were change from baseline in FVC%, FEV1%, CT score, symptom score, RILI classification score and acute pulmonary exacerbation free survival at week 24. Exploratory endpoints were progression free survival (PFS) and overall survival (OS). Repeated-measures data were analyzed using a linear mixed effects model. This was an exploratory trial and did not adjust alpha for multiple comparisons, so alpha was set to 0.05 (two-sided) for all endpoints.

Results

A total of 134 patients were enrolled, with 121 completing follow-up by February 16, 2024, there were 60 randomized to the pirfenidone group and 61 to the control group. Compared with the control group, the adjusted least squares mean changes from baseline to week 24 in DLCO%, FVC%, and FEV1% in the pirfenidone group increased by 10.6%, 9.4%, and 6.8%, respectively (P = 0.002, P = 0.004, and P = 0.051), and the proportion of improvement in CT ground-glass, reticulation, and honeycombing scores at week 24 compared to baseline increased by 28.0%, 50.8%, and 7.6%, respectively (P = 0.030, P = 0.002, and P = 0.358), and the 24-week survival rate without acute pulmonary exacerbation increased by 20.1% (P = 0.026). Cough, fever, dyspnea, radiation pneumonitis, and radiation pulmonary fibrosis scores at week 24 were not statistically different between the two groups, nor were PFS and OS (P = 0.056, P = 0.932, P = 0.897, P = 0.076, P = 0.152, P = 0.339, and P = 0.345). The incidence of grade 3, 4, and 5 adverse events was similar in the pirfenidone and control groups (11.7% vs 11.5%, 1.7% vs 3.3%, and 8.3% vs 6.6%), and no pirfenidone related grade ≥ 4 adverse events were observed.

Conclusion

Pirfenidone can significantly improve lung function, mild to moderate radiation pulmonary fibrosis, and acute pulmonary exacerbation free survival in patients with RILI compared with the control group, and its side effects are acceptable. Further study is required for the use of pirfenidone for the treatment of RILI.