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© 2002 American Society for Clinical Oncology
An Evolving Role for Oral Fluoropyrimidine DrugsComprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL EVER SINCE THE demonstration of clinical activity of continuous-infusion regimens of fluorouracil (5-FU) in both breast1 and colorectal2 cancer, there has been an interest in developing oral formulations of 5-FU, which could more conveniently maintain drug levels over time than the more cumbersome protracted intravenous infusions of 5-FU. Oral formulations of 5-FU have been designed to increase the time of pharmacologic exposure to 5-FU, typically by releasing drug into the circulation at a slower rate than results from direct intravenous bolus injection. To accomplish this, a prodrug of 5-FU is often used. The prodrugs are orally bioavailable but require metabolism to 5-FU, ideally within the tumor. Exposure to 5-FU (from either administered 5-FU itself or from 5-FU that is formed from a prodrug) can be further enhanced by using an inhibitor of 5-FU catabolism. A number of inhibitors of 5-FU catabolism have been synthesized, with most designed to inhibit the initial, rate-limiting step in pyrimidine catabolism, dihydropyrimidine dehydrogenase (DPD).3 Eniluracil, a pyrimidine analog that lacks antitumor activity of its own, is one of the most potent DPD inhibitors to be clinically evaluated. It inactivates DPD by forming a covalent bond that permanently alters the active site of the enzyme.4 After oral administration of eniluracil at a standard dose (10 mg), there is rapid cessation of DPD activity in both tumor and normal tissues within 60 minutes of oral administration of eniluracil.5,6 This inactivation of DPD has been hypothesized to produce several potentially beneficial therapeutic effects, including inhibition of degradation of 5-FU within the gastrointestinal tract, with the result that the 5-FU administered together with eniluracil is absorbed with essentially 100% oral bioavailability. In addition, a potentially more favorable pharmacokinetic pattern results, such that the pattern of the area under the plasma concentration versus time curve of 5-FU increases, appearing more like a continuous infusion than a bolus.5,7 In the study by Rivera et al8 in this issue of the Journal of Clinical Oncology, the oral regimen of eniluracil plus 5-FU is demonstrated to have modest activity and an acceptable toxicity profile in anthracyline- and taxane-resistant breast cancer. The study evaluated 84 patients in a multicenter phase II trial, which demonstrated a response rate of 10%, a median progression-free survival of 9.9 weeks, and a median overall survival of 40.4 weeks. On the basis of this study alone, one might consider further evaluation of eniluracil plus 5-FU as a possible second- or third-line chemotherapy regimen in breast cancer, particularly as a substitute for continuous infusions of 5-FU in patients. This, however, will unlikely occur, because drug development of eniluracil was terminated by the manufacturer last year. This decision came after the analysis of two large, appropriately powered, randomized phase III studies in advanced colorectal cancer. It was in this clinical setting that the decision was made to conduct the primary evaluation of this new oral fluoropyrimidine regimen. Both of these phase III studies demonstrated inferiority in overall survival of the eniluracil plus 5-FU regimen compared with those treated with a standard parenteral 5-FU regimen.9,10 Although the basis for the observed inferiority is not clearly understood, one concern is that the dose of 5-FU used together with the eniluracil was too low and therefore inadequate to form sufficient nucleotide, 5-fluorodeoxyridine monophosphate, which is necessary to inhibit thymidylate synthase, the ultimate site of action of 5-FU. Alternatively, the schedule for administering eniluracil plus 5-FU (twice daily for the initial 28 days of a 5-week schedule followed by 7 days with no therapy) was suboptimal. In contrast to the eniluracil plus 5-FU regimen, another recently introduced oral fluoropyrimidine, capecitabine, has faired much better in clinical evaluation in both breast cancer and colorectal cancer. Like eniluracil, capecitabine is also a third-generation fluoropyrimidine, designed to permit effective oral administration of 5-FU.3 Capecitabine differs from eniluracil and other DPD-inhibitory fluoropyrimidines in not relying on DPD inhibition as the basis of its activity. As a prodrug of 5-FU, capecitabine is selectively activated within the tumor mainly through the action of thymidine phosphorylase. Most tumors, including breast and colorectal cancers, have higher levels of thymidine phosphorylase within tumor than in the normal tissue from which the tumor arises. This is believed to account for both tumor selectivity as well as the tolerable host toxicity. An initial phase II clinical study with capecitabine in 162 heavily pretreated anthracyline- and taxane-resistant breast cancer patients demonstrated that this regimen was active, with a response rate of 20% and a median overall survival of more than 54 weeks.11 Toxicity was tolerable, with only mild side effects. Two additional phase II studies12,13 produced similar results. This led to the approval of capecitabine by the United States Food and Drug Administration (FDA) in 1998 for third-line treatment of breast cancer, with acceptance now in more than 35 countries. Although eniluracil plus 5-FU regimen has never been directly compared with the capecitabine regimen in breast cancer, the larger patient experience from the above three phase II studies with capecitabine suggest that this regimen is perhaps superior to the eniluracil plus 5-FU regimen described in this issue.8 The explanation for the apparent superiority of capecitabine compared with eniluracil remains unclear. This may in fact be due to the selectivity arising from higher levels of thymidine phosphorylase in the tumor, which permits more rapid and effective activation of capecitabine to 5-FU within the tumor. Alternatively, it may represent an inadequate dose or schedule used with the eniluracil plus 5-FU regimen. Although there has been a tendency to view all of the oral fluoropyrimidines (and intravenous 5-FU for that matter) as being essentially the same,14 there are pharmacologic data3 to suggest unique qualities for each of these drugs and that each is not just 5-FU. Thus one could argue that it may be premature to dismiss a drug such as eniluracil, which, although it seems inferior to 5-FU plus leucovorin and possibly capecitabine as well in the above clinical trials, may have pharmacologic attributes that could prove useful in the future (eg, using eniluracil to inactivate DPD in tumors that are resistant due to overexpression of DPD15 to render them 5-FU sensitive). Perhaps more interesting than the use of single-agent capecitabine is the suggestion that the efficacy of docetaxel in breast cancer can be increased by combining with capecitabine.16 The use of this combination is suggested by the interesting observation that docetaxel upregulates thymidine phosphorylase, the enzyme that is important in activation of capecitabine intratumorally to 5-FU.17 This combination was shown to be superior to docetaxel alone in a multicenter phase III study of 511 anthracycline-resistant patients with superior response rate (41.6% v 29.7%; P = .006), superior progression-free survival (6.1 v 4.2 months; P = .0001), and superior overall survival (13.7 v 11.1 month; P = .01). On the basis of these findings, the FDA approved the use of this combination as a second-line regimen for the treatment of advanced breast cancer in September 2001. It should be noted that other drugs besides docetaxel and radiation may also upregulate thymidine phosphorylase,18 and this pharmacologic observation may be used in the design of future combination chemotherapy and combined-modality regimens. Lastly, it should also be noted that in the treatment of advanced colorectal cancer, the oral capecitabine regimen also seems to have the advantage. The eniluracil plus 5-FU regimen similar to that used in the breast cancer study in this issue8 was compared with a standard parenteral (bolus) 5-FU/leucovorin regimen (Mayo Clinic regimen) in two large phase III studies. Both studies9,10 demonstrated that the eniluracil regimen was inferior. In contrast, similar studies comparing the standard capecitabine regimen with a standard parenteral (bolus) 5-FU/leucovorin regimen (Mayo Clinic regimen) in two large phase III studies demonstrated equivalence.19,20 Based on these findings, the FDA approved capecitabine in March 2001 for use as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. At the present time, it seems that capecitabine will be the only oral fluoropyrimidine used in the treatment of breast cancer, particularly in the United States. Although other oral fluoropyrimidines, such as uracil and tegafur (UFT) or S-1, have been approved for use in cancer patients elsewhere in the world, it is unlikely at this time that these drugs or eniluracil will be used in the United States. The data using capecitabine in breast cancer as a single agent or combined with other agents such as docetaxel seem to have promise, although it should be noted that the use of sequential monotherapy regimens (eg, docetaxel and then capecitabine or vice versa) has not yet been directly compared with the combination approach to determine whether a survival advantage truly exists. Future studies will need to evaluate capecitabine in other regimens in combination for breast cancer as well as the possibility for a role in earlier therapy.
NOTES R.B.D. has received grant support as well as support for consultant and speaker activities from Bristol Myers Squibb, Glaxo Smith Kline, Otsuka, Pharmacia, Roche, and Taiho Pharmaceuticals. REFERENCES
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Regazzoni S, Pesce G, Marini G, et al: A low-dose, continuous intravenous infusion of 5-fluorouracil for metastatic breast cancer. Ann Oncol 7: 807-813, 1996 2. Falcone A, Allegrini G, Lencioni M, et al: Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: A phase II study. Cancer Chemother Pharmacol 44: 159-163, 1999[CrossRef][Medline] 3. Diasio RB: Improving fluorouracil chemotherapy with novel orally administered fluoropyrimidines. Drugs 58: 119-126, 1999 (suppl 3)
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Schilsky RL, Hohneker J, Ratain MJ, et al: Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 16: 1450-1457, 1998 6. Heslin MJ, Yan J, Shao L, et al: Dihydropyrimidine dehydrogenase (DPD) rapidly regenerates after inactivation by eniluracil (776C85) in primary and metastatic colorectal cancer. Proc Am Soc Clin Oncol 19: 176a, 2000 (abstr 682)
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Rivera E, Sutton L, Colwell B, et al: Multicenter phase II study of a 28-day regimen of oral eniluracil and fluorouracil in the treatment of patients with anthracycline- and taxane-resistant advanced breast cancer. J Clin Oncol 20: 987-993, 2002 9. Van Cutsem E, Sorensen J, Cassidy J, et al: International phase III study of oral eniluracil (EU) plus 5-fluorouracil (5-FU) versus intravenous (IV) 5-FU plus leucovorin (LV) in the treatment of advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 20: 131a, 2001 (abstr 522) 10. Levin J, Schilsky R, Burris H, et al: North American phase III study of oral eniluracil (EU) plus oral 5-fluorouracil (5-FU) versus intravenous (IV) 5-FU plus leucovorin (LV) in the treatment of advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 20: 132a, 2001 (abstr 523)
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Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17: 485-493, 1999 12. Blum JL, Buzdar AU, Dieras V, et al: A multicenter phase II trial of Xeloda (capecitabine) in taxane-refractory metastatic breast cancer. Proc Am Soc Clin Oncol 18: 107a, 1999 (abstr 403) 13. O‘Reilly SM, Moiseyenko V, Talbot DC, et al: A randomized phase II study of Xeloda (capecitabine) versus paclitaxel in breast cancer patients failing previous anthracycline therapy. Am Soc Clin Oncol 17: 163a, 1998 (abstr 627)
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Mayer RJ: Oral versus intravenous fluoropyrimidines for advanced colorectal cancer: By either route, it’s all the same. J Clin Oncol 19: 4093-4096, 2001 (editorial) 15. Diasio RB, Johnson MR: The importance of pharmacogenetics/pharmacogenomics for the cancer chemotherapy drug 5-fluorouracil. Pharmacology 61: 299-203, 2000 16. O’Shaughnessy J: Results of a large phase III trial of Xeloda/Taxotere combination therapy versus Taxotere monotherapy in metastatic breast cancer patients: The Xeloda Breast Cancer Study Group. Breast Cancer Res Treat 23a, 2000 (abstr 172)
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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 58: 685-690, 1998
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Sawada N, Ishikawa T, Sekiguchi F, et al: X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 5: 2948-2953, 1999
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Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19: 4097-4106, 2001
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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