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XELOX as Adjuvant Therapy for Stage III Colon Cancer
The treatment of stage III colon cancer mandates systemic chemotherapy.1 Over the decades, the standard of care for adjuvant chemotherapy has advanced from fluorouracil (5-FU) + folinic acid (FA) to more modern therapies such as oxaliplatin. An oral fluoropyrimidine, capecitabine, has been approved as monotherapy for stage III CRC; however, clinical trials attempting to show an overall survival benefit for capecitabine in combination with oxaliplatin have failed to meet the study endpoint. NO16968 (XELOX in Adjuvant Colon CancerTreatment [XELOXA]), a multinational randomized study, was designed to investigate adding oxaliplatin to an oral fluoropyrimidine in the adjuvant treatment of colon cancer,while maintaining efficacy of treatment compared to earlier trials and offering a potentially more convenient regimen. Oxaliplatin was combined with capecitabine (XELOX) and compared with bolus 5-FU/FA (Mayo Clinic [MC] or Roswell Park[RP] regimens) in patients with stage III colon cancer. Bolus 5-FU/FA was selected as the comparator regimen as it was the global standard of care at the time NO16968 was designed. Haller and colleagues reported the primary efficacy analysis from NO16968 in a recent issue of the Journal of Clinical Oncology.2

Patients and Methods

Patients who had undergone curative resection were randomly assigned to XELOX (oxaliplatin 130mg/m2 on day 1 plus capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks for 24weeks) or a standard bolus 5FU/FA adjuvant regimen (MC for 24 weeks or RP for32 weeks). The primary study end point was disease-free survival (DFS), defined as the time between random assignment and recurrence; the occurrence of a new primary colon cancer, death from any cause, or the last date at which the patient was known to be disease free.2


The intention-to-treat population comprised 1,886 patients; 944 patients were randomly assigned to XELOX and 942 to 5FU/FA (MC, n = 664; RP, n = 278). After 57 months of follow-up for the primary analysis, 295 patients (31.3%) in the XELOX group had relapsed,developed a new primary colon cancer, or died compared with 353 patients (37.5%) in the FU/FAgroup (hazard ratio [HR] for DFS, 0.80; 95% CI, 0.69 to 0.93; P = .0045). The 3-year DFS rate was70.9% with XELOX and 66.5% with FU/FA. The hazard ratio (HR) for overall survival (OS) for XELOX comparedto FU/FA was 0.87 (95% CI, 0.72 to 1.05; P = .1486). The 5-year OS for XELOX and 5-FU/FA were77.6% and 74.2%, respectively.2

The authors concluded that the results of NO16968 show that XELOX is superior to bolus 5-FU/FA in terms of DFS, the primary study endpoint, as adjuvant therapy for stage III colon cancer. Predefinedmultivariate analyses were supportive of the primary efficacy findings.The superiority of XELOX compared with 5FU/FA was maintained at 4 and 5 years, indicating that the benefits of XELOX are durable. The statistically significant and clinically relevant improvement in 3-year DFS in NO16968 is important given that 3-year DFS is a strong predictor of 5-year OS for both fluoropyrimidine monotherapy and combination chemotherapy, and is recognized by regulatory authorities as a primary end point for adjuvant colon cancer trials. These findings should therefore be viewed as robust evidence of the efficacy of XELOX as adjuvant therapy in stage III colon cancer.2 Follow-up is ongoing to assure that the clinical benefit of the XELOX regimen is maintained.

ManageCRC.com Commentary

While the Mayo and Roswell Park regimens may not be considered modern or standard of care, some clinics or economically disadvantaged world societies cannot provide oxaliplatin, or patients may not be able to tolerate a platinum-based regimen. Another consideration is the current shortage of leucovorin in the US.3 XELOX (sometimes referred to as CapeOX) provides an alternative at lower cost to the financial bottom line and patient side effects. Capecitabine (Xeloda), an oral 5-FU prodrug has been FDA-approved as monotherapy for treatment of stage III colon cancer in the US since 2005.  Clinicians have been using Xeloda off label in XELOX-type regimens for years, basing their judgment on the monotherapy clinical study, X-ACT.4 An important cautionary note posited by a member of this website’s Advisory Panel is that Xeloda monotherapy studies showing non-inferiority to intravenous fluorouracil may prompt clinicians to freely substitute Xeloda in regimens for colon cancer, assuming that it should be an equivalent substitute in a combination regimen. However, that assumption does not take into account there may be a synergistic mechanism of action that is present in intravenous administration that cannot be duplicated with an oral prodrug. If that possibility is ruled out, then FDA approval for a new indication - Xeloda in combination with oxaliplatin (XELOX) - is needed to eliminate issues with reimbursement.


  1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) Colon Cancer v 3.1011. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf (Free registration required.)
  2. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011; 29:1465-1471. doi:10.1200/JCO.2010.33.6297  Link to abstract http://jco.ascopubs.org/content/early/2011/03/07/JCO.2010.33.6297.abstract
  3. United States Food & Drug Administration (FDA). Current Drug Shortages. February 2011. Retrieved from http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm
  4. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III coloncancer. N Engl J Med 2005;352:2696-2704. Link to free full text http://www.nejm.org/doi/pdf/10.1056/NEJMoa043116

Article Created On : 5/2/2011 1:55:37 PM             Article Updated On : 5/2/2011 1:55:37 PM