Total Neoadjuvant Therapy With PD-1 for Locally Advcancer Rectal Cancer

Study Title:A Single-Arm, Multicenter Clinical Study to Evaluate the Efficacy and Safety of Total Neoadjuvant Chemoradiotherapy Combined with PD-1 Inhibitor Immunotherapy in Locally Advanced Rectal Cancer with High-Risk Features for Recurrence

Background and Rationale:

Locally advanced rectal cancer (LARC) with high-risk features, such as involved mesorectal fascia, extramural vascular invasion, or low-lying tumors, is associated with a significant risk of local recurrence and distant metastasis following standard treatment. Total neoadjuvant therapy (TNT), which administers both chemotherapy and chemoradiotherapy prior to surgery, has emerged as a strategy to improve pathological outcomes and systemic control. The integration of immune checkpoint inhibitors, specifically PD-1 inhibitors, into TNT regimens is a promising approach. It is hypothesized that radiotherapy may potentiate the immune response by increasing tumor antigen exposure, thereby enhancing the efficacy of immunotherapy and potentially leading to higher rates of complete response and improved long-term survival.

Primary Objective:

The primary objective of this study is to evaluate the efficacy of the combined TNT and PD-1 inhibitor regimen, as measured by the pathological complete response (pCR) rate, defined as the absence of viable tumor cells in the primary tumor and lymph nodes upon pathological examination after surgical resection.

Secondary Objectives:

Secondary objectives are to further assess the treatment's efficacy and safety, including:

Rate of Clinical Complete Response (cCR):The proportion of patients achieving a complete response based on clinical, endoscopic, and radiological assessments prior to surgery.

R0 Resection Rate:The proportion of patients undergoing surgery with microscopically negative margins.

Tumor Regression Grade (TRG):The degree of tumor cell destruction scored by pathological assessment.

Event-Free Survival (EFS):The time from treatment initiation to disease progression, recurrence, or death from any cause.

Overall Survival (OS):The time from treatment initiation to death from any cause.

Safety and Tolerability:The incidence and severity of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), with a specific focus on immune-related adverse events (irAEs).

Study Design:

This is a single-arm, open-label, multicenter, Phase II clinical study**. All enrolled participants will receive the same investigational treatment regimen.

Study Population:

The study will enroll adult patients (age ≥ 18 years) with histologically confirmed, locally advanced rectal adenocarcinoma. Eligible participants must have high-risk features for recurrence, which may include:

Clinical stage T3-4 and/or N2 disease. Threatened or involved mesorectal fascia (MRF+). Presence of extramural vascular invasion (EMVI+). Low-lying tumors where sphincter preservation is a concern. Patients must have an ECOG performance status of 0-1 and adequate organ function.

Intervention:

Patients will receive the "Total Neoadjuvant Chemoradiotherapy Combined with Immunotherapy" regimen, which consists of:

1. Induction Immunochemotherapy:Combination of a PD-1 inhibitor (e.g., Pembrolizumab or Nivolumab) with CAPOX or FOLFOX chemotherapy for a specified number of cycles.
2. Chemoradiotherapy:** Concurrent administration of radiotherapy (total dose of 25 Gy in 5 fractions) with a radiosensitizing fluoropyrimidine chemotherapy (e.g., capecitabine).
3. Consolidation Immunotherapy:Additional cycles of the PD-1 inhibitor following chemoradiation.

Surgical resection (Total Mesorectal Excision) will be performed approximately 8-12 weeks after the completion of all neoadjuvant therapy.

Statistical Analysis:

The pCR rate will be summarized with a 95% confidence interval. Secondary time-to-event endpoints like EFS and OS will be estimated using the Kaplan-Meier method. Safety analysis will include all patients who received at least one dose of the study treatment.