Background
Multicenter, randomized, open-label phase 3 trial; N=458; stage II/III locally advanced rectal cancer (LARC) with ≥1 high-risk feature (cT4a-b, cN2, mesorectal fascia involvement, or cT3c-d with extramural vascular invasion); intensified doublet total neoadjuvant therapy (TNT) with long-course radiotherapy vs conventional neoadjuvant chemoradiotherapy; randomized 232 vs 226.
Results
Interventions and follow up: Arm A: Doublet long-course TNT — induction, concurrent, and consolidation capecitabine + oxaliplatin (CAPOX) with long-course radiotherapy, then surgery (n=232)
Arm B: Conventional neoadjuvant chemoradiotherapy (capecitabine + long-course RT) → surgery → adjuvant chemotherapy (n=226)
Primary endpoint: Disease-free survival (DFS)
mFollow up: 51 mo
Results: DFS (3-yr): 74.8% vs 66.0%; HR 0.674 (95% CI 0.489–0.929); P=.016
MFS (metastasis-free survival): 77.7% vs 67.6%; HR 0.655 (95% CI 0.469–0.915)
pCR: 26.4% vs 9.8%; P<.001
Locoregional failure: 6.03% vs 6.19%; P=.943
OS (3-yr): 90.3% vs 87.9% (not significantly different)
Arm B: Conventional neoadjuvant chemoradiotherapy (capecitabine + long-course RT) → surgery → adjuvant chemotherapy (n=226)
Primary endpoint: Disease-free survival (DFS)
mFollow up: 51 mo
Results: DFS (3-yr): 74.8% vs 66.0%; HR 0.674 (95% CI 0.489–0.929); P=.016
MFS (metastasis-free survival): 77.7% vs 67.6%; HR 0.655 (95% CI 0.469–0.915)
pCR: 26.4% vs 9.8%; P<.001
Locoregional failure: 6.03% vs 6.19%; P=.943
OS (3-yr): 90.3% vs 87.9% (not significantly different)
Adverse events
Grade ≥3 (neoadjuvant phase): 27.6% vs 8.6%; P<.001
Grade ≥3 (entire treatment course): 28.0% vs 24.3%; P=.371
Major postoperative complications: 3.98% vs 2.94%; P=.567
Grade ≥3 (entire treatment course): 28.0% vs 24.3%; P=.371
Major postoperative complications: 3.98% vs 2.94%; P=.567
Conclusions
Compared with conventional neoadjuvant chemoradiotherapy plus adjuvant chemotherapy, doublet long-course TNT (oxaliplatin-containing chemotherapy delivered throughout) improved disease-free survival, metastasis-free survival, and pathologic complete response with manageable toxicity, supporting intensified doublet TNT as a standard option within the modern TNT paradigm for high-risk LARC.
Key Limitations
Open-label design and single-country (Chinese) enrollment limit generalizability. The control arm delivered oxaliplatin as adjuvant therapy after chemoradiotherapy, so the trial largely tests front-loading and intensification of the same agents rather than a wholly novel drug. Acute grade ≥3 toxicity during the neoadjuvant phase was substantially higher with doublet TNT. There was no comparison against short-course radiotherapy-based TNT (RAPIDO/STELLAR) or non-doublet consolidation, overall survival remains immature, and organ-preservation/watch-and-wait outcomes were not assessed.
Clinical Context
Total neoadjuvant therapy—delivering chemotherapy and radiotherapy before surgery—is now standard for high-risk LARC (RAPIDO, PRODIGE-23, STELLAR). TNTCRT specifically supports an intensified doublet (CAPOX) long-course chemoradiotherapy TNT backbone over conventional single-agent nCRT plus adjuvant chemotherapy, aligning with NCCN and ESMO endorsement of TNT for high-risk rectal cancer.