Nodal status is the single most important prognostic factor in colon cancer and recurrences are often systemic.

5-fluorouracil (5-FU)/leucovorin (LV)-based adjuvant chemotherapy is now considered to be the standard of care for stage III disease in the USA.

Historically, single-agent chemotherapeutic agents such as thiotepa or fluoropyrimidines did not prove helpful. Combination trials of chemotherapy and immune modulators helped refine the recommendations made for adjuvant treatment.

The National Institutes of Health published a consensus statement in 1990 establishing 5-FU plus levamisole as the standard adjuvant therapy for stage III colon cancer.

While the usefulness of 5-FU/levamisole in stage III disease was being confirmed, leucovorin emerged as a beneficial agent for the treatment of metastatic disease. Its applicability to stage II and stage III disease was confirmed by the IMPACT (International Multicenter Pooled Analyses of Colon Cancer Trials) study in 1995; 3-year disease-free survival increased from 62 to 71 % (p = 0.0001), while overall survival increased from 78 to 83 % (p = 0.029) in the 5-FU/leucovorin group.

The relative merits of levamisole and leucovorin as modulators of 5-FU-based adjuvant chemotherapy and the optimal duration of treatment were documented in studies between 1998 and 2000.

Based on these studies, treatment was changed to 6 months of adjuvant chemotherapy with 5-FU/leucovorin for stage III disease.

While the efficacy and benefits of adjuvant chemotherapy for stage III node-positive disease are unequivocal, the role of adjuvant chemotherapy for stage II node-negative disease remains controversial.

The likelihood of reaching a resolution on this subject is remote: in order to detect a significant survival benefit among stage II colon cancer patients (who have an estimated 5-year survival of 80 %), an adjuvant trial with a no-treatment control arm would require a sample size of 5,000–8,000 patients.

Irinotecan and oxaliplatin are effective in treating stage IV (metastatic) colorectal cancer but no survival advantage was achieved by adding irinotecan to 5-FU (5-year survival was 74 % vs. 71 %) and toxicity (gastrointestinal and hematologic) was increased for stage III disease.

The multicenter international randomized MOSAIC trial confirmed that the addition of oxaliplatin to 5-FU/leucovorin (FOLFOX) further decreases the risk of recurrence in stage II and stage III disease by 23 %, resulting in a significant improvement in 3-year disease-free survival.

This improvement in survival has proven durable in stage III disease and 6-year overall survival recently has been reported to be 73 % in the FOLFOX group compared to 69 % in the 5-FU group. Toxicity also proved to be acceptable, with fewer than 1.5 % of patients experiencing grade 3 peripheral sensory neuropathy.

For stage II patients, the addition of oxaliplatin offered no survival advantage over 5-FU alone.

As a result of these studies, FOLFOX is now recommended for adjuvant therapy in stage III colon cancer. In select stage II patients, especially those with high-risk features such as T4 tumors, vascular invasion, or poor differentiation, FOLFOX may have a role.