Capecitabine: Have We Got the Dose Right?

Rachel Midgley; David J Kerr


Nat Clin Pract Oncol. 2009;6(1):17-24. 

In This Article

Regional Variation in Capecitabine Metabolism and Toxicity

An interesting phenomenon came to light during the multinational trialing phase of capecitabine, following a retrospective multivariate analysis by Haller and colleagues of data from three phase III trials of 5-FU, capecitabine and oxaliplatin for the treatment of early and advanced colorectal cancer. The trials, described in Figure 2, accrued a total of 3,053 patients from Europe, Asia and the US. Logistic regression, which was adjusted for a range of factors when possible (age, gender, creatinine clearance, drug regimen), was used by Haller and colleagues to compare regional (US versus non-US) differences in serious (i.e. grade 3 and/or 4) toxic effects.[13] The results are summarized in Table 1 and Table 2 , and show a significantly worse toxic-effect profile in patients recruited from the US than in those from Asia or elsewhere, for both early and advanced disease. Given that the authors adjusted for the standard range of factors known to influence the pharmacokinetics of capecitabine, these logistic regressions could provide a hazard ratio for treatment-associated toxic effects in which potentially confounding variables are controlled.

Trials analyzed to assess the toxic effects of capecitabine. (A) Two identical phase III trials (SO14796 and SO14695) in first-line metastatic colorectal cancer. (B) One phase III trial (NO16968 XELOXA) in adjuvant stage III colon cancer. Abbreviations: 5-FU, 5-fluorourarcil; ECOG PS, Eastern Cooperative Oncology Group performance status; LV, leucovorin; XELOX, capecitabine and oxaliplatin.

Market research from the manufacturers of capecitabine indicates that the clinical community has voted with its empirical feet—it is relatively rare for US-based oncologists to prescribe the label-recommended dose of capecitabine (1,250 mg/m2 twice daily for 14 days) compared with their European colleagues. Instead, a starting dose of 1,000 mg/m2 twice daily for 14 days is commonplace in the US.

We postulate that there are a number of factors that can explain the differential tolerability of capecitabine according to country of treatment; these factors are body weight, genetic polymorphisms associated with ethnic groups, trial methodology and reporting, psychosocial factors, and dietary folate intake.

Body Weight

Body weight is the only baseline demographic factor that is consistently different between patients recruited in the US (significantly higher body weight) and outside of the US. A preliminary analysis of the effect of body weight in trial NO16968, comparing patients less than 90 kg in weight with those who weigh more than 90 kg, indicated that lower body weight patients suffered more frequent grade 3 and/or 4 adverse events, and that the difference between US and non-US patients is maintained regardless of weight category; these findings suggest that weight does not account for the geographical variance observed.[14]


Clearly the pharmacogenetic differences outlined earlier can also segregate patients by ethnic group and, although no differences have been found in the main pharmacokinetic parameters for capecitabine when comparing Japanese and Caucasian patients, there are recorded interethnic differences in the frequency of certain SNPs.[15] Such disparities are, however, unlikely to account for the considerable differences in drug handling between white US and white European citizens, given the similarity in the genetic origins of these two groups. Nevertheless, this is an area that would benefit greatly from well-powered prospective trials.

Trial Methodology and Reporting

The possibility of variations in trial methodology and data reporting of toxic effects affecting observed outcomes in different groups of patients has been raised by some investigators. Obviously, the toxic events associated with chemotherapy (i.e. nausea, fatigue and, to an extent, vomiting, diarrhea and stomatitis) could be elicited to a different extent in disparate geographical groups; however, variation in reporting, despite general adoption of the Common Toxicity Criteria grading system, could partially explain observed differences.This subjective consideration will not be important for objective toxic effects quantified in the laboratory, such as neutropenia and renal or hepatic impairment, and is perhaps less likely to be important for more extreme (grade 3 or 4) adverse effects, as reporting of serious toxic events is less open to interpretation.

Psychosocial Factors

Psychosocial factors could account for cultural differences in patient populations, as it is recognized that some societies are keener than others to continue treatment regardless of toxic effects and advice to the contrary, the so-called 'over compliance syndrome'. Additional features that might affect compliance with protocol dose-reduction schemes include the quality of information given, the educational status of the patient, the accessibility of the best available educational tools, and physician and nurse experience with capecitabine and their familiarity with the dose-modification regimens. Analysis of the relevant clinical trials does not indicate that there is a significant difference in the incidence of grade 2 toxicities in the US compared with the rest of the world. It is true, however, that the overall incidence of dose reductions for capecitabine remains higher for patients in the US (32.1%) than for those outside the US (20.4%).[13]

Dietary Folate Intake

Another reason for the poor safety profile of fluoropyrimidines in the US might be related to differences in dietary folate intake, especially given international variation in policies for folate fortification.[16,17] The mechanism that is probably the most important mode of action of fluoropyrimidines relies on the presence of folates—binding of the 5-FU metabolite 5-fluoro-2'-deoxyuridine 5'-monophosphate to TS is stable only in the presence of the reduced form of folate (N,1 N[10]–methylene tetrahydrofolate).

A relationship between dietary folate intake and both the efficacy and safety of fluoropyrimidines is supported by preclinical data. In a breast cancer xenograft model, 5-FU-treated rats fed a high folate diet had improved tumor response and prolonged survival compared with animals fed a low folate diet.[18] 5-FU toxicity was also shown to be significantly increased in rats receiving a high folate diet.[19]

In addition, two recent clinical studies have indicated a relationship between dietary folate intake and fluoropyrimidine toxicity.[20,21] In one study, 86 Canadian patients receiving adjuvant 5-FU and leucovorin (Mayo Clinic Regimen) were prospectively assessed for biomarkers of folate metabolism. Multivariate analyses identified baseline serum folate as an independent positive predictor of grade 3 and/or 4 toxic effects and/or dose modification; the odds ratio for grade 3 and/or 4 toxic events for each 10 nmol/l increment in serum folate was 2.20 (95% CI 1.12–4.34; P = 0.016).[20] Similar results were found in a study of capecitabine monotherapy (2,000 mg/day dose on an intermittent schedule), in which patients with higher baseline levels of serum folate had a significantly increased incidence of toxic events (P = 0.005).[22]

Folates cannot be synthesized endogenously by humans, and total body stores have a daily turnover of around 1%. Food sources rich in folate include green leafy vegetables, liver, legumes, citrus, fortified cereals, pastas and grain products. Naturally occurring (polyglutamyl) folates must undergo deconjugation before they can be absorbed in the small intestine. After absorption, folates are reduced to the active form (tetrahydrofolic acid) by dihydrofolate reductase, and this active form is stored mainly in the liver.

The US has an aggressive policy of fortifying food with folic acid, and requires that all flour, rice, pasta, cornmeal and other grain products are enriched with 140 μg folic acid per 100 g. Similar programs have been initiated in Canada and a number of countries in South America and the Middle East, but are unusual in Europe. One could speculate, therefore, that folic acid supplementation could be a major factor contributing to the perceived excess capecitabine toxicity noted in the US.

Two other pieces of indirect evidence to support this view can be gathered from the drug development paths for the anti-folate TS inhibitory agents raltitrexed and pemetrexed, in which low serum folate levels and few adverse effects have been observed. It is hypothesized that US patients tolerate higher doses of these agents than do European patients because they have reduced folate in high amounts in intracellular pools, which competes with the drug for target sites on TS and reduces the degree of inhibition of the target enzyme by the drug, thus attenuating toxicity.[4,23] The subject of inter-regional variation definitely warrants further prospective evaluation in appropriately powered clinical trials.


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