Preoperative Treatment of Locally Advanced Rectal Cancer

Abstract

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: We conducted a multicenter, unblinded, noninferiority, 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. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio 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 noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 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 was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

Figure 1.. Enrollment, Randomization, and Follow-up.

Sites were not required to provide screening logs during the recruitment phase, and therefore the number of patients assessed for eligibility is not available. FOLFOX consists of fluorouracil, leucovorin, and oxaliplatin; the chemoradiotherapy used in the trial consisted of pelvic radiation therapy plus sensitizing chemotherapy with a fluoropyrimidine. Patients in the FOLFOX group received six cycles of FOLFOX, with chemoradiotherapy given only if the primary tumor decreased in size by less than 20% or if FOLFOX was discontinued because of side effects; patients in the chemoradiotherapy group received chemoradiotherapy alone.

Figure 2. Noninferiority Margin and Kaplan–Meier Curves for Disease-free Survival, Overall Survival, and Freedom from Local Recurrence.

In Panel A, the dashed line at a hazard ratio of 1.29 indicates the noninferiority margin. Values to the left of 1.29 are those for which FOLFOX with selective use of chemoradiotherapy would be considered noninferior to chemoradiotherapy alone with respect to disease-free survival. The adjusted hazard ratio was estimated with a multivariable Cox model with adjustment for age and nodal status (node-positive vs. node-negative). The widths of the confidence intervals in Panels C and D have not been adjusted for multiplicity, and therefore these intervals should not be used to infer definitive treatment effects. NI denotes noninferiority.