Short-Course Radiotherapy Followed by Immunotherapy Combined With Chemotherapy for Microsatellite Stable Locally Advanced Rectal Cancer: A Prospective, Randomized, Controlled Phase II Clinical Trial

Microsatellite stable (MSS) locally advanced rectal cancer (LARC) remains a major therapeutic challenge despite advances in multimodal treatment. Colorectal cancer is the third most common malignancy worldwide and the second leading cause of cancer-related death. In China, rectal cancer accounts for nearly half of all colorectal cancers, with approximately 70% of patients presenting with locally advanced disease, which is associated with a high risk of recurrence and poor long-term survival. Neoadjuvant chemoradiotherapy followed by total mesorectal excision (TME) has become the standard treatment for LARC based on landmark trials such as CAO/ARO/AIO-94, NSABP-R03, and MRC-CR07, which demonstrated improved local control and reduced recurrence. However, the optimal neoadjuvant strategy remains under active investigation. Currently, long-course chemoradiotherapy and short-course radiotherapy (SCRT) are the two principal preoperative radiotherapy approaches. Long-course chemoradiotherapy achieves superior tumor downstaging and pathological complete response (pCR) rates but requires prolonged treatment duration and is associated with greater acute toxicity. In contrast, SCRT offers shorter treatment time, lower cost, and reduced toxicity. Importantly, delayed surgery after SCRT can significantly enhance tumor regression and achieve pCR rates comparable to those of long-course chemoradiotherapy. The development of total neoadjuvant therapy (TNT) has further transformed rectal cancer management by moving systemic chemotherapy to the preoperative setting, thereby improving treatment compliance, tumor response, and organ preservation. Among TNT strategies, consolidation chemotherapy after radiotherapy appears to provide superior tumor regression compared with induction chemotherapy. Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated remarkable efficacy in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer. However, the majority of rectal cancers are mismatch repair-proficient/microsatellite stable (pMMR/MSS) tumors, which are generally considered immunologically "cold" and poorly responsive to immunotherapy alone. Radiotherapy can enhance antitumor immunity through increased antigen presentation, dendritic cell activation, CD8+ T-cell infiltration, and stimulation of systemic immune responses. Preclinical and clinical studies suggest synergistic effects between radiotherapy and immune checkpoint blockade. Several prospective studies combining chemoradiotherapy, chemotherapy, and immunotherapy in MSS LARC have reported encouraging pCR rates, particularly when immunotherapy is administered during the consolidation phase. SCRT-based TNT combined with immunotherapy has shown especially promising efficacy, with pCR rates exceeding those achieved with conventional chemoradiotherapy. Nevertheless, whether improved tumor regression can translate into durable survival benefits remains unclear. In this context, postoperative immunotherapy maintenance may represent an important strategy to further improve long-term disease control. Sintilimab is a fully human anti-PD-1 monoclonal antibody that restores T-cell-mediated antitumor immunity by blocking the PD-1/PD-L1 pathway. Previous studies have demonstrated favorable pharmacokinetics, durable receptor occupancy, and manageable toxicity profiles. Based on this rationale, we designed a prospective randomized phase II study to evaluate the efficacy and safety of SCRT sequentially combined with sintilimab and XELOX chemotherapy in MSS LARC. Patients in the experimental arm will receive SCRT followed by four cycles of XELOX plus sintilimab before TME surgery, followed by postoperative XELOX plus sintilimab and one year of immunotherapy maintenance. Patients in the control arm will receive SCRT combined with XELOX chemotherapy without maintenance immunotherapy. The primary endpoint is 3-year disease-free survival (3y-DFS). Secondary endpoints include pCR, objective response rate (ORR), overall survival (OS), 3-year OS rate, and treatment safety. This study aims to determine whether the addition of sintilimab and postoperative immunotherapy maintenance can improve long-term survival while maintaining acceptable safety. Through integration of radiotherapy, chemotherapy, and immunotherapy, this study seeks to establish a more effective TNT-based strategy for MSS rectal cancer.

Sex

All

Minimum age

18 Years

Maximum age

75 Years

Inclusion Criteria:

1. Age 18-75 years, regardless of gender;
2. Stage II/III disease (cT3-T4N0 or cT2-4N+) without distant metastasis on magnetic resonance imaging (MRI) or endoscopic ultrasound (EUS), according to the 8th edition of the AJCC Cancer Staging Manual (2018);
3. The lower boundary of the lesion is ≤ 10 cm from the anal verge, confirmed by colonoscopy or digital rectal examination;
4. Pathologically confirmed or re-reviewed rectal adenocarcinoma;
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
6. Meet the following laboratory diagnostic indicators:

   Hemoglobin ≥ 90 g/L, white blood cell count ≥ 3.5×10⁹/L;
7. Neutrophil count ≥ 1.5×10⁹/L, platelet count ≥ 100×10⁹/L;
8. Creatinine ≤ 1.0×upper normal limit (UNL), blood urea nitrogen (BUN) ≤ 1.0×UNL;
9. Alanine aminotransferase (ALT) ≤ 1.5×UNL;
10. Aspartate aminotransferase (AST) ≤ 1.5×UNL;
11. Alkaline phosphatase (ALP) ≤ 1.5×UNL;
12. Total bilirubin (TBIL) ≤ 1.5×UNL;
13. Urinary protein (-); normal bleeding and coagulation time.
14. No history of allergy to platinum-based drugs;
15. For patients with primary rectal cancer, no surgery (except palliative colostomy), chemotherapy, or other anti-tumor treatments have been performed from diagnosis to enrollment;
16. No previous radiation therapy to the intended radiation field;
17. Signed informed consent form.

Exclusion Criteria:

1. Previous treatment with anti-PD-1/L1, anti-CTLA-4 immunotherapeutic drugs, or other experimental immunotherapeutic agents;
2. Patients with severe autoimmune diseases: active inflammatory bowel disease (including Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (such as Wegener's granulomatosis), etc.;
3. Symptomatic interstitial lung disease or active infectious/non-infectious pneumonia;
4. Patients with risk factors for intestinal perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal cancer, or other known risk factors for intestinal perforation;
5. History of other malignant tumors, excluding curable non-melanoma skin cancer and carcinoma in situ of the cervix;
6. Patients with active infection, heart failure, myocardial infarction within 6 months, unstable angina pectoris, or unstable arrhythmia;
7. Physical examination or clinical laboratory findings that the investigator believes may interfere with the results or increase the risk of treatment complications in patients, or other uncontrollable diseases;
8. Lactating or pregnant women;
9. Congenital or acquired immunodeficiency diseases including human immunodeficiency virus (HIV), or history of organ transplantation or allogeneic stem cell transplantation;
10. Known active hepatitis B virus (HBV) infection (HBV-DNA ≥ 2000 U/mL), hepatitis C virus (HCV) infection, or active pulmonary tuberculosis infection;
11. Patients who have received tumor vaccines or other vaccines within 4 weeks before the start of treatment; (Note: Seasonal influenza vaccines for injection are mostly inactivated vaccines and thus allowed, while intranasal preparations are usually live attenuated vaccines and thus not allowed);
12. Patients receiving concurrent use of other immunomodulators, chemotherapeutic drugs, drugs in other clinical studies, or long-term cortisol therapy are not eligible for enrollment;
13. Patients with mental illness, substance abuse, or social problems that affect compliance will not be enrolled after review by doctors;
14. Patients with allergies or contraindications to the study drugs.