Patients with clinical stage T2N1 or T3N0–1 rectal cancers who are eligible for sphincter-sparing surgery might be able to avoid preoperative radiotherapy if given induction FOLFOX prior to surgery.

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.

Comment

The large, well-conducted trial indicates that the vast majority of patients with clinical stage T2N1 or T3N0–1 rectal cancers who are eligible for sphincter-sparing surgery can avoid the use of preoperative radiotherapy if given induction FOLFOX. This trial will change practice. The use of radiotherapy preoperatively will increasingly be relegated to more advanced rectal cancers or to patients requiring a permanent colostomy.