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N Engl J Med. 2018 Mar 29;378(13):1177-1188. doi: 10.1056/NEJMoa1713709.

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.

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From the Divisions of Medical Oncology (A.G.) and Biomedical Statistics and Informatics (Q.S., J.P.M., L.A.R., D.J.S.), Mayo Clinic, Rochester, MN; Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Martino-IST, Genoa (A.F. Sobrero), Ospedale Papa Giovanni XXIII, Bergamo (R.L.), and IRCCS Mario Negri Institute for Pharmacological Research, Milan (V.T.) - all in Italy; Karmanos Cancer Institute, Wayne State University, Detroit (A.F. Shields); National Cancer Center Hospital East, Chiba (T. Yoshino), Yokohama City University School of Medicine, Yokohama (T. Yamanaka), and the University of Tokyo, Tokyo (T.W.) - all in Japan; the Institute of Cancer Sciences, University of Glasgow, Glasgow (J.P.), the University of Oxford, Oxford (R.K.), Christie Hospital, Manchester (M.S.), and University Hospital Southampton, Southampton (T.I.) - all in the United Kingdom; Hôpital Européen Georges-Pompidou, Sorbonne Paris Cite/Paris Descartes University (J.T.), and Saint-Antoine Hospital and Sorbonne Universités, Pierre and Marie Curie University-Paris 6 (T.A.), Paris, and Methodology and Quality of Life Unit, INSERM Unité 1098, Besançon (D.V.) - all in France; the Department of Medical Oncology, University Hospital of Heraklion, Faculty of Medicine, University of Crete, Heraklion (J.S.), and Bioclinic Thessaloniki, Thessaloniki (I.B.) - both in Greece; Dana-Farber Cancer Institute, Boston (J.A.M.); and Duke Cancer Institute, Durham, NC (D.N.).



Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures.


We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12.


After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority).


Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

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