Originally published as JCO Early Release 10.1200/JCO.2004.05.017 on July 26 2004

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Comparison of the Efficacy, Toxicity, and Pharmacokinetics of a Uracil/Tegafur (UFT) Plus Oral Leucovorin (LV) Regimen Between Japanese and American Patients With Advanced Colorectal Cancer: Joint United States and Japan Study of UFT/LV

From the Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo; Division of Gastrointestinal Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Chiba; Department of Internal Medicine, National Shikoku Cancer Center, Ehime, Japan; Division of Hematology & Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, Ithaca, NY; Oncology Section, Department of Veterans Affairs Medical Center, Washington, DC; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Section of Hematology & Oncology, Indiana University Cancer Center and The Walther Cancer Institute, Indianapolis, IN

Address reprint requests to Kuniaki Shirao, MD, Division of Gastrointestinal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; e-mail: kshirao{at}gan2.ncc.go.jp

	ABSTRACT

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PURPOSE: To compare the efficacy, toxicities, and pharmacokinetics of an oral regimen consisting of uracil/tegafur (UFT) and leucovorin (LV) between Japanese patients and patients in the United States with previously untreated metastatic colorectal cancer.

PATIENTS AND METHODS: Forty-four Japanese patients and 45 patients in the United States were enrolled in concurrent nonrandomized phase II trials. UFT 300 mg/m²/d and leucovorin 75 mg/d were administered orally for 28 days followed by a 7-day rest period. The total daily dose of each drug was divided into three equal doses. Treatment was repeated every 5 weeks until disease progression. Blood samples for the pharmacokinetic study were obtained after the initial dose on day 1 of the first course.

RESULTS: The response rate for the Japanese patients and the patients in the United States was 36.4% (95% CI, 22.4% to 52.2%) and 34.1% (95% CI, 20.5% to 49.9%), respectively. The only major toxicity was diarrhea, and other toxicities were mild in both populations. The incidence of grade 3 or higher diarrhea in the Japanese and Americans was 9% and 22%, respectively. Although the area under the curve and maximum concentration of fluorouracil were found to be slightly higher in the Japanese patients than the patients in the United States, and area under the curve–adjusted body surface area appeared to be comparable between the two groups.

CONCLUSION: The efficacy and pharmacokinetic parameters of UFT and LV are comparable in Japanese and American patients; however, a difference in toxicity profile, specifically diarrhea, was noted. This oral regimen of UFT and LV is considered to have similar activity against metastatic colorectal cancer and to have acceptable toxicity in patients in both countries.

	INTRODUCTION

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Colorectal cancer is the second most frequent cause of cancer deaths in the United States and most European countries, and its incidence has recently been increasing in Japan, where the number of deaths attributed to colorectal cancer now ranks third after lung cancer and gastric cancer. Colorectal cancer is therefore a major health problem worldwide, and the median survival time of patients with metastatic colorectal cancer treated with supportive care alone is approximately 4 to 6 months.¹ Systemic chemotherapy has recently been shown to prolong survival time, and median survival times now range from 17 to 21 months.^2,3

Combination of irinotecan with fluorouracil (FU)/leucovorin (LV) as a first-line treatment for metastatic disease has produced a survival benefit,^2,4 but recently there has been concern about the toxicity of the weekly bolus combination.⁵ A randomized cooperative group study has yielded preliminary data that supports the continued role of intravenous(IV) FU and LV as the backbone of treatment for metastatic colorectal cancer.⁶

Uracil/tegafur (UFT) is a preparation composed of tegafur and uracil in a molar ratio of 1:4. Tegafur is a prodrug of FU and is mainly converted to FU in the liver.⁷ In preclinical studies, the coadministration of uracil with tegafur enhanced the antitumor activity achieved with tegafur alone. Uracil strongly inhibits the degradation of FU to 2-fluoro-beta-alanine, thereby increasing the concentration of FU in plasma without increasing the toxicity resulting from 2-fluoro-beta-alanine.⁸ LV is used to modulate FU biochemically, and has been widely adopted for the treatment of advanced colorectal cancer. Given the extensive use of LV with FU, the combination of UFT with oral LV was assessed for treatment of colorectal cancer, and administration schedules of UFT and oral LV were developed in phase I and II studies.^9-12 Those studies showed that the combination was very effective against metastatic colorectal cancer and had an acceptable safety profile. A randomized cross-over trial in advanced colorectal cancer showed that oral UFT/LV compared favorably with IV FU/LV in terms of toxicity and patient's preference, and that it prolonged FU exposure to a level comparable to the exposure achieved with continuous IV FU administration.¹³

The results of two large phase III studies on the UFT/LV regimen in Western countries were reported recently and demonstrated similar survival between IV FU/LV and UFT/LV in Western patients with metastatic colorectal cancer.^14,15 UFT was developed in Japan and is commonly used there, and the Japanese experience has demonstrated that UFT is well tolerated and displays evidence of antitumor activity in a variety of solid tumors.¹⁶ Although several dosage regimens of UFT alone have been tried in colorectal cancer in Japan, there have been few studies on the combination of UFT plus LV in Japan.

We conducted the present study to determine whether the results of these phase III studies could be extrapolated to Japanese patients. If it showed equality of efficacy, safety, and pharmacokinetics in both Japanese and American patients, then the results of the Western phase III trials could be extrapolated to Japanese patients. This study was designed as an identical nonrandomized phase II analysis to evaluate the impact of ethnic factors on the efficacy and safety of a particular dosage and dose regimen in American and Japanese patients. The end point of the study was estimation of the efficacy, safety, and pharmacokinetic parameters of UFT/LV in American and Japanese patients with previously untreated metastatic colorectal cancer.

	PATIENTS AND METHODS

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Patient Selection
Patients had to be either Japanese or American nationals. The patients enrolled at the Japanese sites had to have been born in Japan and have lived more than 75% of their life in Japan, including the 2 years before enrollment. Patients enrolled at the US sites had to have been born in the United States and have lived more than 75% of their life there, including the 2 years before enrollment. Patients in both countries were entered into the study only if they fulfilled the following eligibility criteria: (1) histologic confirmation of colorectal carcinoma, (2) inoperable metastatic disease or recurrent metastatic disease after surgery, (3) measurable lesions, (4) age 20 years but 75 years, (5) performance status (PS) 2 on the Eastern Cooperative Oncology Group (ECOG) scale, (6) no prior chemotherapy for advanced disease (prior adjuvant chemotherapy for colorectal cancer must have been completed at least 6 months before enrollment), (7) adequate bone marrow function (absolute granulocyte count 1,500/µL and platelet count 100,000/µL), (8) adequate liver function (serum bilirubin level 1.5 mg/dL and serum transaminase levels 100 U/L), (9) adequate renal function (serum creatinine level 1.5 mg/dL), (10) no other severe medical conditions, (11) no other active malignancies, (12) no pregnant or breast-feeding women, and (13) provision of written informed consent.

Treatment Schedule
The dose of UFT was 300 mg/m²/d for 28 days followed by a 7-day rest period. The total daily dose was divided into three doses administered orally every 8 hours (at approximately 7 AM, 3 PM, and 11 PM). UFT (Taiho Pharmaceutical Ltd, Tokyo, Japan) was supplied in the form of 100-mg capsules (100 mg tegafur). The daily dose of UFT was rounded up or down to the nearest 100 mg. If the capsule dose could not be divided equally, the highest dose was administered in the morning and the lower doses in the evening. Leucovorin (Lederle Laboratories, Wayne, NJ) was supplied as 25-mg tablets and administered orally at a dose of 75 mg/d. The total daily dose was divided equally into three doses administered concurrently with UFT. Patients consumed no food for an hour before and after taking the drugs. A course of therapy was defined as 28 consecutive days of treatment followed by a 7-day rest period, and courses were repeated every 5 weeks until disease progression or severe toxicity was observed. Patient compliance was verified by counting the remaining pills at the end of each course of treatment. Treatment was interrupted for grade 3 or higher granulocytopenia or thrombocytopenia, or grade 2 to 4 nonhematologic toxicity. If treatment was discontinued because of a grade 2 nonhematologic toxicity, UFT and LV were resumed at the same doses when the toxicity had completely resolved. Whenever grade 3 or 4 toxic effects occurred, the UFT dose was reduced by 50 mg/m²/d in subsequent courses, but the dose of LV remained at 75 mg/d.

Evaluation
Patients were evaluated by appropriate investigations, including physical examination, chest x-ray, and computed tomographic scans of the abdomen and chest, before entry into the study to determine the extent of disease. A complete blood cell count, liver function tests, renal function tests, and urinalysis were performed at least once every 2 weeks during treatment. Appropriate investigations were repeated as necessary to evaluate the sites of marker lesions before every course or every other course. The tumor response of the lesions was evaluated according to WHO criteria.¹⁷ National Cancer Institute common toxicity criteria were applied to evaluate the toxicity of this therapy.¹⁸ The eligibility and suitability of the subjects for assessment and their response to treatment were reviewed extramurally.

Pharmacokinetics
On day 1, blood specimens were obtained immediately before drug administration and at 0.25, 0.5, 1, 1.5, 2, 3, 5, and 8 hours after drug administration. They were collected in heparinized tubes and centrifuged in a refrigerated centrifuge, and the plasma obtained was frozen at –20°C until analysis.

Concentrations of tegafur (FT) were determined by a validated high-performance liquid chromotography (HPLC) assay with ultraviolet detection based on the method reported by Muranaka et al.¹⁹ A validated gas chromatographic-mass spectrometric assay method was used to quantitate FU and uracil in the plasma samples. The assay method used was based on a method published previously for FU²⁰ and was modified to include simultaneous quantitation of uracil as reported by Muranuka et al.¹⁹ LV and 5-methyl tetrahydrofolate (5-MTHF) were determined by validated HPLC methods that were modifications of methods reported previously.^21,22 LV and 5-MTHF were extracted from plasma as described by Etienne et al²¹; however, LV was resolved from endogenous interference by gradient HPLC (mobile phase A, 40% acetonitrile-50% methanol in 25 mmol/L KH₂PO₄ [pH 2.3]; mobile phase B, 25 mmol/L KH₂PO₄ [pH 2.3]), and 5-MTHF was resolved from endogenous interference by isocratic HPLC with a mobile phase consisting of 5% acetonitrile-50% methanol in 25 mmol/L KH₂PO₄ (pH 2.3). Both LV and 5-MTHF were detected at 310 nm.²²

For FT, FU, and uracil, the standard curves were linear (R² > 0.991) over the concentration range of 50 to 20,000, 1 to 5, and 20 to 5,000 ng/mL, respectively. Based on the analysis of quality control samples, the accuracy was –0.9% to 3.4% and the inter- and intrarun precision was 6.0% to 7.9% of the assays for FT; 5.7% to 11.0% and 2.0% to 8.6% for FU; and 2.8% to 8.0% and 1.2% to 8.7% for uracil. For both LV and 5-MTHF, the standard curves were linear (R² > 0.992) over the concentration range of 50 to 2,000 ng/mL; the accuracy was 1.5% to 3.0%, and the inter- and intrarun precision was 5.9% to 8.7% of the assay for LV, and 1.8% to 3.3% and 4.5% to 7.8% for 5-MTHF, respectively.

The plasma concentration-time data following administration for five analyses were analyzed by a noncompartmental method using the computer program WINNonlin (version 3.1; Pharsight Co, Apex, North Carolina). The peak plasma concentration (C_max) and the time to reach the peak concentration (T_max) were recorded directly from the experimental observations. The area under the plasma concentration-time curve (AUC) from time 0 to T, AUC_0-T, where T is the time of the last measurable concentration, was calculated by the trapezoidal method. No weighting factor was used, and the slope of the terminal phase of the plasma profile, K, was determined by log-linear regression of at least three data points, which yielded a minimum mean square error. The absolute value of K was used to estimate the terminal half-life (t_1/2) according to the formula t_1/2 = ln2/K. AUC from time 0 to infinity, AUC_0-inf, was determined by summing the areas from time 0 to the time of the last measured concentration, calculated using conventional trapezoidal and log-trapezoidal methods, and the extrapolated area. The extrapolated area was determined by dividing the final concentration by the slope of the terminal log-linear phase. Since a terminal log-linear phase was not identified in a minority of the patients, the t_1/2 and AUC_0-inf values of these patients could not be calculated.

Statistical Methods
Response rates of metastatic colorectal cancer between 16.6% to 21.5% for UFT alone and between 18% and 43% for UFT plus LV have been reported in some phase II studies. The sample size in this study was calculated based on a target activity level of 31.5% and minimum activity level of 20%, to ensure the lower limit of the 90% CI, and thus the number of patients required in each country was 44. Time to progression was measured from the start of treatment to the date of progression. Progression time was censored at the close out date if progressive disease was not observed.

The equivalence of AUC and C_max in analyses was concluded if the 90% CI with a power of 80% for difference of logarithmic means between Japanese and American patients was entirely within the range of –0.36 to 0.36.

This trial was approved by the institutional review board of the clinical oncology program at all hospitals participating in this study.

	RESULTS

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Eighty-nine patients with advanced metastatic colorectal carcinoma were entered onto the trial between November 1998 and September 2000. Forty-four patients were entered in Japan, and all were assessable for toxicity and response. Forty-five patients were entered in the United States, and 44 were assessable for response. One patient in the United States was judged ineligible because no target lesions were available. The 44 patients in the United States consisted of 30 white patients, four Hispanic patients, and 10 black patients.

The characteristics of the eligible patients are listed by country in Table 1. Almost all patients in both groups had good performance status. Almost all patients in both groups had undergone surgery, and five (11%) Japanese patients and 10 (23%) patients in the United States (hereafter, "American patients") had received FU-based adjuvant chemotherapy. The characteristics of the 88 eligible Japanese and American patients were matched for age, sex, performance status, and prior therapy.

Toxicity
Forty-four Japanese patients and 45 American patients were assessable for toxicity. Table 4 shows the highest grade of toxicities during all treatment courses according to patient. Although the incidence of grade 3 and 4 hematologic toxicities in the American patients was almost the same as in the Japanese patients, the incidence of all grades of thrombocytopenia was higher in the American patients than in the Japanese patients. Diarrhea occurred in 38.6% of the Japanese and 68.9% of the American patients (P = .006). The incidence of grade 3 and 4 diarrhea was also higher in the American patients (22.2%) than in the Japanese patients (9.1%). Five American patients exhibited grade 3 or 4 dehydration due to diarrhea. All-grade and grade 3 and 4 nausea and vomiting were higher in the American patients than in the Japanese patients. However, the incidences of the grade 3 or 4 toxicities were not high, even among the American patients. All-grade and grade 3 or 4 stomatitis/mucositis occurred more often in the Japanese patients (34.1% and 4.5%, respectively) than in the American patients (17.8% and 0%, respectively). Hand-foot syndrome was rarely observed in either group. The incidence of grade 3 and 4 abnormal bilirubin and AST and ALT values was almost the same in both groups (2.3% to 5.6%).

Pharmacokinetics
Blood specimens for pharmacokinetic analysis were available from 44 patients in Japan and 43 patients in the United States, and a summary of the results along with the numbers of patients available for each parameter is provided in Table 5. A patient was judged nonassessable for pharmacokinetic analysis if three or more blood specimens were missing.

View larger version (11K): [in this window] [in a new window]   Fig 1. Plasma fluorouracil concentration versus time curve.

View larger version (10K): [in this window] [in a new window]   Fig 2. Plasma leucovorin concentration versus time curve.

View larger version (14K): [in this window] [in a new window]   Fig 3. Area under the curve (AUC0-8h) of fluorouracil (FU) according to body-surface area (BSA).

	DISCUSSION

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The response rate in this trial was 36.4% in the Japanese patients and 34.1% in the American patients. The patient characteristics in both groups were almost identical, and the response rates were very similar, suggesting no difference between Japanese and American patients in regard to the efficacy of a combination of UFT and LV. These response rates are also compatible with the results (response rate, 18% to 43%) of other phase II studies of UFT/LV for colorectal cancer in Western countries.^11,12,23-27 The response rates in this trial and other phase II trials of UFT/LV were generally higher than with UFT alone in metastatic colorectal cancer in Japan (21.5%; 14 of 65 patients)¹⁶ and the United Kingdom (16.6%; six of 36 patients).²⁸ However, the doses, schedules, eligibility criteria, and response criteria in the trials differed, rendering a comparison of efficacy difficult. Nevertheless, the data support addition of the effect of LV to UFT, the same as with FU and LV, and this additional effect appears to be the same in different countries.

The incidence and degree of toxicity did not differ much between the countries, except for gastrointestinal toxicities and thrombocytopenia. The incidences of all grades of diarrhea, nausea and vomiting, and grade 3/4 diarrhea were higher in the American patients than in the Japanese patients. McCollum et al²⁹ have reported that treatment-related toxicity differs between the black and white patients receiving FU-based treatment, with white patients experiencing statistically significantly higher rates of diarrhea, nausea and vomiting, and stomatitis. The same tendency, except for stomatitis, was also observed among American patients in the present study. In particular, for diarrhea, the incidence of grade 3/4 diarrhea was 29% (nine of 31 patients) in the white patients, 0% (zero of 10 patients) in the black patients, and 25%(one of four patients) in the Hispanic patients. This difference in the incidence and degree of diarrhea between the Japanese and American patients in our study may be a reflection of racial/ethnic differences, although this has not been verified. However, diarrhea was manageable with antidiarrheal drugs or by temporary interruption of UFT/LV, and few patients in either group had to cease treatment because of diarrhea. Furthermore, a difference in the incidence of thrombocytopenia between the two countries was observed in the present study, although McCollum et al²⁹ reported no difference in thrombocytopenia according to race. However, in our trial, the grade was 1 for all American patients in which the incidence of thrombocytopenia was higher. Moreover, the mean nadir of thrombocytes between the countries did not differ (Japanese patients, 189,000/µL; American patients, 198,000/µL). Therefore, no significant difference in thrombocytopenia was apparent between the countries. UFT administration is only rarely complicated by hand-foot syndrome,^13-15 and similarly was rare in both groups in this trial. Although some differences in toxicities in both countries were observed in this trial, the incidence and degree of toxicities in both countries were mostly consistent with the results of the other phase II trials of UFT/LV.^11,12,23-27

The mean AUC and C_max of FT and uracil in the present study were slightly higher in the Japanese patients than the American patients, and the AUC and C_max of FU, which is an active form of UFT, were also slightly higher in the Japanese patients than the American patients. The mean AUC values of FU in two other studies designed administering UFT 200 mg plus LV 30 mg in Western patients were 96.0³⁰ and 118 ng·h/mL,³¹ respectively. Moreover, Borner et al¹³ reported that the mean AUC value of FU on day 8 after administration of oral UFT 300 mg/m²/d plus oral LV 90 mg/d to European patients was 113 µmol/L x min (244.8 ng·h/mL). The actual values for the mean AUC of FU obtained in those studies are similar to our data in American patients (164.0 ± 118.4 ng · h/mL) and similar to the results obtained in the Japanese patients (223.1 ± 154.8 ng·h/mL) in the present trial. Bolus intravenous FU has been reported to result in a significantly higher AUC and C_max of FU, indicating higher FU exposure than with oral UFT, and large phase III studies have confirmed higher toxicity and equal efficacy of intravenous FU in comparison to oral UFT.^14,15 These findings indicate that high FU exposure may not be necessary for tumor response, but may translate into toxicity.

We performed an analysis of covariance on the AUC of FU adjusted for certain characteristics (BSA, UFT dose, performance status, complications) and found that the most significant factor was BSA (P = .0029). Because the dose of UFT administered in the pharmacokinetic study was not decided according to BSA, we examined the AUC of FU according to BSA. The result was that the distributions of the AUCs of FU were similar among patients in both countries in the same BSA range. Therefore, the AUCs of FU are thought to be comparable between Japanese and American patients. However, the reasons for the difference in diarrhea between the patients in the two countries having almost the same pharmacokinetic profile could not be identified, except for the possibility of racial influences.

5-MTHF is a metabolic product of LV, and 5-MTHF and LV are known to enhance the antitumor activity of FU. Our results also showed a slightly higher AUC and C_max of LV and 5-MTHF in the Japanese patients than in American patients. Meropol et al³⁰ has reported that there is no interaction between UFT and LV and that the plasma concentration of FU is unaffected by LV. This finding may suggest that the plasma concentration of FU is regulated by uracil, not LV, through inhibition of dihydropyrimidine dehydrogenase.

The results of the present study indicate that UFT/LV is equally active in Japanese and American patients. However, a difference in toxicity profile, especially diarrhea, was noted. Although the AUC and C_max of FU were found to be slightly higher in the Japanese patients than in the American patients, AUC-adjusted BSA appeared to be comparable between the countries. This oral regimen of UFT and LV was considered to have similar activity against metastatic colorectal cancer and to have acceptable toxicity in patients in both countries.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by the Taiho Pharmaceutical Company, Tokyo, Japan.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted May 2, 2003; accepted April 12, 2004.

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