Lay Summary: Folfox is a standard of care treatment for stage III and probably stage II colon cancer. It is recommended by NCCN and other guidelines. It is FDA approved: ELOXATIN, used in combination with infusional 5-FU/LV, is indicated for adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
and treatment of advanced colorectal cancer.
Approximately 80,000 patients will be diagnosed with either stage II or stage III colon cancer in 2007. Although some controversy still exists regarding the role of adjuvant therapy for patients with stage II disease (but newer studies are beginning to show benefit even is stage II), studies have confirmed the benefits of treatment for those with stage III disease.
The use of DFS as a primary endpoint in colon cancer adjuvant trials was further demonstrated by the updated results of the MOSAIC [Multi-center International Study of Oxaliplain/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer] trial, which compared the benefit of adding oxaliplatin to 5-FU/leucovorin (LV) (FOLFOX 4) as adjuvant treatment compared with 5-FU/LV alone. The 3-year DFS with FOLFOX 4 was 78.2% vs 72.9% for 5-FU/LV alone (hazard ratio [HR] = 0.77; P = .002). At 5 years, overall survival remained superior with FOLFOX 4 (73.3% vs 67.4%; HR = 0.80; P = .03). The survival benefit (82.1% vs 74.9 %; HR = 0.74) was seen primarily in “high-risk” patients with stage II disease (ie, T4, bowel obstruction/perforation, poorly differentiated tumors, venous invasion, or fewer than 10 examined nodes) and in those with stage III disease (66.4% vs 58.9%; HR = 0.78; P = .005). The addition of oxaliplatin did not appear to benefit patients with low-risk stage II disease. Median follow-up at 6 years revealed that the benefit of FOLFOX 4 was confined to patients with stage III disease: 73.0% vs 68.6%; HR = 0.8; P = .029. For those with stage II disease, survival at 6 years was equivalent, nearly 87% with either 5-FU/LV or FOLFOX 4.
Toxicities associated with oxaliplatin, such as neutropenia, were common (41%), but febrile neutropenia was uncommon (1.8%). Peripheral neuropathy developed in approximately 15% of patients, but grade 3 neuropathy was seen in only 0.7%, indicating significant recovery from the neurosensory effects of oxaliplatin in the vast majority of patients.
These data clearly support the treatment of patients with stage III colorectal cancer with FOLFOX-based adjuvant regimens as an acceptable standard of practice. These results are consistent with those of the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial, which demonstrated efficacy with addition of oxaliplatin to bolus 5-FU/LV as adjuvant treatment. Guidelines still support adjuvant chemo for stage II colon cancer but with reservation. NCCN on p. 47 discusses that only a Disease free survival has been revealed in some studies and that treatment should be individualized to higher risk disease and decisons made with full explanation to the patient.
Oral fluoropyrimidines such as capecitabine have been tested in the adjuvant treatment of patients with stage III disease, and the combination with oxaliplatin appears to have acceptable toxicities. Efficacy data are not yet available and are reviewed under Xelox.
Sargent DJ, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group. Time dependent patterns of failure and treatment benefit from adjuvant therapy for resectable colon cancer. Lessons from the 20,800 patient ACCENT dataset. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4008. O’Connell MJ, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group. Survival following recurrence in patients with adjuvant colon cancer: findings from the 20,800 patient ACCENT dataset. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4009. de Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with median follow up of six years. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4007. Wolmark N, Wieand S, Kuebler JP, Colangelo L, Smith RE. A phase III trial comparing 5FU/LV to 5FU/LV and oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP protocol C07. Proc Am Soc Clin Oncol. 2005;25:264s. Abstract LBA3500. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696-2704