Current stages of adjuvant treatment of colon cancer.

In 1990, Moertel et al. [1] established the use of adjuvant therapy with fluoropyrimidine in stage III colon cancer. While the initial treatment had a duration of 1 year, subsequent studies demonstrated equivalent efficacy for a 6-month treatment duration with 5-fluorouracil (5-FU) in combination with folinic acid (FA) [2]. The absolute increase in survival gain is ∼15%. Investigators from the X-act study [3] reported that the oral fluoropyrimidine capecitabine was non-inferior to the classical bolus 5-FU/FA regimen. A total of 1987 patients entered this study. Of note is that the initially applied capecitabine dose of 2500 mg/m given on days 1–14, repeated on day 21 had to be reduced in ∼60% of patients due to gastrointestinal toxic effect and hand–foot syndrome. This creates some uncertainty for those patients, in which capecitabine rather than i.v. 5-FU is considered. Patients treated with capecitabine had a 5-year overall survival of 71.4% when compared with 68.4% for patients with bolus 5-FU folinic acid. The hazard ratio of 0.86 even indicated a slight albeit non-statistically significant superiority of capecitabine over bolus 5-FU/folinic acid (P-value of 0.06). Nevertheless, this study demonstrated that capecitabine is an alternative to i.v. bolus 5-FU/folinic acid. André et al. [4] reported that infusional 5-FU in combination with oxaliplatin (FOLFOX 4 regimen) was superior over infusional 5-FU–folinic acid alone with a hazard ratio of 0.80 [95% confidence intervals (CIs) 0.65–0.97] and an absolute survival gain of 4.2% (P-value 0.023) in stage III colon cancer patients at 6 years. Such results were subsequently confirmed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) study C-07 [5] using bolus 5-FU–oxaliplatin (FLOX) instead of infusional FOLFOX. The indirect toxic effect comparison of the United States and the European regiment favours FOLFOX over FLOX. Based on these results, we would expect an additional 4% gain in survival accounting for a total of ∼20% for patients treated with FOLFOX when compared with those who received surgery only (Figure 1). Haller et al. [6] randomised a total of 1886 patients to receive the classical bolus 5-FU/folinic acid regimen or capecitabine in combination with oxaliplatin, at 7-year followup. A hazard ratio of 0.83 (95% CI 0.70–0.99, P-value = 0.0367) indicated that also capecitabine–oxaliplatin was able to improve the overall survival with a reduction of death due to colon cancer by 6%. There is no direct comparison of FOLFOX versus capecitabine–oxaliplatin in the adjuvant setting. To gain an understanding of the relative benefits of capecitabine, capecitabine–oxaliplatin, bolus 5-FU–oxaliplatin and infusional 5-FU–oxaliplatin (FOLFOX) against standard bolus 5-FU/folinic acid the results regarding hazard ratios, absolute differences and P-values are displayed in Table 1. According to this cross-trial comparison, FOLFOX appears to be the most efficacious one based on the hazard ratio of 0.80 (95% CI 0.66–0.98). The hazard ratio of capecitabine alone (0.86, 95% CI 0.69–1.01) is very close to the combination of capecitabine–oxaliplatin (0.83, 95% CI 0.70–0.99) reinforcing capecitabine as an alternative to oxaliplatin-containing regimens in those patients in which oxaliplatin is not desirable or acceptable due to side-effects or other reasons. Nevertheless, the 95% CIs of those hazard ratios are overlapping and physicians are encouraged to consider either of these regimens for their individual patients. Oxaliplatin is associated with long-lasting neuropathy. Fortunately, higher grades are mostly reversible after 1 year. Lower grades of toxic effect may last for several years and may be a burden to individual patients. As the survival gain is only estimated to be ∼4% in addition to what has already been achieved with 5-FU/ FA alone, a careful estimate of the benefit and toxic effects shall be discussed with the patient.