Modifying the
capecitabine dosing schedule from 14 days on, 7 days off (14/7) to 7 days on, 7 days off (7/7) may enable higher doses and improved antitumor efficacy in
colorectal cancer xenografts.
Capecitabine 14/7 (267 or 400 mg/kg) and 7/7 (467 or 700 mg/kg) schedules in doublet and triplet combinations with optimally dosed
bevacizumab (5 mg/kg) and
oxaliplatin (6.7 mg/kg) were studied in female athymic nude mice bearing HT29 colorectal xenografts. Additional studies of suboptimally dosed
bevacizumab (2.5 mg/kg) and
capecitabine 7/7 (360 mg/kg) were done in a similar Colo205
tumor xenograft model. Monotherapy and combination regimens were administered to groups of 10 animals and compared with vehicle controls. In the HT29 model,
tumor growth inhibition and increase in life span (ILS) were significantly greater with
capecitabine 7/7 than with 14/7 (P<0.05). The additional benefit of
capecitabine 7/7 versus 14/7 was biologically significant according to National Cancer Institute criteria (>25% ILS). Adding
bevacizumab to
capecitabine 7/7 resulted in significantly greater survival relative to either agent alone (P<0.0001). When
oxaliplatin was added, efficacy was significantly better with the triplet combination including
capecitabine 7/7 (
tumor growth inhibition>100% and ILS 234%) compared with 14/7 (95% and 81%, respectively). In the Colo205 model, combination
therapy with
capecitabine 7/7 plus
bevacizumab resulted in significantly greater survival relative to either agent alone (P<0.0001). In conclusion, in athymic nude mice bearing moderately
thymidine phosphorylase-expressing HT29 or Colo205 colorectal xenografts, a
capecitabine 7/7 schedule permits increased
drug delivery compared with traditional 14/7 regimens, greatly improving monotherapy activity without major toxicity.