Colon to Rectum
N Engl J Med. 2023;389(4):322–34
Preoperative treatment of locally advanced rectal cancer
Background: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain.
Methods: The authors conducted a multicenter, unblinded, non-inferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by < 20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Non-inferiority would be claimed if the upper limit of the 2-sided 90.2% confidence interval (CI) of the hazard ratio (HR) for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects.
Results: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was non-inferior to chemoradiothera py for disease-free survival (HR for disease recurrence or death = 0.92; 90.2% CI: 0.74–1.14; p = 0.005 for non-inferiority). Five-year disease-free survival was 80.8% (95% CI: 77.9–83.7) in the FOLFOX group and 78.6% (95% CI: 75.4–81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (HR for death = 1.04; 95% CI: 0.74–1.44) and local recurrence (HR = 1.18; 95% CI: 0.44–3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy.
Conclusions: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX (fluorouracil, leucovorin, and oxaliplatin) was non-inferior to preoperative chemoradiotherapy with respect to disease-free survival.