Although 5-fluorouracil (5-FU) remains the most
active single agent in the treatment of metastatic colorectal cancer,
less than a third of patients achieve objective responses. The use
of permanent venous-access devices and portable infusion pumps have
allowed continuous infusion of 5-FU over prolonged periods. Compared
with bolus schedules, protracted infusions of 5-FU are associated
with less toxicity, improved response rates, and the suggestion of
improved survival.[2,3] Clinical trials exploring the biochemical
modulation of 5-FU by calcium leucovorin have demonstrated improved
response rates. Significant toxic effects, primarily diarrhea,
mucositis, and neutropenia have been observed. Approximately 20% to
30% of patients require hospitalization for the treatment of these
effects, which contribute to a decrement in quality of life and
personal comfort and increase the expense of palliative treatment.
In addition to the treatment regimen of eniluracil and oral 5-FU,
which is discussed elsewhere in this journal, oral fluorinated
pyrimidines under general development for the treatment of colorectal
carcinoma, including capecitabine (Xeloda), UFT plus leucovorin
(Orzel), and S-1 are reviewed herein. The goal of each of these
products is to provide prolonged tumor exposure to therapeutic levels
of 5-FU. Each, however, employs a unique mechanism of action to
accomplish this goal and potentially to improve therapeutic efficacy
of 5-FU. Oral 5-FU has not gained widespread clinical acceptance
because of its erratic absorption due to the varying levels of
dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal
tract. The 5-FU prodrugs have been developed to circumvent this
problem. These drugs are absorbed as intact molecules and are
subsequently converted to 5-FU to exert antitumor activity. Because
these oral agents provide prolonged 5-FU exposure at lower peak
concentrations than those observed with bolus intravenous
administration of 5-FU, toxic effects such as neutropenia and
stomatitis are greatly reduced. In addition, preclinical studies have
suggested that these oral agents have potential advantages over
intravenous 5-FU, which may increase therapeutic efficacy.[7-10]
Capecitabine was developed as a tumor-selective fluoropyrimidine
carbamate to achieve higher intratumoral 5-FU levels and less
toxicity than 5-FU (Figure 1).
Capecitabine passes unchanged through the gastrointestinal tract and
is metabolized in the liver by carboxylesterase to 5'-deoxy-5-fluorocytidine
(5'-DFCR). This is then converted to doxifluridine (5'-DFUR) by
cytidine deaminase located in the liver and also in tumor tissue.
Lastly, 5'-DFUR is metabolized by thymidine phosphorylase to 5-FU at
the tumor site.[7,11] The exposure of healthy body tissues to
systemic 5-FU is therefore reduced. Preclinical studies have
demonstrated capecitabines activity in both 5-FU-sensitive and
5-FU-resistant tumors. In xenograft models, concentrations of
5-FU were found to be higher in tumor than in plasma or healthy
tissue following capecitabine administration.
Phase I trials of capecitabine in patients with advanced or
metastatic solid tumors explored continuous and intermittent
schedules with and without oral leucovorin. Dose-limiting toxicities
included diarrhea, nausea, vomiting, and hand-foot syndrome.[13-15]
Capecitabines pharmacokinetics in the above phase I studies
demonstrated absorption of at least 70% of capecitabine followed by
extensive and rapid conversion to 5'-DFCR and 5'-DFUR. The peak
plasma concentrations of the drug and these metabolites occur within
0.5 to 1.5 hours after administration. At the maximum tolerated dose,
the average plasma concentrations are similar to those reported for
protracted low-dose intravenous 5-FU infusions.
Tumor selectivity was studied in 19 patients with colorectal cancer
requiring surgical resection of primary tumor and/or liver
metastasis. Patients received capecitabine twice daily for 5-7 days
prior to surgery. Concentrations of 5-FU in primary tumors were 2.5
times greater than those measured in adjacent healthy tissues, and
1.17 times greater in liver metastasis than in noncancerous liver
tissue. Concentrations of 5-FU were 14-fold greater in primary tumors
than in plasma. In liver metastases, the ratio in tumor to plasma
approximates 8:1. These results strongly suggest that 5-FU in tumor
is generated in the tissue by the conversion of 5'-DFUR to 5-FU via
thymidine phosphorylase, rather than from the systemic circulation.
A randomized open-label phase II trial of three schedules of
capecitabine (continuous, intermittent, and intermittent with
leucovorin) in patients with metastatic colorectal cancer
demonstrated that all treatment groups had similar response rates
(21% to 24%). The median time to disease progression was 230 days,
127 days, and 165 days, respectively. The addition of leucovorin to
the intermittent schedule neither increased the overall response rate
nor elicited a discernible delay in the median time to disease progression.
The intermittent schedule (capecitabine 2,500 mg/m² in two
divided doses daily for 2 weeks followed by 1 week rest) was selected
for further development in colorectal cancer. Phase III trials in
patients with advanced colorectal carcinoma are comparing the
intermittent capecitabine schedule to intravenous 5-FU plus
leucovorin and examining efficacy parameters of tumor response, time
to disease progression, and survival, as well as quality of life and
pharmacoeconomic resource utilization.
Tegafur, a prodrug of 5-FU, is hydroxylated and converted to 5-FU by
hepatic microsomal enzymes; this may lead to a gradual but sustained
level of 5-FU in tumors. Japanese clinical trials using oral,
divided-dose schedules of tegafur demonstrated its clinical efficacy
with mild toxic effects. Uracil was then added to tegafur, which led
to the subsequent development of UFT (Figure
2). Uracil biochemically modulates 5-FU by completely inhibiting
dihydropyrimidine dehydrogenase (DPD), leading to increased and
sustained levels of 5-FU. Schedule-dependent toxic effects were
noted in US trials examining UFT as a single agent in 5- and 28-day
schedules; the dose-limiting toxicities were neutropenia and
Initial US phase I trials of UFT plus oral leucovorin examined an
administration schedule of 28 consecutive days repeated every 35
days. Daily doses of both drugs were divided and administered every 8
hours. The dose-limiting toxicity was diarrhea; the recommended phase
II dose was UFT 300 to 350 mg/m²/day plus leucovorin 150
mg/day. Pharmacokinetic studies of UFT plus oral leucovorin
administered every 8 hours demonstrate that 5-FU levels can be
measured throughout the 8-hour period between doses. Studies of
single-dose UFT demonstrate that uracil, tegafur, and 5-FU plasma
concentrations typically rose quickly following dosing, with maximum
plasma concentrations achieved in approximately 1 hour. In contrast
to tegafur but consistent with the very short plasma half-lives of
uracil and 5-FU, plasma concentrations of both the latter drugs
decline rapidly after maximum plasma concentrations are achieved.
A phase II trial of the above combination in patients with advanced,
bidimensionally measurable metastatic colorectal carcinoma
demonstrated an overall response rate of 42.2%. These patients
had not received prior chemotherapy for metastatic disease. Diarrhea
was the major dose-limiting toxicity, with prolonged diarrhea
developing at UFT 350 mg/m²/day. The dose was reduced to 300
mg/m²/day. Of importance was the absence of grade 3 or 4
neutropenia, oral mucositis, or hand-foot syndrome. Other phase II
studies of UFT plus leucovorin in patients with advanced colorectal
cancer have reported response rates and toxicity profiles similar to
those reported in the above trial.[24,25] In two large phase III
trials in advanced colorectal cancer, patients are being assigned to
receive intravenous 5-FU plus leucovorin or the oral regimen of UFT
plus leucovorin. In addition, the National Surgical Adjuvant Breast
and Bowel Project (NSABP) has initiated a trial comparing UFT plus
oral leucovorin with intravenous weekly 5-FU plus leucovorin as
postoperative adjuvant therapy in patients with stage II or III colon carcinoma.
S-1 (BMS-247616) combines tegafur with two 5-FU modulators:
5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate at a
molar ratio of 1:0.4:1 (tegafur:CDHP:potassium oxonate) (Figure
3).[9,10,26,27] CDHP inhibits 5-FU decomposition and is 200-fold
more potent in inhibiting DPD than is uracil. Comparisons between
5-FU levels generated from tegafur plus CDHP and those from tegafur
plus uracil indicate significantly higher 5-FU peak levels and AUCs
when tegafur is administered with CDHP.[9,26] Potassium oxonate
blocks 5-FU phosphorylation by selectively inhibiting it via orotate
phosphoribosyltransferase. Since both antitumor activity and
gastrointestinal toxicity (ie, diarrhea) are attributed to 5-FU
phosphorylation, potassium oxonate selectively inhibits the
phosphorylation of 5-FU in normal gastrointestinal tissues while
minimizing its inhibition in tumor tissues.
In a phase I study of S-1 reported by the Early Clinical Studies
Group of the European Organization for Research and Treatment of
Cancer (EORTC), S-1 was administered twice daily for 4 weeks followed
by a 1-week rest period. The maximum tolerated dose in this study was
45 mg/m² twice daily for 4 weeks; the dose-limiting-toxicity was
diarrhea. Pharmacokinetic studies demonstrated that S-1
effectively inhibited DPD, resulting in cytotoxic 5-FU
concentrations. In Japan, phase II trials of S-1 have indicated its
impressive activity in advanced gastric cancer, (49% complete and
partial response rate), and colorectal cancer (35.5% responses rate),
and a mild toxicity profile was reported.[29,30] Myelosuppression was
the dose-limiting toxicity reported in Japanese trials. The incidence
of gastrointestinal toxic effects in the Japanese trials was low,
suggesting the influence of potassium oxonate in reducing diarrhea.[29-33]
The agents discussed herein, capecitabine, UFT plus leucovorin, and
S-1, contain prodrugs of 5-FU that are converted in vivo to 5-FU to
exert antitumor activity. These drugs circumvent the problem of
erratic oral absorption of 5-FU by being absorbed as intact molecules
(capecitabine and tegafur) and subsequently being converted to 5-FU.
Preclinical studies suggest that these agents may produce antitumor
activity superior to that produced by intravenous 5-FU by achieving
higher intratumoral 5-FU levels, by providing sustained 5-FU
exposure, or by biochemically modulating 5-FU. Whether these
preclinical rationales translate into improved therapeutic activity
in the treatment of advanced colorectal cancer will be determined in
phase III trials. Phase III trials are comparing each agent with
bolus regimens of 5-FU plus leucovorin with regard to antitumor
activity, toxicity, symptom improvement, quality of life, and
treatment cost. These agents must demonstrate patient survival that
is at least equivalent to that produced by standard intravenous
5-FU-plus-leucovorin regimens in addition to benefits such as greater
ease of administration and decreased toxicity.
1. Kemeny N: Current approaches to metastatic colorectal cancer.
Semin Oncol 21(suppl 7):67-75, 1994.
2. Lokich JJ, Ahlgren JD, Gullo JJ, et al: A prospective randomized
comparison of continuous infusion fluorouracil with a conventional
bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic
Oncology Program Study. J Clin Oncol 11:1888-1893, 1993.
3. Meta-analysis Group in Cancer: Efficacy of intravenous continuous
infusion of fluorouracil compared with bolus administration in
advanced colorectal cancer. J Clin Oncol 16:301-308, 1998.
4. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of
fluorouracil by leucovorin in patients with advanced colorectal
cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992.
5. Buroker TR, OConnell MJ, Wieand S, et al: Randomized
comparison of two schedules of fluorouracil and leucovorin in the
treatment of advanced colorectal cancer. J Clin Oncol 12:14-20, 1994.
6. Cao S, Rustum YM, Spector T: 5-Ethynyluracil (776C85): Modulation
of 5-FU efficacy and therapeutic index in rats bearing advanced
colorectal carcinoma. Cancer Res 54:1507-1510, 1994.
7. Ishitsuka H, Miwa M, Ishikawa T, et al: Capecitabine: An orally
available fluoropyrimidine with tumor selective activity (abstract
2426). Proc Am Assoc Cancer Res 36:407, 1995.
8. Taguchi T: Experience with UFT in Japan. Oncology 11(9)[suppl
9. Shirasaka T, Shimamato Y, Ohsimo H, et al: Development of a novel
form of oral 5-fluorouracil derivative (S-1) directed to the
potentiation of the tumor selective cytotoxicity of 5-fluorouracil by
two biochemical modulators. Anticancer Drugs 7:548-557, 1996.
10. Rustum YM, Cao S, Shirasaka T, et al: A new 5-fluorouracil
prodrug, S-1, orally bioavailable with high therapeutic index in
model system active in phase II clinical trial (abstract 799). Proc
Am Soc Clin Oncol 16:227a, 1997.
11. Ishikawa T, Utoh M, Sawada N, et al: XelodaTM (capecitabine): An
orally available tumor-selective fluoro-pyrimidine carbamate
(abstract 727). Proc Am Soc Clin Oncol 16:208a, 1997.
12. Cao S, Lu K, Ishitsuka H, et al: Antitumor activity of
capecitabine against fluorouracil-sensitive and resistant tumors
(abstract 795). Proc Am Soc Clin Oncol 16:226a, 1997.
13. Hughes M, Planting A, Twelves C, et al: A phase I study of
intermittent twice daily oral therapy with capecitabine in patients
with advanced and/or metastatic solid cancer. Ann Oncol 7(suppl
14. Meropol NG, Budman DR, Creaven PJ, et al: A phase I study of
continuous twice daily treatment with capecitabine in patients with
advanced and/or metastatic solid tumors. Ann Oncol 7(suppl 1):87, 1996.
15. Taguchi T, Ishitani K, Saito H, et al: A Japanese phase I study
of continuous twice daily treatment with capecitabine in patients
with advanced and/or metastatic solid tumors. Ann Oncol 7(suppl
16. Twelves C, Budman DR, Creaven PJ, et al: Pharmacokinetics and
pharmacodynamics of capecitabine in two phase I studies (abstract
1509). Proc Am Soc Clin Oncol 15:476, 1996.
17. Schuller J, Cassidy J, Reigner BG, et al: Tumor selectivity of
Xeloda in colorectal cancer patients (abstract 797). Proc Am Soc Clin
Oncol 16:227a, 1997.
18. Findlay M, Van Cutsem E, Kocha W, et al: A randomized phase II
study of Xeloda (capecitabine) in patients with advanced colorectal
cancers (abstract 798). Proc Am Soc Clin Oncol 16:227a, 1997.
19. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and
cohort investigation in UFT phase II studies. Cancer Chemother
Pharmacol 22:333-338, 1988.
20. Pazdur R, Lassere Y, Diaz-Canton E, et al: Phase I trials of
uracil-tegafur (UFT) using 5 and 28 day administration schedules:
Demonstration of schedule dependent toxicities. Anticancer Drugs
21. Pazdur R, Lassere Y, Diaz-Canton E, et al: Phase I trial of
uracil-tegafur (UFT) plus oral leucovorin: 28-day schedule. Cancer
Invest 161:145-151, 1998.
22. Pazdur R: Phase I and pharmacokinetic evaluations of UFT plus
oral leucovorin. Oncology 11(9)(suppl 10):35-39, 1997.
23. Pazdur R, Lassere Y, Rhodes V, et al: Phase II trial of uracil
and tegafur plus oral leucovorin: An effective oral regimen in the
treatment of metastatic colorectal carcinoma. J Clin Oncol 12:2296-2300,
24. Saltz LB, Leichman CG, Young CW, et al: A fixed-ratio combination
of uracil and ftorafur (UFT) with low dose leucovorin: An active oral
regimen for advanced colorectal cancer. Cancer 75:782-785, 1995.
25. Gonzalez-Baron M, Feliu J, de la Gandara J, et al: Efficacy of
oral tegafur modulation by uracil and leucovorin in advanced
colorectal cancer: A phase II study. Eur J Cancer 31:2215-2219, 1995.
26. Shirasaka T, Shimamoto Y, Fukushima M: Inhibition by oxonic acid
of gastrointestinal toxicity of 5-fluorouracil without loss of its
antitumor activity in rats. Cancer Res 53:4004-4009, 1993.
27. Tatsumi K, Fukushima M, Shirasaka T, et al: Inhibitory effect of
pyridimine barbituric acid and pyridine derivative on 5-fluorouracil
degradation in rat liver extracts. Gan To Kagaku Ryoho 78:748-755, 1987.
28. Peters GJ, Van Groeningen CJ, Schomage JH, et al: Phase I
clinical and pharmacokinetic study of S-1, an oral 5-fluorouracil
(5-FU)-based antineoplastic agent (abstract 800). Proc Am Soc Clin
Oncol 16:227a, 1997.
29. Ohtsu A, Sakata Y, Horikoshi N, et al: A phase II study of S-1 in
patients with advanced gastric cancer (abstract # 1005). Proc Am Soc
Clin Oncol 17:262a, 1998.
30. Baba H, Ohtsu A, Sakata Y, et al: Late phase II study of S-1 in
patients with advanced colorectal cancer in Japan (abstract # 1065).
Proc Am Soc Clin Oncol 17:277a, 1998.
31. Horikoshi N, Mitachi Y, Sakata Y, et al: S-1, new oral
fluoropyrimidine, is very active in patients with advanced gastric
cancer (early phase II study). (abstract 466). Proc Am Soc Clin Oncol
32. Taguchi T, Horikoshi N, Kinoshita H, et al: Early phase II study
of S-1 in patients with advanced breast cancer (abstract 151). Proc
Am Soc Clin Oncol 15:121, 1996.
33. Fujii M, Kanzaki J, Satake B, et al: Early phase II study of S-1
in patients with advanced head and neck cancer (abstract 894). Proc
Am Soc Clin Oncol 15:316, 1996.