Increased Esophageal Perforation After Combination of Anti-PD-1 Immunotherapy With Radiotherapy for Esophageal Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> Recent studies demonstrated that immunotherapy can improve the survival of patients with locally advanced and metastatic esophageal carcinoma. Combination of anti-programmed death receptor-1 (PD-1) immunotherapy and radiotherapy (RT) was a promising therapeutic strategy. Therefore, a number clinical trials are underway to study the effect of anti-PD-1 immunotherapy combined with RT in patients with esophageal carcinoma. Esophageal perforation is a severe side-effect of esophageal radiation, but there is limited information about the toxicity profile of their combined treatment. We reviewed our experience to assess the impact of anti-PD-1 immunotherapy with or without antiangiogenic tyrosine kinase inhibitors (TKIs) in combination with esophageal RT on the risk of esophageal perforation for patients with locally advanced and metastatic esophageal carcinoma. <h3>Materials/Methods</h3> Patient and treatment characteristics were collected on all consecutive patients from November 2017 to December 2020 at our institution who were treated with esophageal RT, with or without anti-PD-1 immunotherapy and/or antiangiogenic TKIs (e.g., anlotinib or apatinib). Clinical, radiologic, and endoscopic features of perforation were collected. Associations among perforation incidence and therapy received were examined with Fisher's exact test as were associations between perforation features and outcomes. <h3>Results</h3> Of 180 patients with locally advanced and metastatic EC who received esophageal RT with palliative or curative intent, perforation developed in 13 (7.2%). Fifty (27.8%) patients were treated with anti-PD-1 immunotherapy, 13 (7.2%) with antiangiogenic TKIs, and 8 (4.4%) received both anti-PD-1 immunotherapy and antiangiogenic TKIs. The incidence of perforation was higher in cases with and without anti-PD-1 immunotherapy (9 of 50 [18.0%] vs 4 of 130 [3.1%]; respectively, <i>P</i> = 0.002). Among the nine patients with anti-PD-1 immunotherapy who developed perforation following RT, 2 of 27 (7.4%) received anti-PD-1 immunotherapy only before RT, and 7 of 23 (30.4%) received anti-PD-1 immunotherapy after RT (including 4 in combination with antiangiogenic TKIs). Time to onset of perforation from ranged from 16 days to 189 days during anti-PD-1 immunotherapy in the 7 patients who received anti-PD-1 immunotherapy after RT. <h3>Conclusion</h3> In conclusion, this is the first report of esophageal perforation after treatment with anti-PD-1 immunotherapy and RT. We observed a higher incidence of perforation when anti-PD-1 immunotherapy and esophageal RT were administered in patients with esophageal carcinoma, especially anti-PD-1 immunotherapy administered after RT. Owing to the limitations of this study, the results warrant further confirmation. However, careful consideration should be given to the possibility of an increased risk of perforation in patients treated with anti-PD-1 immunotherapy after esophageal RT, and careful monitoring for perforation is recommended.