Risk Factors of Treatment-Related Pneumonitis after Thoracic Radiotherapy/Chemoradiotherapy Combined with Anti-PD-1 mAb in Esophageal Squamous Cell Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> Treatment-related pneumonitis (TRP) and radiation recall pneumonitis (RRP) has recently been identified as a toxicity triggered by thoracic irradiation combined with anti-PD-1 mAb in esophageal squamous cell carcinoma (ESCC). However, the incidence, risk factors and dose-volume parameters remain unknown. <h3>Materials/Methods</h3> We analyzed 97 patients with ESCC who received thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 mAb. There were 74 patients of newly diagnosed/locally advanced unresectable esophageal cancer, 22 patients of recurrent after radical resection /metastatic esophagus cancer, and 1 patient of resectable esophageal cancer with neoadjuvant therapy. 41 patients received concurrent thoracic radiotherapy and anti-PD-1 mAb, 56 patients received sequential thoracic radiotherapy and anti-PD-1 mAb. The median radiation dose of PTV was 59.4Gy (range from 45Gy to 66Gy, 1.8Gy-2.2Gy per fraction). TRP and RRP were classified according to the CTCAE version 5.0 and the effect of dose-volume parameters of lung on TRP and RRP was analyzed. <h3>Results</h3> The average value of V_5, V_10, V_20, V₃₀ and MLD of lung was 49.2% (27.9%-73.6%), 35.9% (21.7%-48.6%), 21.3% (12.7%-29.9%), (1.5% -17.5%) and 1092.5cGy (666.9cGy-1569.6cGy), respectively. The incidence of TRP was 46.4% (45/97). 41.2% of patients developed grade 1 or 2 pneumonitis and 4.1% of patients was grade 3 pneumonitis. Of note, there was 1 death probably related with TRP. The incidence of RRP was 14.4% (14/97). 14.4% of patients developed grade 1 or 2 pneumonitis and there was no grade ≥3 RRP. The median onset time of TRP and RRP was 16 weeks after receiving anti-PD-1 mAb (2.6 weeks-65.9 weeks) and 48.9 weeks (27 weeks-91.1 weeks) after thoracic radiotherapy, respectively. Result of multivariate analysis showed that V₅ was an independent risk factor of grade ≥2 TRP (P=0.003, OR=1.106). The incidence of grade ≥2 TRP in the V₅≥55.7% group was significantly higher than that in the V₅<55.7% group (56.5% vs 16.2%). There was only a trend towards higher V₅, V₃₀, V₃₅, and MLD related to RRP without statistical significance. <h3>Conclusion</h3> We demonstrate a high risk of TRP in ESCC patients receiving thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 mAb and mostly pneumonitis was grade 1 and grade 2. While the occurrence of RRP is relatively less and the severity is mild. TRP (grade≥2) is associated with V₅≥55.7%, so clinicians should pay more attention to restriction of V₅ and V₅<55.7% might be a safer volume. Therapy strategy combined thoracic radiotherapy/chemoradiotherapy with anti-PD-1 mAb might be a safe choice, it is worth a further exploration.