Definitive Proton Radiotherapy Combined With Chemotherapy and Immunotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase I Clinical Study

The standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC) is definitive concurrent chemoradiotherapy (CCRT). However, conventional photon-based radiotherapy is associated with excessive radiation exposure to normal tissues and a high incidence of treatment-related toxicities. Proton radiotherapy, one of the major advances in radiation oncology in recent years, offers the dosimetric advantage of reduced radiation to surrounding normal tissues, thereby decreasing the rate of adverse events. Two recent clinical studies have suggested that, compared with conventional photon radiotherapy, proton radiotherapy can significantly reduce the incidence of treatment-related toxicities and potentially improve patient survival outcomes.

Immune checkpoint inhibitors (ICIs) have been widely used in both locally advanced and advanced esophageal cancer and have demonstrated promising clinical efficacy. Preliminary results from several ongoing phase III clinical trials indicate that combining ICIs with concurrent chemoradiotherapy is both safe and effective. Moreover, proton radiotherapy, by minimizing the low-dose radiation exposure to circulating peripheral lymphocytes, may better preserve systemic immune function. Therefore, compared to photon therapy, proton radiotherapy may theoretically enhance the synergistic effect when combined with ICIs, offering a potential survival benefit.

Based on this rationale, we propose a phase I clinical trial to investigate the safety and preliminary efficacy of definitive proton chemoradiotherapy combined with immune checkpoint inhibition in patients with locally advanced esophageal squamous cell carcinoma.