Severe sequence-specific toxicity when capecitabine is given after fluorouracil and leucovorin

Purpose Options for single-agent fluoropyrimidine adjuvant therapy after bowel cancer resection include intravenous fluorouracil with leucovorin (FU/LV) or oral capecitabine. These treatments have similar efficacy but differ in convenience and toxicity. We therefore wished to compare their overall acceptability to patients. Patients and Methods Patients scheduled for adjuvant single-agent fluoropyrimidine therapy were randomly allocated to receive once-weekly FU/LV (425 mg/m 2 FU, 45 mg LV) for 6 weeks followed by two 3-week cycles of capecitabine (1250 mg/m 2 b.d., days 1-14), or the same treatments in reverse order. After 12 weeks, patients were asked which treatment they preferred, and received this for a further 12 weeks. The primary endpoint was patient preference. Results Real-time adverse event monitoring led to early trial closure, after 40 of the planned 74 patients had been randomized, because of excess sequence-specific toxicity. Eleven of 14 (79%) patients receiving capecitabine as their second treatment experienced grade ≥3 toxicity. This compared with 5/18 (28%) receiving capecitabine first and none receiving FU/LV first (0/16) or second (0/12). Similar imbalances were seen in the proportion of patients requiring interruption of treatment. Conclusion In chemo-naïve patients, capecitabine produced more toxicity than FU/LV, but at levels in line with previously reported data. However, treatment with capecitabine after FU/LV caused markedly increased toxicity, indicating a sequence-specific interaction. The mechanism has not been determined, but interaction with intracellularly retained folate after FU/LV therapy is a possibility. Oncologists need to be aware of this risk if considering crossing patients over from FU/LV to capecitabine-based regimens.