This study explores the key clinical issues in the field of neoadjuvant therapy for locally advanced rectal cancer. There are three core problems with the currently recommended total neoadjuvant therapy (TNT) in the guidelines: the lack of evidence-based consensus on the timing of radiotherapy and chemotherapy, the undefined number of chemotherapy cycles, and the uncertainty in the selection of the precise radiotherapy mode. In recent years, the combination of immune checkpoint inhibitors (ICIs) with the PD-1/PD-L1 inhibitors as the core and the TNT regimen has shown a trend of further enhancing tumor regression, providing a possibility for the organ function preservation of rectal cancer. However, existing clinical studies exhibit a high degree of heterogeneity in treatment strategies. In particular, there is a lack of high-quality evidence-based medical evidence in core aspects such as the timing of ICIs intervention and the combination of treatment regimens. This study is designed as a prospective, multicenter, randomized controlled phase II study. The "pick the winner" strategy for screening the optimal regimen is adopted to evaluate the efficacy of four neoadjuvant regimens (Group SCRT-4: short-course radiotherapy → 4 cycles of chemotherapy + ICIs; Group SCRT-6: short-course radiotherapy → 6 cycles of chemotherapy + ICIs; Group LCRT-4: concurrent chemoradiotherapy → 4 cycles of chemotherapy + ICIs; Group LCRT-6: concurrent chemoradiotherapy → 6 cycles of chemotherapy + ICIs). By evaluating indicators such as the complete response rate, organ preservation rate, safety, long-term survival, as well as the anal function and quality of life of patients, treatment strategies with clinical advantages will be screened out, providing an evidence-based basis for subsequent phase III confirmatory trials.
Age 18-75 years, regardless of gender;
Pathologically confirmed rectal adenocarcinoma with immunohistochemical results indicating pMMR (proficient mismatch repair) or genetic testing confirming MSS (microsatellite stability);
cT3 with tumor inferior margin ≤ 6 cm from the anal verge;
cT3c/d with tumor inferior margin ≥ 6-12 cm from the anal verge; ③ cN2; ④ cT4; ⑤ MRF+ (mesorectal fascia involvement); ⑥ EMVI+ (extramural vascular invasion);
Prior treatment with anti-PD-1/L1 and/or anti-CTLA-4 immunotherapy or other investigational immunotherapeutic agents;
History of severe autoimmune diseases, including active inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (e.g., granulomatosis with polyangiitis);
Symptomatic interstitial lung disease or active infectious/non-infectious pneumonitis;
Risk factors for bowel perforation, such as active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal carcinomatosis, or other known predisposing conditions;
Parallel
Sintilimab
DrugPD-1 inhibitor
Short-course radiotherapy
RadiationPelvic radiation, SCRT, 5 Gy x 5 alone
Long-course concurrent chemoradiotherapy
RadiationPelvic radiation, 50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine (825 mg/m2, twice a day).
CAPOX
Combination productchemotherapy regimen, Oxaliplatin 130 mg/m2 IV day 1，Capecitabine 1000 mg/m2 twice daily PO for 14 days(3 weeks per cycle)
Rate of complete response
The rate of pathological complete response plus clinical complete response
Rate of TRG grade
Dowrak TRG grade
Tumor downstaging rate
rate of ypT0-2N0
Rate of acute toxicities during radiation, chemotherapy ± immunotherapy
Incidence of acute toxicities during radiation, chemotherapy ± immunotherapy
Rate of surgical complications
Clavien-Dindo Grade
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