Background
Spanish GCR-3 phase II RCT in 108 patients with locally advanced rectal adenocarcinoma, inferior margin within 12 cm of the anal verge, MRI-defined high-risk features (tumor within 2 mm of the mesorectal fascia, lower-third ≤6 cm, cT3-4, or cN+). An early proof-of-concept study of treatment sequencing.
Interventions and follow up
Arm A: CRT >> surgery (TME) >> adjuvant CAPOX
Arm B: Total neoadjuvant treatment (induction CAPOX >> CRT >> surgery)
CRT: 50.4 Gy with capecitabine 825 mg/m² BID plus oxaliplatin 50 mg/m² on days 1, 8, 15, 22, 29
Primary endpoint: Pathologic complete response
Median follow up: 22 mo
Arm B: Total neoadjuvant treatment (induction CAPOX >> CRT >> surgery)
CRT: 50.4 Gy with capecitabine 825 mg/m² BID plus oxaliplatin 50 mg/m² on days 1, 8, 15, 22, 29
Primary endpoint: Pathologic complete response
Median follow up: 22 mo
Results
pCR (ypT0N0M0): 13% vs 14%, P=.94 (Arm A vs B)
Downstaging: 58% vs 43%, P=.13
R0 resection: 87% vs 86%, P=.40
CAPOX completion (all 4 cycles): 57% vs 94%
Downstaging: 58% vs 43%, P=.13
R0 resection: 87% vs 86%, P=.40
CAPOX completion (all 4 cycles): 57% vs 94%
Adverse events
CAPOX (grade 3-4, adjuvant vs induction): 54% vs 19%, P=.0004 (Arm A vs B)
Preoperative CRT (grade 3-4): 29% vs 23%; most common diarrhea 16% vs 5%
Surgical: 30-day postoperative complications of any grade 45% vs 51%, P=.30
Preoperative CRT (grade 3-4): 29% vs 23%; most common diarrhea 16% vs 5%
Surgical: 30-day postoperative complications of any grade 45% vs 51%, P=.30
Conclusions
Total neoadjuvant treatment did not improve pCR but achieved markedly better chemotherapy compliance and lower toxicity than postoperative adjuvant CAPOX, providing early support for delivering systemic therapy before surgery in rectal cancer.
Key Limitations
Small phase II trial powered for pCR, not survival. Short follow-up (22 mo). Not designed to demonstrate an oncologic outcome benefit; subsequent large phase III TNT trials (PRODIGE 23, RAPIDO) provided definitive evidence.
Clinical Context
This was among the first randomized trials to test the total neoadjuvant therapy concept now standard for high-risk locally advanced rectal cancer per ESMO. Definitive confirmation came from PRODIGE 23 and RAPIDO. No specific drug approval arises from this trial.