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

1. Background Esophageal squamous cell carcinoma (ESCC) is a highly prevalent malignancy in China, ranking sixth in incidence and fourth in cancer-related mortality, posing a serious threat to public health. Over 50% of newly diagnosed patients present with locally advanced esophageal squamous cell carcinoma. The RTOG 8501 and RTOG 9405 trials established definitive concurrent chemoradiotherapy (CCRT) as the standard of care for inoperable locally advanced esophageal squamous cell carcinoma, yielding a 5-year overall survival (OS) rate of approximately 30%. However, despite optimization of physical radiation dose and fractionation in photon radiotherapy and modifications in chemotherapy regimens, further improvements in clinical outcomes have been limited.

Recent research has focused on two primary strategies to enhance the efficacy of definitive CCRT in locally advanced esophageal squamous cell carcinoma: the incorporation of proton radiotherapy, and the integration of immune checkpoint inhibitors (ICIs).

Conventional photon therapy using 6-8 MV X-rays typically involves a total dose of 50-60 Gy delivered over 28-30 fractions, with or without elective nodal irradiation (ENI). However, photon radiotherapy is limited by large gross tumor volumes (GTV) and widespread lymphatic involvement, leading to excessive radiation exposure to organs-at-risk (OARs). Elevated doses to the heart and lungs increase the risk of late toxicities such as radiation-induced heart disease and pulmonary fibrosis, thereby impairing cardiopulmonary function and survival. Additionally, high-dose exposure to circulating lymphocytes and the thoracic vertebrae compromises systemic immunity by inducing lymphopenia, adversely affecting prognosis.

Proton radiotherapy, with its Bragg peak effect, delivers maximal radiation dose at the end of its range, significantly sparing surrounding normal tissues. Biologically, this translates into a lower incidence of late toxicities in the heart and lungs and reduced lymphocyte depletion, potentially leading to improved clinical outcomes. Emerging clinical data suggest that compared to conventional photon therapy, PRT reduces treatment-related toxicities and may improve survival.

ICIs have shown promising efficacy in advanced EC and are increasingly being investigated in earlier disease stages. Several phase III trials (ESCORT-CRT, Keynote 975, RATIONAL 311, etc.) are evaluating the combination of CCRT with ICIs in locally advanced esophageal squamous cell carcinoma, and preliminary data indicate that this approach is both safe and effective. Since proton radiotherapy minimizes radiation dose to circulating lymphocytes, it may exhibit superior synergy with immunotherapy compared to photon radiotherapy, potentially offering enhanced therapeutic benefit.