The combination of uracil and tegafur (UFT) in a 4:1 molar
concentration was developed by Fujii et al. Tegafur is a 5-fluorouracil
(5-FU) prodrug and uracil competes with 5-FU as a substrate for
dihydropyrimidine dehydrogenase, an enzyme that enhances the
catabolism of 5-FU. In preclinical studies, the coadministration of
uracil with tegafur enhanced concentration of 5-FU in tumors and
increased antineoplastic activity.[2-6] Phase I and II trials in
patients with advanced cancer and metastatic colon cancer indicate
that UFT administered orally with the biochemical modulator
leucovorin for more than 28 days resulted in response rates of 25% to
43% and a toxicity profile acceptable for the adjuvant setting.[7-9]
The National Surgical Adjuvant Breast and Bowel Project (NSABP) has
undertaken two large clinical trials designed to evaluate the role of
adjuvant therapy in patients with resected Dukes B and C colon
cancer. In NSABP Protocol C-04, 5-FU/levamisole (Ergamisol) was
compared with 5-FU/leucovorin and 5-FU/levamisole/leucovorin. Initial
results from this study demonstrated no statistically significant
differences in disease-free survival or overall survival among the
three groups. A pairwise comparison, however, suggested a small
disease-free and overall survival benefit for 5-FU/leucovorin
compared with 5-FU/levamisole. In NSABP Protocol C-05,
5-FU/leucovorin was compared with 5-FU/leucovorin/interferon
alfa-2a.[10,11] Toxicity increased, but no disease-free or overall
survival benefit was demonstrated for 5-FU/leucovorin/interferon
alfa-2a compared with 5-FU/leucovorin.
Results from the C-04 trial, in conjunction with the NSABP Protocol
C-03 (demonstrating superiority with the 5-FU/leucovorin regimen over
the semustine [MeCCNU]/vincristine [Oncovin]/5-FU [MOF] regimen) and
the Intergroup trial (comparing 5-FU/levamisole with 5-FU/leucovorin)
have confirmed the efficacy of 5-FU/leucovorin in Dukes B, and
Dukes C patients.[12,13]
The existing evidence indicates the activity of the regimen of UFT
(uracil and tegafur) plus oral leucovorin (a combination being
developed under the trade name Orzel) in the treatment of metastatic
colon cancer. We decided to explore the role of this option in the
adjuvant setting. To this end, from February 14, 1997 to March 31,
1999, the NSABP conducted Protocol C-06, a prospective, randomized
trial designed to compare the efficacy of 5-FU plus leucovorin with
that of UFT plus leucovorin in the treatment of patients with stage
II or III colon cancer. A detailed discussion of the conduct of this
trial has been published in an earlier issue of Oncology.
Patients and Methods
To be eligible for the trial, patients had to have a life expectancy
of 10 years; an Eastern Cooperative Oncology Group performance status
of 0, 1, or 2; adequate hematologic function (leukocyte count >
4,000/µL and platelet count ³ 100,000/µL);
adequate renal and hepatic function (normal serum creatinine,
alanine aminotransferase, aspartate aminotransferase, and total
bilirubin); and resected American Joint Committee on Cancer (AJCC)
stage II (T3,4, N0, M0; modified Astler-Coller B2, B3) or stage III
(any T, N1,2,3, M0) colon cancer.
For the purposes of the study, a colon tumor is defined as one
located above the peritoneal reflection on surgical exploration or
more than 15 cm from the anal verge on endoscopy. The presence of
more than one synchronous colon cancer does not preclude the
patients involvement in the study, as long as eligibility is
based on the more advanced primary tumor. Involvement of adjacent
structures (eg, bladder, small intestine, ovary) by direct extension
of the primary tumor is acceptable, if surgical margins are
tumor-free and surgical en bloc resection is deemed to be
curative by the surgeon.
Specific exclusion criteria include the presence of a free
perforation (as manifested by free air or fluid in the abdomen), a
history of prior colon or rectal cancer, use of prior chemotherapy or
radiotherapy for the present malignancy, and a history of prior
noncolonic malignancy unless the patient has been disease-free for 10
years or more (excluding basal and squamous cell carcinoma of the
skin and carcinoma in situ of the cervix). Informed consent is
required from all patients.
Following stratification based on the number of involved lymph nodes,
patients are randomly assigned to treatment with either 5-FU plus
leucovorin or UFT plus leucovorin (Figure
1). The 5-FU plus leucovorin regimen is given for three cycles
of leucovorin (500 mg/m² over 2 hours) and intravenous 5-FU (500
mg/m² bolus, 1 hour after initiation of leucovorin), both given
weekly for six doses, with a 2-week rest period between cycles. The
UFT plus leucovorin regimen consists of five 28-day cycles of oral
UFT 300 mg/m²/d and oral leucovorin 90 mg/d in three divided
doses (q8h). There is a 1-week rest period between cycles. The drug
dose is calculated before the onset of each cycle, and body surface
area determination is based on actual body weight (up to a maximum of
2 m² for any patient).
For patients assigned to receive 5-FU/leucovorin, a complete blood
count is performed before each weekly treatment and hepatic and renal
function tests are performed every 8 weeks prior to each cycle. For
patients assigned to receive UFT plus leucovorin, complete blood
counts are assessed weekly and renal and hepatic function tests are
performed every 5 weeks prior to each cycle. Carcinoembryonic antigen
levels are measured postoperatively, before randomization, and at
6-month intervals. A history is taken and a physical examination
performed before each treatment. Chest x-ray and barium enema or
endoscopy are done at baseline (as clinically indicated) and repeated
annually. If the patient is polyp-free, an endoscopy is performed
every 3 years.
The primary aim of the study is to compare the relative efficacy of
the two regimens in prolonging disease-free and overall survivals.
Secondary aims include evaluating the prognostic significance of
specific biomarkers (DNA mismatch repair gene mutations, p53
oncogene mutations, allelic loss of the deleted colon cancer gene,
proliferation status, and thymidylate synthase levels) for
disease-free survival and overall survival, and the relationship of
biomarkers to each other and to tumor and patient characteristics.
Quality-of-life (QOL) assessments are performed using two
quality-of-life questionnaires. If any differences in disease-free or
overall survival exist between the two regimens, the questionnaires
may help determine the risks and benefits. The first questionnaire is
administered before randomization, before each cycle of chemotherapy,
and 1 year after randomization. This is done to determine differences
over time in symptoms and treatment burdens between the two regimens.
The second QOL questionnaire is administered before randomization, at
15 weeks, and again at 1 year after randomization. This questionnaire
is used to provide a more detailed comparison of QOL during therapy.
Between February 14, 1997 and March 31, 1999, 1,608 patients were
enrolled in NSABP protocol C-06, with 803 assigned to receive 5-FU
plus leucovorin and 805 assigned to receive UFT plus leucovorin. As
shown in Table 1, the treatment
arms were well balanced for age, gender, race, Dukes stage, and
This interim analysis assessed toxicity in 756 patients assigned to
5-FU plus leucovorin and 774 patients assigned to UFT plus
leucovorin. To date, an average of 2.6 cycles of 5-FU plus leucovorin
per patient and 4.3 cycles of UFT plus leucovorin per patient have
As shown in Table 2, grade ³
3 granulocytopenia occurred in nine patients receiving UFT plus
leucovorin and eight patients receiving 5-FU plus leucovorin. Grade ³
3 thrombocytopenia occurred in one patient treated with UFT plus oral
leucovorin and one patient treated with 5-FU plus leucovorin. Sepsis
developed in 91 patients (12%) receiving 5-FU plus leucovorin and 31
patients (4%) receiving UFT plus leucovorin. Grade ³
3 nausea or vomiting was reported in 53 (7%) and 27 (3%) of patients
receiving 5-FU plus leucovorin and 54 (7%) and 23 (< 4%) of
patients receiving UFT plus leucovorin. Grade 3 or greater diarrhea
occurred in 212 (28%) patients treated with 5-FU plus leucovorin, and
225 (29%) patients treated with UFT plus leucovorin.
Transient abnormalities in liver function were observed in a few
patients, predominately in the UFT plus leucovorin arm. While on
protocol, 10 deaths occurred in the 5-FU plus leucovorin group: three
cardiac deaths, three related to infection, one pulmonary embolus,
and three otherwise not classified. Six deaths were associated with
UFT plus leucovorin therapy: one hemorrhagic, one related to
diarrhea, one cardiac, one pulmonary embolus, and two not otherwise classified.
This interim analysis indicates that the toxicities seen in patients
with resected stage II or III colon cancer who were assigned to
adjuvant combination chemotherapy with either UFT plus leucovorin or
5-FU plus leucovorin are similar and that both regimens are well
tolerated. Enrollment in this multi-institutional trial concluded on
March 31, 1999. If the final analysis and comparison of toxicity
profile demonstrate that UFT plus leucovorin offers overall survival
benefits similar to or greater than those associated with 5-FU plus
leucovorin, UFT plus leucovorin could become the new treatment
standard for adjuvant therapy of patients with resected stage II or
III colon cancer.
1. Fujii S, Ikenaka K, Fukushima M, et al: Effect of uracil and its
derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil.
Gann 69:763-772, 1978.
2. Taguchi T, Nakano Y, Fujita M, et al: Clinical studies of the
anticancer activity of FT-207. Jpn J Cancer Clinic 18:550-553, 1972.
3. Fujii S, Kitano S, Ikenaka K, et al: Studies of coadministration
of uracil or cytosine on antitumor activity of FT-207 or 5-FU
derivatives. Jpn J Cancer Chemother 6:377-384, 1979.
4. Ikenaka K, Shirasaka T, Kitano S, et al: Effect of uracil on
metabolism of 5-fluorouracil in vitro. Gann 70:353-359, 1979.
5. Suemasu K, Nomoto C, Higashi Y: Concentration of 5-FU level in the
tissue and blood of the patients with breast cancer by preoperative
administration of UFT. Jpn J Cancer Chemother 9:667-671, 1982.
6. Watanabe H, Yamamoto S, Naito T: Clinical results of oral UFT
therapy under cooperative study. Jpn J Cancer Chemother 7:1588-1596, 1980.
7. Meropol NJ, Rustum YM, Petrelli NJ, et al: A phase I and
pharmacokinetic study of oral uracil, ftorafur, and leucovorin in
patients with advanced cancer. Cancer Chemother Pharmacol 37:581-586, 1996.
8. 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
9. Saltz LB, Leichman CG, Young CW, et al: A fixed-ratio combination
of uracil and ftorafur (UFT) with low-dose leucovorin. Cancer
10. Wolmark N, Rockette H, Mamounas EP, et al: The relative efficacy
of 5-FU+leucovorin (FU+LV), 5-FU+levamisole (FU+LV+LEV) in patients
with Dukes B and C carcinoma of the colon: First report of
NSABP C-04 (abstract). Proc Am Soc Clin Oncol 15:205, 1996.
11. Wolmark N, Bryant J, Hyams DM, et al: The relative efficacy of
5-FU+leucovorin (FU-LV) and 5-FU-LV+interferon alfa-2A (IFN) in
patients with Dukes B and C carcinoma of the colon: First
report of NSABP C-05 (abstract). Proc Am Soc Clin Oncol 17:981, 1988.
12. Wolmark N, Rockette H, Fisher B, et al: The benefits of
leucovorin modulated fluorouracil as postoperative adjuvant therapy
for primary colon cancer. Results from NSABP Protocol C-03. J Clin
Oncol 11:1879-1887, 1993.
13. Haller DG, Catalano PJ, Macdonald JS, et al: Fluorouracil (5-FU),
leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon
cancer. Preliminary results of INT-0089 (abstract). Proc Am Soc Clin
Oncol 15:211, 1996.
14. Smith R, Wickerham DL, Wieand HS, et al: UFT plus leucovorin vs
5-FU plus leucovorin in colon cancer. Oncology 13:44-47, 1999.