Question: What is the role of oxaliplatin combined with 5-fluorouracil (5-fu) and folinic acid (FA) in the first- and second-line treatment of advanced (unresectable locally advanced or metastatic) colorectal cancer? Perspectives: Evidence was selected and reviewed by two members of the Gastrointestinal Cancer Disease Site Group (GI DSG) of Cancer Care Ontario’s Program in Evidence- Based Care (PEBC) and by a methodologist. The resulting practice guideline report has been reviewed and approved by the GI DSG, which comprises medical and radiation oncologists, surgeons, a pathologist, and patient representatives. External review by Ontario practitioners was obtained through a mailed survey. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee. Outcomes: Outcomes of interest were 1-year survival, response rates, and quality of life. Methodology: The MEDLINE, CANCERLIT, EMBASE, Guidelines International Network, and Cochrane Library databases were systematically searched for relevant studies. Recommendations were formed based on the evidence reviewed. Through a survey, these recommendations were appraised by Ontario clinicians; the recommendations were then revised by the GI DSG. The systematic review and modified recommendations were approved by a review body within PEBC. Results: The literature review found twenty-one randomized controlled trials and two meta-analyses. Evidence on first-line treatment found infusional 5-FU/FA/oxaliplatin (FOLFOX) to be superior to bolus 5-FU/FA/irinotecan (IFL) for rates of median survival and tumour response, with lower incidences of most adverse effects except peripheral neuropathy. For second-line treatment after fluoropyrimidine monotherapy, FOLFOX is a reasonable alternative for patients with contraindications to second- line irinotecan. After progression on infusional 5-FU/FA/irinotecan (FOLFIRI), FOLFIRI is the preferred therapy. Evidence from a single randomized trial suggests that additional benefits can be expected with the addition of bevacizumab to the FOLFOX regimen in second- line treatment. Practice Guideline: These recommendations apply to adult patients with advanced colorectal cancer who have high performance status (Eastern Cooperative Oncology Group score 0–2). Refer to Appendix A for available treatment options and to Appendix B for recommended dosages and schedules. The FOLFOX regimen is an important component of therapy for advanced colorectal cancer. First-line Therapy In one trial, FOLFOX was shown to be superior to IFL. The FOLFOX regimen has superior rates of median survival and tumour response. Compared with IFL, FOLFOX has lower incidences of severe nausea, vomiting, diarrhea, and febrile neutropenia, but a higher incidence of peripheral neuropathy. Short-term infusional 5-FU/FA in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are both acceptable alternatives for fit patients when combination therapy is the preferred treatment. Choice of first-line therapy may rely on patient factors and preferences—for example, less neuropathy with irinotecan versus less alopecia with oxaliplatin. Second-line Therapy After progression on first-line anti-thymidylate synthase monotherapy (for example, 5-FU/FA, capecitabine), irinotecan is standard secondline therapy. The FOLFOX regimen is a reasonable alternative for patients with contraindications to the use of second-line irinotecan. After progression on both irinotecan and an antithymidylate synthase agent, FOLFOX is the preferred therapy. Recent trials suggest that, as compared with FOLFOX alone, FOLFOX combined with bevacizumab provides additional survival benefits. Qualifying Statements: The role of radiation therapy, either alone or in combination with chemotherapy, for locally advanced unresectable colorectal cancer is not addressed in this guideline. Use of chronomodulated regimens is a topic that intersects with the use of oxaliplatin/5-FU combinations, particularly chronomodulation of 5-FU in these combinations. Chronomodulation of oxaliplatin has not been extensively studied, and the topic of chronomodulation is beyond the scope of this guideline and is not addressed. Although data exist to support the use of bevacizumab in combination with FOLFOX in second-line treatment, no first-line treatment data are available on which to make a recommendation.