Preoperative Chemotherapy Without Radiotherapy for Locally Advanced Rectal Cancer

Total neoadjuvant therapy for patients with locally advanced rectal cancer — whereby chemoradiotherapy and chemotherapy are administered prior to surgery — offers the potential for enhanced treatment tolerance and delivery, improvements in pathologic response at surgery, and nonoperative management for colostomy candidates who achieve a clinical complete response. However, for patients with high- or mid-rectal cancers undergoing total mesorectal excision, the role of neoadjuvant radiotherapy has been increasingly questioned.

To test the concept of avoiding neoadjuvant radiotherapy in this setting, investigators conducted a multicenter, noninferiority, randomized, phase 3 trial (PROSPECT) involving 1128 patients with clinical stage T2N1 or T3N0–1 high- or mid-rectal cancer who were candidates for sphincter-sparing surgery. Most patients were male, half had T3N1 cancers, 91% had T3N0–1 cancers, and 64% had cancers 5 to 10 cm from the anal verge. Half of patients received conventional neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy. The other half received induction chemotherapy with 6 cycles of FOLFOX, and those with a ≥20% reduction in the primary tumor proceeded to surgery without radiotherapy and received adjuvant chemotherapy.

At 5 years, disease-free survival was noninferior with induction FOLFOX versus chemoradiotherapy (80.8% vs. 78.6%; hazard ratio, 0.92, P=0.005), meeting the primary endpoint. Rates of local recurrence were similar with FOLFOX or chemoradiotherapy (1.8% and 1.6%, respectively), as were 5-year overall survival (89.5% and 90.2%) and pathologic complete response (21.9% and 24.3%). Nearly 90% of patients treated with FOLFOX avoided radiotherapy; 9.1% required neoadjuvant chemoradiotherapy after FOLFOX, and 1.4% required postoperative chemoradiotherapy. No new safety signals were observed.