This is a prospective, open-label, randomized, parallel-group phase II trial evaluating the efficacy and safety of a low-dose radiotherapy sensitization strategy combined with a PD-1 antibody (pucotenlimab) and CAPEOX as neoadjuvant therapy in patients with pMMR/MSS locally advanced rectal adenocarcinoma. Participants will be randomized 1:1 to receive either 2 Gy or 5 Gy low-dose radiotherapy. Low-dose radiotherapy is delivered as a single fraction of 2 Gy (Arm A) or 5 Gy (Arm B). On the day after radiotherapy, participants will start pucotenlimab 200 mg IV Q3W (administered on Day 2 of each 21-day cycle) plus CAPEOX chemotherapy. Early response will be assessed after 2 cycles using endoscopy and pelvic MRI to guide subsequent treatment: participants with partial response may discontinue radiotherapy and continue neoadjuvant systemic therapy; participants with stable disease may switch to standard chemoradiotherapy; participants with progressive disease will receive multidisciplinary-team-guided salvage therapy. After 4 cycles, participants with clinical complete response may adopt a watch-and-wait strategy; otherwise, they will undergo radical surgery 2-4 weeks after completion of neoadjuvant therapy. Long-term follow-up will include recurrence and survival outcomes and quality of life.
Written informed consent provided prior to any study-specific procedures.
Age 18 to 75 years at the time of enrollment.
Histologically confirmed rectal adenocarcinoma.
Tumor located within 10 cm from the anal verge, as assessed by endoscopy or imaging.
Clinical T4b disease, defined as tumor invasion into adjacent organs or structures on baseline imaging.
Circumferential resection margin (CRM) <2 mm or definite involvement of the mesorectal fascia on baseline MRI.
Evidence of distant metastasis outside the pelvis.
Prior pelvic or abdominal radiotherapy.
Parallel
Low-dose radiotherapy
RadiationLow-dose radiotherapy delivered by linear accelerator to the primary rectal tumor and regional lymphatic drainage areas using IMRT or 3D-CRT techniques. Participants receive either 2 Gy or 5 Gy according to randomized assignment, administered prior to initiation of systemic neoadjuvant therapy.
Pucotenlimab
DrugPucotenlimab is a programmed cell death protein 1 (PD-1) monoclonal antibody. It is administered at a fixed dose of 200 mg by intravenous infusion on Day 2 of each 21-day cycle, every 3 weeks (Q3W), during the neoadjuvant treatment phase.
CAPEOX/XELOX
DrugCAPEOX chemotherapy consists of oxaliplatin 130 mg/m² administered intravenously on Day 1 and capecitabine 1000-1250 mg/m² administered orally twice daily on Days 1-14 of each 21-day cycle during neoadjuvant therapy.
Complete Response Rate (CR)
The Combined CR rate is defined as the percentage of participants achieving either Clinical Complete Response (cCR) or Pathologic Complete Response (pCR). cCR is assessed via pelvic MRI, digital rectal examination (DRE), and endoscopy following the completion of 4 cycles of neoadjuvant therapy (each cycle is 21 days). For patients who do not achieve cCR and subsequently undergo radical surgery (scheduled 2-4 weeks after the last dose of neoadjuvant therapy), pCR is assessed by pathological examination of the resected surgical specimen (Tumor Regression Grading, TRG 0) according to the AJCC/College of American Pathologists (CAP) guidelines.
3-year Disease-Free Survival (DFS)
Disease-free survival is defined as the time from randomization to the first documented occurrence of tumor recurrence (local or distant) or death from any cause, whichever occurs first.
5-year Overall Survival (OS)
Overall survival is defined as the time from randomization to death from any cause.
Distant Metastasis Rate
The proportion of participants who develop distant metastasis during follow-up, confirmed by radiologic or pathologic assessment.
R0 Resection Rate
The proportion of participants who achieve microscopically margin-negative (R0) resection at the time of surgery.
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