Author(s): Deborah Schrag, M.D., M.P.H., Qian Shi, Ph.D., Martin R. Weiser, M.D., Marc J. Gollub, M.D., Leonard B. Saltz, M.D., Benjamin L. Musher, M.D., Joel Goldberg, M.D., Tareq Al Baghdadi, M.D., Karyn A. Goodman, M.D., Robert R. McWilliams, M.D., Jeffrey M. Farma, M.D., Thomas J. George, M.D., Hagen F. Kennecke, M.D., Ardaman Shergill, M.D., Michael Montemurro, M.D., Garth D. Nelson, M.S., Brian Colgrove, B.S., Vallerie Gordon, M.D., Alan P. Venook, M.D., Eileen M. O’Reilly, M.D., Jeffrey A. Meyerhardt, M.D., M.P.H., Amylou C. Dueck, Ph.D., Ethan Basch, M.D., George J. Chang, M.D., and Harvey J. Mamon, M.D., Ph.D.
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.
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.
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.
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. opens in new tab.)
Author AffiliationsFrom the Departments of Medicine (D.S., L.B.S., E.M.O.), Surgery (M.R.W.), and Radiology (M.J.G.), Memorial Sloan Kettering Cancer Center, and the Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai (K.A.G.) — both in New York; Alliance Statistics and Data Management Center (Q.S., G.D.N., B.C., A.C.D.) and the Department of Oncology (R.R.M.), Mayo Clinic, Rochester, MN; SWOG Cancer Research Network and the Department of Medicine, Baylor College of Medicine (B.L.M.), and the Department of Colon and Rectal Surgery, M.D. Anderson Cancer Center (G.J.C.) — both in Houston; the Departments of Surgery (J.G.) and Radiation Oncology (H.J.M.), Brigham and Women’s Hospital, and the Department of Medical Oncology, Dana–Farber Cancer Institute (J.A.M.) — both in Boston; IHA Hematology Oncology, Ypsilanti, MI (T.A.B.); ECOG-ACRIN Cancer Research Network and Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia (J.M.F.); NRG Oncology and the University of Florida Health Cancer Center, Gainesville (T.J.G.); Canadian Cancer Trials Group, Kingston, ON (H.F.K.), and the Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg (V.G.) — both in Canada; Alliance Protocol Office, Chicago (A.S.); the Swiss Group for Clinical Cancer Research, Bern, Switzerland (M.M.); Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco (A.P.V.); and the Department of Medical Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill (E.B.).