Survival Impact of CAPOX Versus FOLFOX in the Adjuvant Treatment of Stage III Colon Cancer

Published:February 06, 2018DOI:



      Capecitabine and oxaliplatin (CAPOX) and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) are both used in the adjuvant treatment of colon cancer, and while their efficacy is assumed to be similar, they have not been directly compared. We reviewed the toxicity profiles, relative dose intensity (RDI), and survival associated with these regimens across a multi-institutional cohort.

      Patients and Methods

      We identified 394 consecutively treated patients with stage III colon cancer who received an oxaliplatin-containing regimen. RDI was defined as the total dose received divided by the intended total dose if all cycles were received.


      FOLFOX was associated with increased mucositis (6.2% vs. 0.7%, P = .0069) and neutropenia (25.9% vs. 8.6%, P < .0001), while CAPOX was associated with increased dose-limiting toxicities (DLTs) (90.7% vs. 80.2%, P = .0055), diarrhea (31.8% vs. 9.0%, P < .0001), and hand–foot syndrome (19.9% vs. 2.1%, P < .0001). Higher median RDI of fluoropyrimidine (93.7% vs. 80.0%, P < .0001) and oxaliplatin (87.2% vs. 76.3%, P < .0001) was noted for patients receiving FOLFOX. Reducing the duration from 6 to 3 months would have prevented 28.7% of FOLFOX and 20.5% of CAPOX patients from ever experiencing a DLT (P = .0008). Overall survival did not differ by regimen (hazard ratio = 0.73; 95% confidence interval 0.45-1.22; P = .24). However, CAPOX was associated with improved disease-free survival (3-year disease-free survival 83.8% vs. 73.4%, P = .022), which remained significant in high-risk (T4 or N2) (P = .039) but not low-risk patients (P = .19).


      CAPOX may be associated with improved disease-free survival despite greater toxicities and lower RDI. Reducing adjuvant chemotherapy duration to 3 months would prevent 26% of patients from ever experiencing a DLT.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Colorectal Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Böckelman C.
        • Engelmann B.E.
        • Kaprio T.
        • Hansen T.F.
        • Glimelius B.
        Risk of recurrence in patients with colon cancer stage II and III: a systematic review and meta-analysis of recent literature.
        Acta Oncol (Madr). 2015; 54: 5-16
        • Loree J.M.
        • Cheung W.Y.
        Optimizing adjuvant therapy and survivorship care of stage III colon cancer.
        Future Oncol. 2016; 12: 2021-2035
        • Moertel C.G.
        • Fleming T.R.
        • Macdonald J.S.
        • et al.
        Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma.
        N Engl J Med. 1990; 322: 352-358
        • Haller D.G.
        • Catalano P.J.
        • Macdonald J.S.
        • et al.
        Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089.
        J Clin Oncol. 2005; 23: 8671-8678
      1. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators.
        Lancet. 1995; 345: 939-944
        • André T.
        • De Gramont A.
        • Vernerey D.
        • et al.
        Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to IIII colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study.
        J Clin Oncol. 2015; 33: 4176-4187
        • Maniadakis N.
        • Fragoulakis V.
        • Pectasides D.
        • Fountzilas G.
        XELOX versus FOLFOX6 as an adjuvant treatment in colorectal cancer: an economic analysis.
        Curr Med Res Opin. 2009; 25: 797-805
        • Di Costanzo F.
        • Ravasio R.
        • Sobrero A.
        • et al.
        Capecitabine versus bolus fluorouracil plus leucovorin (folinic acid ) as adjuvant chemotherapy for patients with Dukes' C colon cancer economic evaluation in an Italian NHS setting.
        Clin Drug Investig. 2008; 28: 645-655
        • Best J.
        • Garrison L.
        Economic evaluation of capecitabine as adjuvant or metastatic therapy in colorectal cancer.
        Expert Rev Pharmacoecon Outcomes Res. 2010; 10: 103-114
        • Ho M.Y.
        • Chang A.Y.
        • Ruan J.Y.
        • Cheung W.Y.
        Population-based cost-minimization analysis of CAPOX versus modified FOLFOX6 in the adjuvant treatment of stage III colon cancer.
        Clin Colorectal Cancer. 2016; 15: 158-163
        • Twelves C.
        • Scheithauer W.
        • Mckendrick J.
        • et al.
        Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy.
        Ann Oncol. 2012; 23: 1190-1197
        • Schmoll H.J.
        • Twelves C.
        • Sun W.
        • et al.
        Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controll.
        Lancet Oncol. 2014; 15: 1481-1492
        • Schmoll H.J.
        • Tabernero J.
        • Maroun J.
        • et al.
        Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results of the NO16968 randomized controlled phase III trial.
        J Clin Oncol. 2015; 33: 3733-3740
        • Cassidy J.
        • Clarke S.
        • Díaz-Rubio E.
        • et al.
        Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer.
        J Clin Oncol. 2008; 26: 2006-2012
        • Pectasides D.
        • Karavasilis V.
        • Papaxoinis G.
        • et al.
        Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or.
        BMC Cancer. 2015; 15: 384
        • Loree J.M.
        • Mulder K.E.
        • Ghosh S.
        • Spratlin J.L.
        Retrospective comparison of CAPOX and FOLFOX dose intensity, toxicity, and clinical outcomes in the treatment of metastatic colon cancer.
        J Gastrointest Cancer. 2014; 45: 154-160
        • Loree J.M.
        • Mulder K.E.
        • Ghosh S.
        • Spratlin J.L.
        CAPOX associated with toxicities of higher grade but improved disease-free survival when compared with FOLFOX in the adjuvant treatment of stage III colon cancer.
        Clin Colorectal Cancer. 2014; 13: 172-177
        • Mamo A.
        • Easaw J.
        • Ibnshamsah F.
        • et al.
        Retrospective analysis of the effect of CAPOX and mFOLFOX6 dose intensity on survival in colorectal patients in the adjuvant setting.
        Curr Oncol. 2016; 23: 171
        • Shi Q.
        • Sobrero A.F.
        • Shields A.F.
        • et al.
        Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): the IDEA (International Duration Evaluation of Adjuvant chemother.
        J Clin Oncol. 2017; 35 (abstract LBA1)
        • Edge S.B.
        • Byrd D.R.
        • Compton C.C.
        • Fritz A.G.
        • Greene F.L.
        • Trotti A.
        AJCC Cancer Staging Manual.
        7th ed. Springer, New York, NY2010
        • Google Developers
        The Google distance matrix API. 2015.
        (Available at:)
        • de Gramont A.
        • Van Cutsem E.
        • Schmoll H.J.
        • et al.
        Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial.
        Lancet Oncol. 2012; 13: 1225-1233
        • Saif M.W.
        • Hashmi S.
        • Zelterman D.
        • Almhanna K.
        • Kim R.
        Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review.
        Int J Colorectal Dis. 2008; 23: 139-145
        • Kerbel R.S.
        • Shaked Y.
        The potential clinical promise of “multimodality” metronomic chemotherapy revealed by preclinical studies of metastatic disease.
        Cancer Lett. 2017; 400: 293-304
        • Bocci G.
        • Kerbel R.S.
        Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect.
        Nat Rev Clin Oncol. 2016; 13: 659-673
        • Biagi J.J.
        • Raphael M.J.
        • Mackillop W.J.
        • Kong W.
        • King W.D.
        • Booth C.M.
        Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis.
        JAMA. 2011; 305: 2335-2342
        • Andre T.
        • Boni C.
        • Navarro M.
        • et al.
        Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.
        J Clin Oncol. 2009; 27: 3109-3116
        • Winterhalder R.
        • Hoesli P.
        • Delmore G.
        • et al.
        Self-reported compliance with capecitabine: findings from a prospective cohort analysis.
        Oncology. 2011; 80: 29-33
        • Bhattacharya D.
        • Easthall C.
        • Willoughby K.A.
        • Small M.
        • Watson S.
        Capecitabine non-adherence: exploration of magnitude, nature and contributing factors.
        J Oncol Pharm Pract. 2012; 18: 333-342