Background
Phase III RCT (n=912) of newly diagnosed high-risk locally advanced rectal adenocarcinoma defined on pelvic MRI (cT4a/cT4b, extramural vascular invasion, cN2, involved mesorectal fascia, or enlarged lateral lymph nodes). Tested total neoadjuvant therapy with short-course RT vs standard long-course chemoradiotherapy.
Interventions and follow up
Arm A (experimental): RT 5×5 Gy over 8 days, then CAPOX ×6 or FOLFOX4 ×9, then TME
Arm B (standard): long-course chemoradiotherapy (50.4 Gy/28 fr or 50 Gy/25 fr) with concomitant capecitabine 825 mg/m2 BID, then TME, then optional adjuvant CAPOX ×8 or FOLFOX4 ×12
Primary endpoint: 3-year disease-related treatment failure (DRTF)
Median follow up: 4.6 years
Arm B (standard): long-course chemoradiotherapy (50.4 Gy/28 fr or 50 Gy/25 fr) with concomitant capecitabine 825 mg/m2 BID, then TME, then optional adjuvant CAPOX ×8 or FOLFOX4 ×12
Primary endpoint: 3-year disease-related treatment failure (DRTF)
Median follow up: 4.6 years
Results
3-yr DRTF: 23.7% vs 30.4%, arm A vs arm B; HR 0.75, 95% CI 0.60–0.95; P=.019
3-yr distant metastases: 20% vs 27%; HR 0.69, 95% CI 0.54–0.90
3-yr locoregional failure: 8% vs 6%
pCR: 28% vs 14%
3-yr distant metastases: 20% vs 27%; HR 0.69, 95% CI 0.54–0.90
3-yr locoregional failure: 8% vs 6%
pCR: 28% vs 14%
Adverse events
Preoperative grade ≥3: more common with experimental arm; diarrhea 18% vs 9% (arm A vs B)
Serious adverse events: similar, ~34% each group
Note: 52% of patients did not receive adjuvant chemotherapy (not mandatory in standard arm)
Serious adverse events: similar, ~34% each group
Note: 52% of patients did not receive adjuvant chemotherapy (not mandatory in standard arm)
Conclusions
Short-course radiotherapy followed by preoperative chemotherapy and TME reduced disease-related treatment failure vs standard long-course chemoradiotherapy in high-risk locally advanced rectal cancer, supporting total neoadjuvant therapy as a new option.
Key Limitations
DRTF was a composite endpoint driven by distant metastases; locoregional recurrence was numerically higher in the experimental arm. Adjuvant chemotherapy was optional in the standard arm, limiting direct comparison. Open-label design.
Clinical Context
Established total neoadjuvant therapy (TNT) as a standard option for high-risk LARC, endorsed by ESMO and ASCO. CAPOX = capecitabine 1000 mg/m2 PO BID D1–14, oxaliplatin 130 mg/m2 IV D1 Q21. FOLFOX4 = oxaliplatin 85 mg/m2 IV D1, leucovorin 200 mg/m2 IV D1–2, bolus fluorouracil 400 mg/m2 then 600 mg/m2 over 22h D1–2 Q14D.