Taxanes and capecitabine in combination: rationale and clinical results.
The clinical utility of capecitabine as a single agent in metastatic breast cancer has been demonstrated with significant responses seen in women already treated with anthracyclines and taxanes. A phase II study in older women with metastatic breast cancer demonstrated capecitabine to be an effective front-line therapeutic agent. Clinical trials of capecitabine in combination with the taxanes, paclitaxel and docetaxel, have been based on the observed upregulation of thymidine phosphorylase (TP) in preclinical studies. This taxane-mediated upregulation is synergistic, time dependent, and persists for up to 10 days. Studies of taxanes administered every 3 weeks with capecitabine have shown favorable antitumor responses and the combination of a taxane with capecitabine was favored over a taxane alone. The day-to-day administration of taxanes and capecitabine led to toxicity concerns, which have hindered their daily use. The administration of taxanes on a weekly schedule has demonstrated a more favorable toxicity profile (i.e., less myelosuppression), and initial studies in combination with capecitabine have demonstrated their utility in various solid tumors. Schedule optimization based on the upregulation of TP may result in a greater therapeutic index, thus allowing for the determination of the most advantageous way of combining these agents.
Maher
James F
JF
Department of Medicine, Arthur G. James Cancer Hospital, Richard J. Solove Research Institute, Ohio State University, B406 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210-1240, USA.
Villalona-Calero
Miguel A
MA
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016019:Survival Analysis; D043823:Taxoids; D013939:Thymidine Phosphorylase / Q000187:drug effects; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C080625:taxane; D000069287:Capecitabine; D013939:Thymidine Phosphorylase; D017239:Paclitaxel; D005472:Fluorouracil