Novel Regimens of Capecitabine Alone and Combined with Irinotecan and Bevacizumab in Colorectal Cancer Xenografts

Background: Xenograft and mathematical models have shown that the antitumor activity of capecitabine can be increased by modifying the schedule from 14 days on, 7 off (14/7) to 7/7. Materials and Methods: Capecitabine at two-thirds maximum tolerated dose (MTD) administered using 14/7 (267 mg/kg) and 7/7 (467 mg/kg) schedules, alone and in doublet and triplet combinations with irinotecan (40 mg/kg intraperitoneally) and bevacizumab (5 mg/kg intraperitoneally) were studied in mice bearing HT29 colorectal xenografts. Results: Tumor growth inhibition was >100% in doublet and triplet regimens with capecitabine 7/7 compared with 70% and 98% , respectively, with 14/7. Increase in lifespan was significantly greater with the 7/7 triplet than the corresponding doublet without bevacizumab (288% versus 225% , respectively). Conclusion: Addition of bevacizumab to capecitabine and irinotecan significantly improved tumor growth inhibition and lifespan in the HT29 xenograft model. Modifying the capecitabine schedule from 14/7 to 7/7 improved the efficacy of doublet and triplet combinations without toxicity. Combination chemotherapy regimens comprising a fluoropyrimidine with either oxaliplatin or irinotecan are now recommended as first-line treatment for patients with advanced colorectal cancer (CRC) (1), although the optimum treatment strategy remains to be defined (2). Irinotecan, a DNA topoisomerase I inhibitor with significant in vitro and clinical activity against metastatic CRC (3-7), was the first chemotherapeutic agent to show a survival benefit when added to traditional fluoropyrimidine-based therapy (8). Treatment with irinotecan, fluorouracil and leucovorin (IFL) reduced the risk of progression by 36% and the risk of death by 22% compared with fluorouracil and leucovorin (5-FU/LV) (8). The addition of bevacizumab, a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF) (9-11), to fluoropyrimidine-irinotecan combination chemotherapy (IFL) resulted in a further improvement in survival in patients with metastatic CRC (44% reduction in risk of death) (12). Recently, infused 5- FU/LV was shown to be more effective than bolus 5-FU in regimens including irinotecan and bevacizumab (13, 14). In this phase III trial, FOLFIRI (infusional 5-FU/LV and irinotecan) plus bevacizumab conferred a statistically significant overall survival benefit when compared with modified IFL (bolus irinotecan and 5-FU/LV) plus bevacizumab (14).