The Oncologist, Vol. 7, Suppl 6, 1–3,
December 2002
© 2002 AlphaMed Press
Introduction
Andrew D. Seidmana,
Matti Aaprob
a Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York, USA;
b Institut Multidisciplinaire d’Oncologie, Clinique de Genolier, Genolier, Switzerland
Correspondence:
Andrew D. Seidman, M.D., Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-5875; Fax: 212-717-3821; e-mail: seidmana{at}mskcc.org
Capecitabine (Xeloda®; F. Hoffmann-La Roche Ltd.; Basel, Switzerland) was rationally designed to generate 5-fluorouracil (5-FU) preferentially at the tumor site, potentially maximizing antitumor activity and/or improving tolerability. As an oral agent, capecitabine is capable of mimicking continuous infusion 5-FU while lacking the complications associated with i.v. administration. Studies have shown that most cancer patients prefer oral chemotherapy to i.v. therapy as long as efficacy is not sacrificed [1, 2]. Another study demonstrated that quality of life was significantly (p = 0.001) better in patients receiving chemotherapy at home versus in the hospital [3]. Oral capecitabine, thereby, provides convenient, patient-oriented chemotherapy.
Once swallowed, capecitabine is rapidly and completely absorbed as an intact molecule through the gastrointestinal mucosa. Capecitabine is not intrinsically cytotoxic, and requires conversion to 5-FU via a three-step enzymatic cascade (Fig. 1
). The first stage is mediated by carboxylesterase in the liver, and the second step is governed by cytidine deaminase in liver/tumor tissue. The final conversion step, which results in the generation of 5-FU, is mediated by thymidine phosphorylase (TP), an enzyme with significantly higher activity in tumor tissue than in normal tissue [4]. TP is identical in structure and function to tumor-associated angiogenic factor and platelet-derived endothelial cell growth factor [5]. It induces neovascularization and prevents tumor cells from entering apoptosis [6]. TP expression correlates with fast malignant growth, aggressive invasion potential, and poor patient prognosis [7]. TP activation may, therefore, enable capecitabine to specifically target aggressive cells. In addition, the crucial role of TP in the activation of capecitabine provides a clear rationale for combining capecitabine with antitumor agents that further upregulate TP in tumor tissue, such as the taxanes, anthracyclines, gemcitabine, and vinorelbine [8, 9].
View larger version (13K):
[in this window]
[in a new window]
|
Figure 1. Enzymatic activation of capecitabine. Abbreviations: 5'–DFCR = 5'deoxy-5'-fluorocytidine; 5'–DFUR = 5'deoxy-5'-fluorouridine; CE = carboxyl-esterase; CyD = cytidine deaminase.
|
|
The tumor selectivity and conversion of capecitabine preferentially in tumor tissue have been confirmed in a "proof of principle" pharmacodynamic study [10]. The study involved 19 patients with colorectal cancer requiring surgical resection. Patients received capecitabine, 1,250 mg/m2 twice daily, for 5-7 days before surgery. Following capecitabine administration, concentrations of 5-FU were, on average, 3.2-fold higher in primary tumor tissue than in normal adjacent tissue, and more than 21 times higher in tumor tissue than in plasma [10] (Fig. 2). In contrast, corresponding ratios for 5-FU concentrations after administration of i.v. 5-FU (bolus or infusion) are close to 1 (range 0.98-1.03), indicating no tumor selectivity [11].
The unique mechanism of activation of capecitabine results in improved efficacy compared with 5-FU in human xenograft models for a range of solid tumors, including breast cancer. In one study, capecitabine administered at its maximum tolerated dose was effective (>50% tumor growth inhibition) in 75% of the tumor xenograft models and inhibited tumor growth by >90% in 29% of the models tested. In contrast, 5-FU and uracil/tegafur were effective in only 4% and 21% of models, respectively, and did not inhibit tumor growth by >90% in any xenograft model [12].
Capecitabine has undergone extensive clinical development worldwide, and as monotherapy, an intermittent regimen of capecitabine 1,250 mg/m2 twice daily, days 1-14 of a 21-day cycle, is the standard approved regimen. This treatment schedule was identified in a three-arm, randomized, phase II study in 109 patients with metastatic colorectal cancer [13]. Patients received continuous capecitabine monotherapy (666 mg/m2 twice daily), intermittent capecitabine monotherapy (1,255 mg/m2 twice daily on days 1-14 in a 21-day cycle), or intermittent capecitabine (829 mg/m2 twice daily on days 1-14 in a 21-day cycle) in combination with leucovorin (LV, 30 mg/m2 twice daily in the same schedule). Confirmed tumor response rates were similar in the three arms, ranging from 21%-24%. However, median time to disease progression appeared more favorable in the intermittent capecitabine monotherapy arm (7.5 months) than in either the continuous capecitabine arm (4.2 months) or the intermittent capecitabine/LV arm (5.4 months). Furthermore, the addition of LV to capecitabine did not appear to enhance efficacy and resulted in more pronounced toxicity than capecitabine monotherapy. Consequently, the investigators recommended using the intermittent monotherapy regimen for further clinical development, based on its favorable efficacy:toxicity ratio, higher dose intensity, and shallower dose-versus-toxicity slope. In addition, the inclusion of a drug-free period was considered more appealing to patients [13].
The standard, intermittent capecitabine monotherapy regimen is approved for taxane-pretreated (paclitaxel-pretreated in the U.S.) metastatic breast cancer in more than 50 countries, including the U.S., Canada, and the entire European Union. Capecitabine has also recently gained regulatory approval in combination with docetaxel for patients with anthracycline-pretreated breast cancer. The articles in this supplement describe clinical data for capecitabine both as monotherapy and in combination with docetaxel, placing these data in context with published data for other agents evaluated in patients with taxane- and anthracycline-pretreated breast cancer, respectively. In addition, the expanding role of capecitabine earlier in the disease course, both alone and as a component of novel combinations, is discussed, and data from ongoing phase I and II trials are presented. The extensive clinical data on capecitabine confirm that this active, oral chemotherapy is a valuable agent in combating breast cancer.
 |
REFERENCES
|
|---|
- Liu G, Franssen E, Fitch MI et al. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110–115.[Abstract/Free Full Text]
- Borner MM, Schöffski P, de Wit R et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin. a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002;38:349–358.
- Payne SA. A study of quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med 1992;35:1505–1509.
- Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34:1274–1281.
- Moghaddam A, Zhang HT, Fan TP et al. Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci USA 1995;92:998–1002.[Abstract/Free Full Text]
- Kitazono M, Takebayashi Y, Ishitsuka K et al. Prevention of hypoxia-induced apoptosis by the angiogenic factor thymidine phosphorylase. Biochem Biophys Res Commun 1998;253:797–803.[CrossRef][Medline]
- Takebayashi Y, Akiyama S, Akiba S et al. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996;88:1110–1117.[Abstract/Free Full Text]
- Ishitsuka H. Capecitabine: preclinical pharmacology studies. Invest New Drugs 2000;18:343–354.[CrossRef][Medline]
- Sawada N, Fujimoto-Ouchi K, Ishikawa T et al. Antitumour activity of combination therapy with capecitabine plus vinorelbine, and capecitabine plus gemcitabine in human tumor xenograft models. Proc Am Assoc Cancer Res 2002;43:1088a.
- Schüller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–297.[CrossRef][Medline]
- Kovach JS, Beart Jr RW. Cellular pharmacology of fluorinated pyrimidines in vivo in man. Invest New Drugs 1989;7:13–25.[Medline]
- Ishikawa T, Sekiguchi F, Fukase Y et al. Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 1998;58:685–690.[Abstract/Free Full Text]
- Van Cutsem E, Findlay M, Osterwalder B et al. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 2000;18:1337–1345.[Abstract/Free Full Text]
Received September 26, 2002;
accepted for publication September 30, 2002.
Top
References
