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Capecitabine

A Review of its Use in the Treatment of Advanced or Metastatic Colorectal Cancer

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Summary

Abstract

Capecitabine is an orally administered fluoropyrimidine which is selectively activated in tumour tissue to the active moiety fluorouracil and is cytotoxic through inhibition of DNA synthesis.

In patients with advanced or metastatic colorectal cancer, first-line therapy with intermittent capecitabine achieved significantly higher objective tumour response rates than therapy with fluorouracil plus leucovorin in pooled analysis. Response rates were also higher in patients pretreated in the adjuvant setting and whose primary site of metastasis was the lung. However, no significant differences between the two treatment groups were seen in the time to disease progression, time to treatment failure or overall survival.

Preliminary data suggest response may be improved by combining capecitabine with other anticancer therapies such as oxaliplatin, irinotecan and radiotherapy.

Capecitabine in therapeutic dosage regimens generally has acceptable tolerability. Diarrhoea and hand-and-foot syndrome are the major dose-limiting toxicities associated with capecitabine therapy, with adverse effects generally of a gastrointestinal nature. Overall, diarrhoea, stomatitis, nausea and alopecia were significantly less common with capecitabine than with bolus fluorouracil and leucovorin. In addition, capecitabine recipients experienced significantly less myelosuppression, although more capecitabine recipients discontinued therapy because of adverse events. Importantly, patients spent less time in hospital after capecitabine than after bolus fluorouracil and leucovorin therapy, and the oral route of administration of capecitabine is likely to be preferred.

In conclusion, capecitabine has shown superior tumour response and less myelosuppression, although more grade 3 hand-and-foot syndrome, in comparison with the ‘Mayo Clinic’ regimen of fluorouracil therapy, but is unlikely to improve survival. Significantly, its oral route of administration is likely to be preferred by patients. Future strategies to improve patient response may involve selection of those patients likely to respond best to capecitabine, through determination of relevant enzyme levels and combination of capecitabine with various antineoplastic agents. Data on the effect of the drug on quality of life would help establish its role. In the meantime, capecitabine appears to offer an effective and more convenient alternative to fluorouracil as first-line monotherapy for the treatment of metastatic colorectal cancer.

Pharmacodynamic Properties

Capecitabine is a specifically designed target-specific oral fluoropyrimidine which is converted to fluorouracil in tumour tissue via a three-step enzymatic cascade. It effects antineoplastic activity via inhibition of DNA synthesis. Both thymidine phosphorylase (TP) and cytidine deaminase, enzymes required for capecitabine activation, show increased activity in tumour tissue from patients with various types of cancer compared with healthy tissue. High intratumoural concentrations of fluorouracil are observed following oral capecitabine administration. Ex vivo, fluorouracil concentrations in human colorectal tumour tissue are approximately 3-fold higher than those in adjacent healthy tissue.

The antineoplastic activity of capecitabine has been demonstrated over a wide range of human colorectal cancer xenograft systems. In vivo, greater antitumour efficacy (assessed by tumour growth inhibition) has been demonstrated over a range of dosages in comparison with both fluorouracil and the oral fluoropyrimidine tegafur/uracil in fluorouracil-sensitive and some refractory tumours. Capecitabine has a therapeutic index of >6.4 in the HCT116 xenograft model. The activity and expression of TP in tumours are correlated with the sensitivity of the tumour to capecitabine and the promotion of tumour growth, respectively.

The activity and the ratio of TP to dihydropyrimidine dehydrogenase are measures that discriminate between capecitabine-sensitive and refractory tumours in xenograft models. Addition of the TP up-regulators paclitaxel, docetaxel, cyclophosphamide, mitomycin and x-ray irradiation to capecitabine increases tumour inhibition compared with capecitabine alone.

Pharmacokinetic Properties

Capecitabine undergoes rapid and extensive enzymatic conversion to a number of intermediary metabolites. The absorption pharmacokinetics of capecitabine and its metabolites appear dose proportional. Maximum plasma capecitabine concentrations (Cmax) of ≈4 mg/L and area under the concentration-time curve (AUC) values of ≈6 mg/L h are seen following oral administration of capecitabine 1250 mg/m2. Plasma capecitabine concentrations decrease rapidly with an elimination half-life of 0.5 to 0.7 hours. Peak concentrations of the primary excretory metabolite α-fluoro-β-alanine (FBAL) occur approximately 5 hours after administration of capecitabine. The metabolites are principally excreted via the kidneys, with 3% of an administered dose excreted as capecitabine. Accumulation of capecitabine has not been reported after repeated doses. The estimated oral bio-availability of capecitabine is nearly 100%.

The pharmacokinetic disposition of capecitabine is not significantly affected by gender or mild to moderate hepatic dysfunction.

Capecitabine taken without food increases both Cmax and AUC and decreases the time to Cmax (tmax), while capecitabine pharmacokinetics are not affected by magnesium hydroxide/aluminium hydroxide to any clinically significant extent.

Therapeutic Use

Capecitabine administered intermittently (1250 mg/m2 twice daily for 2 weeks in a 3-week cycle) has been investigated in adult patients as treatment for advanced or metastatic colorectal adenocarcinoma. Two large, well-designed phase III trials have compared capecitabine monotherapy with the standard fluorouracil-based ‘Mayo Clinic’ regimen (425 mg/m2/day fluorouracil + 20 mg/m2/day leucovorin days 1 to 5 in a 4-week cycle). Some information is available from a prospectively defined integrated analysis of these two identical studies.

In patients with advanced or metastatic colorectal cancer, capecitabine mono-therapy as first-line treatment significantly increased the objective response rate compared with fluorouracil and leucovorin therapy alone; objective response rates were 22 versus 13% (p < 0.0001). In patients pretreated in the adjuvant setting, the overall response rate was doubled in those receiving capecitabine and tripled in patients whose primary site of metastasis was the lung compared with fluorouracil and leucovorin (21.1 vs 9.0% and 33.3 vs 10.3%, respectively). Capecitabine was at least equivalent to the Mayo Clinic regimen with regard to time to disease progression (median 4.6 vs 4.7 months), time to treatment failure (median 4.2 vs 3.6 months) or overall survival duration (median 12.9 vs 12.8 months).

In a randomised phase II study, intermittent capecitabine therapy achieved overall response rates (24%) which were similar to those achieved with continuous capecitabine therapy (21%) and capecitabine in combination with leucovorin (23%) in patients previously untreated for metastatic colorectal cancer. Rates of disease stabilisation were slightly higher in those receiving intermittent and combination capecitabine than in those receiving continuous capecitabine.

Phase I and II studies of first-line treatment with capecitabine in combination with other antineoplastic therapies, notably oxaliplatin, have shown encouraging response rates.

Tolerability

The tolerability profile of capecitabine is typical of infusional fluoropyrimidines and adverse effects are primarily of a gastrointestinal nature. Dose reduction is most commonly indicated for diarrhoea and hand-and-foot syndrome.

Overall, diarrhoea, stomatitis, nausea and alopecia occurred significantly less often in patients receiving capecitabine than in patients administered bolus fluorouracil and leucovorin therapy. Grade 3 or 4 hyperbilirubinaemia and hand- and-foot syndrome occur more frequently in patients receiving capecitabine; grade 3 or 4 stomatitis, neutropenic fever and sepsis were seen less often.

Importantly, patients spent less time in hospital after capecitabine than after fluorouracil therapy, and the oral route of administration of capecitabine is likely to be preferred.

Acceptable toxicity was seen when capecitabine was combined with other antineoplastic therapies including oxaliplatin, irinotecan or radiotherapy in phase I and II studies.

Dosage and Administration

Capecitabine is approved for use throughout the European Union, US, Canada and Australia as a first-line therapy for advanced or metastatic colorectal cancer. The recommended dosage regimen of capecitabine is 1250 mg/m2 twice daily for 14 days in a 3-week cycle to be administered orally after food.

The dosage should be adjusted according to tolerability and the drug is contra-indicated in patients who are pregnant, have severe renal impairment [creatinine clearance <30 ml/min (1.8 L/h)] and those with known hypersensitivity to fluorouracil. The starting dosage should also be reduced to ≈940 mg/m2 in patients with moderate renal impairment [creatinine clearance 30 to 50 ml/min (1.8 to 3 L/h)].

Haemostatic parameters should be closely monitored in those additionally receiving coumarin-derivative anticoagulants because of an increased risk for bleeding. Patients receiving concomitant phenytoin should be regularly monitored for increased plasma phenytoin concentrations.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Jane K. McGavin & Karen L. Goa

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  1. Jane K. McGavin
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Correspondence to Jane K. McGavin.

Additional information

Various sections of the manuscript reviewed by: S. Kahlert, Ludwig-Maximilians-Universität, Klinikum Grosshadern, Munich, Germany; D. Papamichael, Department of Medical Oncology, BOC Oncology Centre, Nicosia, Cyprus; H.-J. Schmoll, Department of Haematology and Oncology, Martin-Luther Universität, Halle/Saale, Germany; C. Twelves, Cancer Research Campaign Department of Medical Oncology, University of Glasgow, Glasgow, Scotland; W. R. Wilson, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand; J. R. Zalcberg, Department of Medical Oncology and Haematology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia

Data Selection

Sources: Medical literature published in any language since 1983 on Capecitabine, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘Capecitabine’ and ‘Colorectal-Cancer’ or ‘Capecitabine adj PK/PD’. Medline search terms were ‘Capecitabine’ or ‘RO 09 1978’ and ‘Colorectal-Neoplasms’. EMBASE search terms were ‘Capecitabine’ or ‘RO 09 1978’ and ‘Colorectal-Cancer’. Searches were last updated 12 Oct, 2001.

Selection: Studies in patients with colorectal cancer who received capecitabine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Capecitabine, colorectal cancer, tolerability, pharmacodynamics, pharmacokinetics, therapeutic use.

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McGavin, J.K., Goa, K.L. Capecitabine. Drugs 61, 2309–2326 (2001). https://doi.org/10.2165/00003495-200161150-00015

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