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

Summary

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.

Conditions

• Rectal Cancer

Interventions

DRUG

Sintilimab

* Stage 1: Short-course radiotherapy combined with 4 cycles of XELOX regimen chemotherapy + sintilimab immunotherapy; * Stage 2: After surgery, receive 4 cycles of XELOX regimen chemotherapy + sintilimab immunotherapy, followed by immunotherapy maintenance until 1 year. Sintilimab: 200mg, intravenous drip (ivgtt), day 1, once every 3 weeks, infused before chemotherapy drugs.

DRUG

Chemotherapy Drugs

* Capecitabine Administration: 1000 mg/m², twice daily, taken half an hour after meals, with a 12-hour interval between doses, administered continuously for 14 days (Days 1-14), repeated every 3 weeks (adjusted according to the degree of myelosuppression after chemotherapy in patients, adjustment within 75%-100% of the standard treatment dose intensity is allowed). * Oxaliplatin Administration: 130mg/m², day 1, repeated every 3 weeks. Oxaliplatin is dissolved in 500 mL of 5% glucose solution (to achieve a concentration above 0.2 mg/mL) and infused intravenously for 2-6 hours (adjusted according to the degree of myelosuppression after chemotherapy in patients, adjustment within 75%-100% of the standard treatment dose intensity is allowed).

RADIATION

radiotherapy

* Irradiation Technology: Intensity-modulated radiation therapy (IMRT) is adopted. * Target Volume Definition and Delineation: * GTV Delineation: Primary tumor area, including the primary rectal lesion, corresponding regional mesorectum and metastatic lymph nodes; * CTV Delineation: Refer to Definition and delineation of the clinical target volume for rectal cancer. * PTV Delineation: On the basis of CTV, 0.5 cm is expanded in the left-right direction, and 1.0 cm is expanded in the anteroposterior and craniocaudal directions; * Normal tissues and organs to be delineated include: bilateral femoral heads, bladder, colon, small intestine within the irradiation range (to be delineated 3 layers above the PTV), and testes (in males). Irradiation Dose: Whole pelvic PTV: 25Gy/5 fractions/1 week Normal Tissue and Organ Dose Limits: Femoral head: V20 \< 5%; Bladder: V20 \< 50%; Colon: V20 \< 10%, Dmax \< 27Gy; Small intestine: V20 \< 10%, Dmax \< 26Gy.

Sponsors & Collaborators

• Tianjin Medical University Cancer Institute and Hospital

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-05-01

Primary Completion

2029-06-01

Completion

2030-03-01

Countries

• China

Study Locations