Summary and Introduction
In the past 5–10 years there has been a growing trend for substituting conventional 5-fluorouracil with the oral prodrug of 5-fluorouracil, capecitabine, in chemotherapy regimens. This regimen change is based on evidence of the efficacy equivalence of these two drugs and the lack of an increase in overall toxic effects when capecitabine is used. Many investigators in different parts of the world have determined their own starting dose for capecitabine, usually based on their experience of toxic events within the population of patients they treat. This starting dose is usually between 1,000–1,250 mg/m,1 which is generally administered twice daily for 14 days followed by 7 days rest. This Review summarizes why there may indeed not be a universally applicable starting dose for capecitabine because of interpatient differences in basic physiology, pharmacogenomics and diet. This article also explores which of these factors contribute to the observed inter-regional geographical variation in capecitabine toxicity, and explains why even within a region various factors should prompt a clinician to modify the starting dose.
The most important step in the development of any drug is the definition of the dose that will be tested in phase III clinical trials and subsequently form the basis of all labeled indications. This fact is especially pertinent in cancer therapy, where most cytotoxic agents have a steep dose–response curve for toxicity and, consequently, narrow therapeutic windows. Capecitabine (Xeloda™; Roche, Nutley, NJ) is an oral prodrug of 5-fluorourarcil (5-FU) that undergoes a three-step enzymatic activation process to be converted to the active drug. This three-step pathway involves the enzymes carboxylesterase, cytidine deaminase and thymidine phosphorylase (Figure 1), all of which are expressed in hepatic and tumor tissue. In particular the final enzymatic reaction, in which 5'-deoxy-5'-fluorouridine (5'DFUR) is converted to 5-FU via thymidine phosphorylase, is highly active in tumor tissue and as such confers a degree of tumor specificity to capecitabine. The active drug 5-FU is converted in a final catabolic step to fluoro-beta-alanine (FBAL); this metabolite has been the focus of many pharmacokinetic publications, which have assessed the reasons for variations in toxic effects observed in patients who receive capecitabine. These studies do not indicate that FBAL is the cause of the toxicity, however, merely that an increase in FBAL might reflect a high amount of 5-FU in the tissues.
Schematic showing the stages in the metabolism of capecitabine. Boxes represent the metabolites of capecitabine, whereas the text between the boxes show the associated enzymes.
Clinical experience with capecitabine has shown that the agent is a valuable substitute for bolus or infusional 5-FU, either as monotherapy or in combination with other cytotoxic drugs. Capecitabine has an established role in the treatment of breast and colorectal cancer. Recently, a large randomized trial (n = 1,401) that compared capecitabine and oxaliplatin (XELOX) with infusional 5-FU, leucovorin and oxaliplatin (FOLFOX) for the treatment of advanced colorectal cancer showed convincing evidence of the equivalence of these two regimens. These results strengthen claims that capecitabine could be considered the fluoropyrimidine of choice, especially given the relative ease of capecitabine administration compared with more-cumbersome infusional therapy. The adverse-effect profile of capecitabine has been well described; grade 3 and/or 4 toxic effects include hand–foot syndrome (incidence 15–20%), diarrhea (10%), fatigue (5%), neutropenia (less than 1%) and stomatitis (2%). Capecitabine-induced coronary artery spasm leading to chest pain or arrhythmias has also been observed (1–4%). Interestingly, some of these adverse effects, hand–foot syndrome for example, are almost exclusively associated with capecitabine and are thought to be a consequence of the more-prolonged low-dose exposure with capecitabine-based regimens compared with regimens containing 5-FU. Indeed, the incidence of dermatological toxic events observed with the continuous infusional 5-FU regimen described by Lokich and colleagues (300 mg/m2 per day continuously) is similar to that observed with capecitabine-based regimens. All other recorded adverse effects are common to both capecitabine and 5-FU, with frequencies dependent on the exact schedule used.
Is there a universally applicable dose for capecitabine? The answer to this general question must be a qualified 'no'. In common with all drugs, a host of factors, both intrinsic and extrinsic to capecitabine, have the potential to cause interpatient variation in dose exposure and response and, therefore, necessitate dose adaptation ( Box 1 ). The term 'dose adaptation' is somewhat misleading in oncology as it is invariably associated with dose reduction; few protocols encompass dose increments for that subset of patients who are 'efficient metabolizers' and who essentially receive an underdose with conventional regimens.
To an extent, all medical oncologists are clinical pharmacologists in that they treat predominantly elderly, comorbid patients who have varying degrees of end-organ dysfunction and who are often on multiple medications; therefore, rational dose modulation must become second nature if the patient is to avoid excessive iatrogenic toxic effects. The purpose of this Review is to evaluate the factors that need to be taken into account when implementing dose adaptations for individual patients, and to consider whether a case should be made for population-based dose modulation by geographical region.
Nat Clin Pract Oncol. 2009;6(1):17-24. © 2009
Nature Publishing Group
Cite this: Capecitabine: Have We Got the Dose Right? - Medscape - Jan 01, 2009.