CRT+MFOLFOX

Background

Phase II nonrandomized sequential-cohort trial in 259 patients with clinical stage II (T3-4, N0) or III (any T, N1-2) invasive rectal adenocarcinoma with a distal tumor border within 12 cm of the anal verge, evaluating escalating cycles of mFOLFOX6 between chemoradiation and surgery.

Interventions and follow up

Group 1: CRT (5-FU 225 mg/m²/d + 45 Gy/25 fractions plus boost) >> TME (no interval chemotherapy)
Group 2: CRT >> 2 cycles mFOLFOX6 >> TME
Group 3: CRT >> 4 cycles mFOLFOX6 >> TME
Group 4: CRT >> 6 cycles mFOLFOX6 >> TME
Primary endpoint: Pathologic complete response
Median follow up: NR

Results

pCR (Groups 1/2/3/4): 18% vs 25% vs 30% vs 38%, P=.0036
Adjusted OR for pCR (vs Group 1): 1.58 (0.59-4.23) vs 1.95 (0.75-5.07) vs 3.49 (1.39-8.75)
Trend: pCR increased with the number of interval mFOLFOX6 cycles

Adverse events

Grade ≥3 (Groups 2/3/4): 3% vs 18% vs 28% (rising with cycle number)
Surgical: No significant increase in postoperative complications with added neoadjuvant chemotherapy

Conclusions

Adding mFOLFOX6 between chemoradiation and TME significantly increased pathologic complete response in a cycle-dependent manner, supporting consolidation chemotherapy and the total neoadjuvant therapy paradigm for locally advanced rectal cancer.

Key Limitations

Nonrandomized sequential-cohort design with potential temporal and selection bias. pCR is a surrogate endpoint, not survival. Increasing toxicity with more cycles. Definitive practice change rests on subsequent randomized TNT trials.

Clinical Context

This trial helped motivate the consolidation-chemotherapy approach within total neoadjuvant therapy, now an ESMO-endorsed strategy for locally advanced rectal cancer, later validated by OPRA, PRODIGE 23, and RAPIDO. No drug approval arises directly from this study.

References