Background
Randomized phase II/III noninferiority trial of 1194 patients with locally advanced rectal cancer (T2N+, T3N+, or T3N-) who were candidates for sphincter-sparing surgery, median tumor distance 8 cm from the anal verge.
Interventions and follow up
Arm A: FOLFOX Q2W x6 cycles, then restaging; selective chemoradiotherapy (CRT) if <20% response or unable to complete ≥5 cycles, otherwise straight to surgery. Postoperative chemotherapy x6 cycles recommended
Arm B: Chemoradiotherapy 50.4 Gy in 28 fractions with concurrent fluorouracil 225 mg/m2 continuous IV or capecitabine 825 mg/m2 BID; postoperative chemotherapy recommended
Primary endpoint: Disease-free survival (noninferiority)
mFollow up: 58 mo
Arm B: Chemoradiotherapy 50.4 Gy in 28 fractions with concurrent fluorouracil 225 mg/m2 continuous IV or capecitabine 825 mg/m2 BID; postoperative chemotherapy recommended
Primary endpoint: Disease-free survival (noninferiority)
mFollow up: 58 mo
Results
5-yr DFS: 80.8% (Arm A) vs 78.6% (Arm B); HR 0.92, 90.2% CI 0.74–1.14; P=.005 for noninferiority
5-yr OS: 89.5% vs 90.2% (no significant difference)
CRT avoidance: 89.6% of Arm A patients avoided chemoradiotherapy
Local recurrence: Low and similar between arms (~1.8% vs 1.6%)
5-yr OS: 89.5% vs 90.2% (no significant difference)
CRT avoidance: 89.6% of Arm A patients avoided chemoradiotherapy
Local recurrence: Low and similar between arms (~1.8% vs 1.6%)
Adverse events
Arm A (grade ≥3, 41.0% overall): Neutropenia 20.3%, pain 3.1%, hypertension 2.9%
Arm B (grade ≥3, 22.8% overall): Lymphopenia 8.3%, diarrhea 6.4%, hypertension 1.7%
Arm B (grade ≥3, 22.8% overall): Lymphopenia 8.3%, diarrhea 6.4%, hypertension 1.7%
Conclusions
Neoadjuvant FOLFOX with selective chemoradiotherapy was noninferior to standard preoperative chemoradiotherapy for DFS in patients with locally advanced rectal cancer eligible for sphincter-sparing surgery, allowing most patients to avoid pelvic radiation.
Key Limitations
Enrolled lower-risk LARC (excluded T4 and bulky N2/threatened CRM); not applicable to total neoadjuvant therapy or organ-preservation (watch-and-wait) strategies; longer follow-up needed for late pelvic recurrence.
Clinical Context
PROSPECT supports a radiation-sparing, chemotherapy-first approach for selected lower-risk LARC, complementing ESMO-endorsed total neoadjuvant therapy for higher-risk disease. It enables individualized de-escalation away from pelvic radiotherapy, sparing long-term bowel, sexual, and fertility toxicity in appropriate candidates.
References