The role of 5-fluorouracil dose in the adjuvant therapy of colorectal cancer

BACKGROUND: In many centres, the use of 5-fluorouracil (5-FU) combined withlevamisole has become standard ther apy for the treatment ofpatients with Dukes' C colon cancer. However, the role of levarnisoleremains unclear. MATERIALS AND METHODS: All of the published adjuvant studies for colorectal cancerin which 5-FU (either as a single agent or in combination withother cytotoxics or levamisole) was compared to a no-treatmentcontrol group were ranked according to the total planned doseof 5-FU (assuming a body weight of 70 kg or a body surface areaof 1.7 m over a three-month time frame. The effect of plannedtotal dose of adjuvant therapy on the reduction of mortalitywas analysed using indirect comparisons of dose on the log oddsratio of death in a linear regression analysis. RESULTS: Overall, this analysis demonstrated a significant reductionin the odds of death for those receiving 5-VU regi mens comparedto untreated controls (estimate 0.82, 95% CI 0.74 to 0.91, p< 0.001). This effect was larger in those re ceiving a largerplanned dose; for a total dose of 5-VU in the first three monthsof greater than 10 grams, 8 to 10 grains, less than 8 gramsor oral 5-PU, estimates were 0.71, 0.79, 0.93 and 1.04, respectively(p=0.02 for trend). Similar results were observed when the plannedtotal dose of 5-VU received over 12 months was analysed. Theanalysis was then repeated by separating those studies in which5-PU and leva misole were compared to a no-treatment control.A larger effect was seen in the 5-FU/levamisole trials (oddsratio, 0.64) compared to the other 5-Hi regimens (odds ratio0.86, p=0.04). However, when adjusted for dose, the effect oflevamisole was no longer significant (p=0.09). CONCLUSION: These data suggest two separate hypotheses. The first is thatthe benefit associated with the use of 5-FU and levamisole givenas adjuvant therapy in Dukes' C colon cancer is directly relatedto the planned total dose of 5-FU administered. Alternatively,in view of the fact that levami sole was part of the treatmentregimens in two of the three studies in which the total planneddose of 5-FU exceeded 10 grams in three months (or 40 grainsin 12 months), levamisole may be critical to outcome and the5-FU total dose or dose intensity less relevant. colorectal carcinoma, dose intensity, 5-fluorouracil, levamisole, total dose