Capecitabine versus 5fluorouracil in colorectal c

Authors: Lakshmi Chintala Susmitha Vaka Joaquina Baranda Stephen K Williamson

Publish Date: 2011/04/09

Volume: 5, Issue: 2, Pages: 129-140

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Abstract

Fluorouracil 5FU remains the most widely used agent for colorectal cancer Capecitabine is a rationally designed 5FU prodrug developed to mimic the continuous infusion of 5FU while avoiding complications and inconvenience of intravenous administration Capecitabine is absorbed intact from the gastrointestinal tract converted enzymatically to active 5FU and released directly into the tumor Capecitabine’s efficacy and safety are shown in multiple phase III trials across different disease stages and therapy lines Three randomized phase III trials demonstrated the equivalence of capecitabine plus oxaliplatin XELOX versus 5FU/leucovorin LV/oxaliplatin FOLFOX The safety of capecitabine compared with 5FU depends on the regimen of 5FU used The adverse event rate with oxaliplatin in combination with infusional 5FU is similar to that of capecitabine plus oxaliplatin but is associated with more neutropenia and venous thrombotic events capecitabine plus oxaliplatinbased regimens tend to be associated with more grade 3 diarrhea and handfoot skin reaction Combination therapy with capecitabine and irinotecan CapeIRI versus 5FU/LV and irinotecan FOLFIRI had more variable results some former schedules resulted in excessive treatmentrelated toxicity More recent data show that lower capecitabine and irinotecan doses different schedules and combination with targeted agents eg bevacizumab have resulted in more favorable outcomesThe most widely used agent in the treatment of colorectal cancer CRC is fluorouracil 5FU which was developed more than 50 years ago by Heidelberger et al 1 5FU enters a complex anabolic process that interferes with normal DNA and RNA functions and accounts for cytotoxicity at the cellular level Because of poor oral absorption and intrapatient variability 5FU is most often administered intravenously IV as a rapid bolus injection it is rapidly distributed with triphasic elimination 2 Preclinical studies suggested that 5FU is a timedependent drug and that cytotoxicity increases with prolonged exposure 2 3 4 Therefore clinical trials were initiated with 5FU administered for extended periods 5 6 Response rates in CRC increased with continuous infusion compared with bolus administration with a more acceptable toxicity profile 7 8 Nevertheless the inconvenience of protracted IV administration provided a strong impetus for the development of oral fluoropyrimidines that could be taken conveniently on a schedule that simulates continuous infusion 9Capecitabine is an example of a rationally designed 5FU prodrug intended to mimic the continuous infusion of 5FU while avoiding the complications and inconvenience associated with IV drug administration It is a fluoropyrimidine carbamate that is converted to the active 5FU by the action of three enzymes an esterase a deaminase and a phosphorylase 9 In the third step the enzyme thymidine phosphorylase TP converts 5′deoxy5fluorouridine to 5FU which is released directly into tumor tissue 10 The enzyme TP has higher concentrations in many tumor types compared with matched normal tissue and is particularly higher in excised human colon cancer 11 This suggests that higher tumor concentrations of 5FU might be expected due to a higher production of active drug in the tumor tissue thereby providing a favorable targettonontarget ratio for toxicity Tumor selectivity and conversion of capecitabine to active 5FU within the tumor tissue have been confirmed in human samples that show a 32fold higher concentration of 5FU in tumor compared with normal tissue and a 21fold higher tumortoplasma ratio In comparison when IV 5FU is administered either by bolus or continuous infusion the concentration of active drug in tumor is not higher than that in normal tissue 11 The greater levels of the TP enzyme in tumor tissue allow for targeted intratumoral release of 5FU and subsequently less systemic toxicity compared with infusions of 5FU 12This review provides an uptodate literature review and overview of how capecitabine compares with 5FU as a single agent as well as in combination with oxaliplatin or irinotecan and in combination with targeted therapy in the treatment of CRC We review the available phase I II and III clinical trials conducted in patients with CRC that document the metabolic activation of this compound and support its use in patients with advanced CRC and how the drug may be incorporated into the standard care of patients with CRC

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