Short-Course Radiotherapy With Tumor-Draining Lymph Node Preservation Followed by PD-1 Inhibitors in pMMR/MSS Stage II-III Rectal Cancer

Official title

Exploratory Study on the Efficacy and Safety of Short-Course Radiotherapy With Tumor-Draining Lymph Node Preservation Followed by PD-1 Inhibitors in pMMR/MSS Stage II-III Rectal Cancer

Overview

This study aims to evaluate the efficacy (pathological complete response rate) of short-course radiotherapy with preservation of tumor-draining lymph nodes followed by sequential PD-1 inhibitor neoadjuvant therapy in patients with stage II-III pMMR/MSS locally advanced rectal cancer.

Detailed description

This study is a single-arm, open-label exploratory clinical trial designed to investigate the feasibility and preliminary efficacy of a novel neoadjuvant treatment strategy for locally advanced rectal cancer. The strategy combines short-course radiotherapy (SCRT) with deliberate preservation of tumor-draining lymph nodes, followed by sequential PD-1 inhibitor therapy, with the aim of enhancing antitumor immune activation prior to definitive surgery. Given the exploratory nature of the study, no blinding will be applied, and both investigators and participants will be aware of the assigned treatment. Approximately 44 eligible patients are planned for enrollment.

The study is conducted across four sequential phases: screening and enrollment, neoadjuvant treatment, surgical intervention, and postoperative follow-up. During the screening phase, eligibility will be confirmed through histopathological evaluation, molecular testing, and standardized imaging assessments to establish disease stage and anatomical suitability for the protocol-defined treatment approach.

Neoadjuvant treatment begins with short-course radiotherapy administered in the first week after enrollment. Radiotherapy will be delivered using volumetric modulated arc therapy (VMAT) following standard procedures for patient positioning, immobilization, CT/MRI simulation, target volume delineation, treatment planning, and image-guided verification. In contrast to conventional pelvic irradiation, the clinical target volume is intentionally limited to the primary rectal tumor, excluding tumor-draining lymph nodes and elective pelvic nodal regions, in order to preserve regional immune structures. The prescribed dose is 25 Gy delivered in five fractions over five consecutive working days. Patients will be closely monitored for acute radiation-related toxicities, which will be graded and managed according to standard criteria.

Two weeks after completion of radiotherapy, patients will initiate immunotherapy. Sintilimab, a PD-1 inhibitor, will be administered intravenously at a fixed dose of 200 mg every three weeks for four cycles. Prior to each cycle, patients will undergo routine safety evaluations, including physical examination and laboratory testing, to assess treatment tolerance and determine eligibility for continued dosing. Treatment interruption, delay, or discontinuation will be guided by protocol-defined toxicity management rules.

A comprehensive restaging assessment will be performed approximately 2-4 weeks after completion of neoadjuvant therapy using standardized imaging modalities, including pelvic MRI and thoracoabdominal CT. Patients without evidence of disease progression will proceed to definitive surgical management. Radical resection with total mesorectal excision (TME) is required, with the specific surgical procedure selected according to tumor characteristics and individual clinical considerations.

Postoperative management will be determined based on pathological findings and multidisciplinary team discussion approximately one month after surgery. All patients will then enter a structured follow-up program lasting three years, with visits scheduled every three months. Follow-up evaluations will focus on disease status, survival outcomes, and the assessment of late treatment-related toxicities, using clinical examinations, laboratory tests, tumor markers, and imaging studies as clinically indicated.

Interventions

• Radiation short-course radiotherapy that preserves tumor-draining lymph nodes
  Patients with stage II-III pMMR/MSS locally advanced rectal cancer receive neoadjuvant therapy with short-course radiotherapy that preserves tumor-draining lymph nodes, followed by 4 cycles of PD-1 inhibitors

Primary outcome measures

• pathologic complete response rate [Time frame: Perioperative]

Secondary outcome measures (11)

• tumor regression grade [Time frame: Perioperative]
• R0 Resection Rate [Time frame: Perioperative]
• 30-Day Postoperative Complication Rate [Time frame: within the first 30 days after the operation]
• 3-Year Local-Regional Recurrence Rate [Time frame: 3 years following surgery]
• 3-Year Distant Metastasis Rate [Time frame: 3 years following the surgery]
• 3-Year Disease-Free Survival (DFS) Rate [Time frame: 3 years following surgery]
• 3-Year Overall Survival (OS) Rate [Time frame: 3 years following surgery.]
• Toxicity Profile During Neoadjuvant Therapy (Graded by CTCAE v5.0) [Time frame: From the initiation of neoadjuvant therapy until 90 days after the last dose]
• EORTC QLQ-C30 questionnaire score [Time frame: Baseline and very 3 months postoperatively until 3 years]
• EORTC QLQ-CR29 questionnaire score [Time frame: Baseline and very 3 months postoperatively until 3 years]
• the Low Anterior Resection Syndrome score [Time frame: Baseline and very 3 months postoperatively until 3 years]

Eligibility criteria

Inclusion criteria

• Age 18-75 years old, regardless of sex.

• Fibrocolonoscopy or digital rectal examination indicates that the distal border of the lesion is located 5-10 cm from the anal verge.

• Pathologically confirmed rectal adenocarcinoma.

• Imaging examinations (including pelvic MRI and chest-abdominal CT) confirm a clinical stage of II/III (cT3-T4aN0 or cT2-4aN+, MRF (-), with no distant metastasis) according to the AJCC Cancer Staging Manual, 8th Edition (2018) (for detailed TNM staging of rectal cancer).

• If N+, metastatic lymph nodes are confined to the mesorectal and superior rectal artery drainage regions, with no lateral pelvic lymph node metastasis.

⑥ Confirmed by immunohistochemistry or molecular testing to be mismatch repair proficient (pMMR) or microsatellite stable (MSS).

⑦ Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-1 (see Appendix 2 for details).

⑧ Meeting the following laboratory criteria: Hemoglobin ≥ 90 g/L, white blood cell count ≥ 3.5 × 10⁹/L; Neutrophil count ≥ 1.5 × 10⁹/L, platelet count ≥ 100 × 10⁹/L; Creatinine ≤ 1.0 × upper limit of normal (ULN), blood urea nitrogen (BUN) ≤ 1.0 × ULN; Alanine aminotransferase (ALT) ≤ 1.5 × ULN; Aspartate aminotransferase (AST) ≤ 1.5 × ULN; Alkaline phosphatase (ALP) ≤ 1.5 × ULN; Total bilirubin (TBIL) ≤ 1.5 × ULN; Urine protein negative; normal coagulation time; normal thyroid function.

⑨ Patients with primary rectal cancer must have undergone no surgical interventions (excluding palliative stoma formation), chemotherapy, or other antitumor treatments from the time of diagnosis to enrollment.

⑩ The planned radiation field must have no history of prior radiotherapy.

• The patient voluntarily agrees to participate in this study, signs the informed consent form, demonstrates good compliance, and is willing to cooperate with follow-up visits and data provision.

Exclusion criteria

• Previous treatment with anti-PD-1/L1, anti-CTLA-4 immunotherapies, or other investigational immunotherapeutic agents is excluded.

• Patients with severe autoimmune diseases are excluded, including active inflammatory bowel disease (such as Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (e.g., Wegener's granulomatosis), etc.

• Patients with symptomatic interstitial lung disease or active infectious/non-infectious pneumonitis are excluded.

• Patients with clinical or imaging evidence of intestinal obstruction or perforation, or those deemed by the investigator to be at high risk of perforation or hemorrhage, are excluded.

• History of other malignancies, excluding curatively treated non-melanoma skin cancer and carcinoma in situ of the cervix, are excluded.

• Patients with severe cardiovascular or cerebrovascular diseases are excluded, including cerebrovascular accidents, transient ischemic attacks, myocardial infarction within 6 months prior to enrollment, or significant vascular diseases (including but not limited to aortic aneurysms requiring surgical repair or recent arterial thrombosis). Also excluded are those with poorly controlled cardiac symptoms or conditions, such as unstable angina, heart failure of New York Heart Association (NYHA) Class II or higher, left ventricular ejection fraction (LVEF) < 50% on echocardiography, or severe arrhythmias uncontrolled by medication.

• Physical examination findings, clinical laboratory abnormalities, or other uncontrolled conditions that, in the investigator's judgment, may interfere with the study results or increase the patient's risk of treatment complications are excluded.

• Lactating or pregnant women are excluded. ⑨ Patients with congenital or acquired immunodeficiency diseases, including human immunodeficiency virus (HIV) infection, or a history of organ transplantation or allogeneic stem cell transplantation, are excluded.

⑩ Known active hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, or active tuberculosis are excluded.

⑪ Patients with concurrent use of other immunomodulators, chemotherapeutic agents, other investigational drugs, or requiring long-term corticosteroid therapy are excluded.

⑫ Patients with psychiatric disorders, substance abuse, or social issues that may affect compliance, as determined upon physician review, are excluded.

⑬ Patients with allergies or contraindications to the investigational drug(s) are excluded.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07394192 · PKUCH- R11

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗