As reported in The New England Journal of Medicine by Deb Schrag, MD, MPH, FASCO, and colleagues, the phase III PROSPECT trial has shown neoadjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) was noninferior in disease-free survival vs chemoradiotherapy among patients with locally advanced rectal adenocarcinoma who were candidates for sphincter-sparing surgery.

The investigators stated, “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 FOLFOX can be used in lieu of chemoradiotherapy is uncertain.”

Deb Schrag, MD, MPH, FASCO

Study Details

In the open-label noninferiority trial, 1,128 patients who received any protocol treatment (per-protocol population) from sites in Canada, Switzerland, and the United States were randomly assigned between June 2012 and December 2018 to receive FOLFOX with selective use of chemoradiotherapy (n = 585) or chemoradiotherapy alone (n = 543). Eligible patients were clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive. Patients in the FOLFOX group could receive chemoradiotherapy if the decrease in primary tumor was < 20% or if FOLFOX was discontinued due to adverse events. FOLFOX was given as six cycles of modified FOLFOX6 every 2 weeks. Chemoradiotherapy consisted of pelvic radiotherapy at 50.4 Gy in 28 fractions, plus sensitizing fluoro­pyrimidine chemotherapy with fluorouracil or capecitabine.

The primary endpoint was disease-free survival in the per-protocol population; noninferiority was 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.

Disease-Free Survival

Median follow-up was 58 months. Overall, 53 patients (9.1%) in the FOLFOX group received neoadjuvant chemoradiotherapy. FOLFOX was noninferior to chemoradiotherapy for dis­ease-free survival (hazard ratio [HR] = 0.92, 90.2% confidence interval [CI] = 0.74–1.14, P = .005 for noninferiority). Disease-free survival at 5 years was 80.8% (95% CI = 77.9%–83.7%) vs 78.6% (95% CI = 75.4%–81.8%).

Five-year overall survival was 89.5% in the FOLFOX group vs 90.2% in the chemoradio­therapy group (HR = 1.04, 95% CI = 0.74%–1.44%). The incidence of local recurrence at 5 years was 1.8% vs 1.6% (HR = 1.18, 95% CI = 0.44%–3.16%). Among 535 vs 510 patients who underwent surgery, pathologic complete response was observed in 21.9% vs 24.3% and R0 resection was achieved in 98.9% vs 97.1%. 

Adverse Events

During neoadjuvant therapy, grade ≥ 3 adverse events occurred in 41.0% of the FOLFOX group vs 22.8% of the chemoradiotherapy group. The most common in the FOLFOX group were neutropenia (20.3%), pain (3.1%), and hypertension (2.9%); the most common in the chemoradiotherapy group were lympho­penia (8.3%), diarrhea (6.4%), and hypertension (1.7%).

Neuropathy was more common and severe in the FOLFOX group; diar­rhea was more common and severe in the chemo­radiotherapy group.

The investigators concluded, “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.”

Dr. Schrag, of the Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit nejm.org.