Clinical Cancer Research The Science of Cancer Health Disparities Infection and Cancer: Biology, Therapeutics, and Prevention
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hoff, P. M.
Right arrow Articles by Pazdur, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hoff, P. M.
Right arrow Articles by Pazdur, R.
Clinical Cancer Research Vol. 9, 134-142, January 2003
© 2003 American Association for Cancer Research

Clinical Trials

Phase I Study with Pharmacokinetics of S-1 on an Oral Daily Schedule for 28 Days in Patients with Solid Tumors1

Paulo M. Hoff2, Everardo D. Saad3, Jaffer A. Ajani, Yvonne Lassere, Cynthia Wenske, Diana Medgyesy, Sunita Dwivedy, Mark Russo4 and Richard Pazdur5

Department of Gastrointestinal Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Our purpose in the study was to determine the maximum tolerated dose and dose-limiting toxicity and investigate the clinical pharmacology of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate.

Experimental Design: Eligible patients had advanced solid tumors, adequate organ function, and no anticancer therapy in the preceding 4 weeks. Dose level 1 was 30 mg/m2/dose, level 2 was 40 mg/m2/dose, and level 3 was 35 allmg/m2/dose, all of the levels comprising two daily doses. S-1 was administered as a single dose at each level, and its pharmacology was studied. The first course was begun 3 days later and consisted of 28 consecutive treatment days, followed by a 1-week rest.

Results: Sixteen patients were enrolled; toxicity could be assessed in all of the 16 and response in 15. At dose level 1, two of nine patients developed grade 3 hyperbilirubinemia or diarrhea. Dose-limiting toxicity (diarrhea) occurred in all three of the patients at dose level 2. The protocol was, therefore, amended to include an intermediate dose level (level 3), which caused grade 3 or 4 diarrhea or hyperbilirubinemia in three of four patients. Dose level 1 was thus considered as the maximum tolerated dose. Other grade 3 or 4 toxic effects at dose level 2 or 3 were granulocytopenia, nausea, and vomiting. The pharmacology of tegafur, CDHP, potassium oxonate, and fluorouracil (a metabolite of tegafur) was characterized by rapid absorption and was consistent with first-order kinetics. One patient with colorectal cancer had a durable partial response.

Conclusions: The recommended S-1 dose for future studies is 30 mg/m2 twice daily, and diarrhea is the most frequent toxic effect. Additional trials of S-1 in the treatment of patients with solid tumors are warranted.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
5-FU6 was introduced by Heidelberger et al. (1) in 1957 and has been used to treat solid tumors since then. Among the various methods of administration investigated, continuous i.v. infusion provides improved response rates and a favorable toxicity profile compared with bolus 5-FU (2, 3, 4) and may be the optimal route of administration. However, this method requires permanent central venous access and the use of portable infusion pumps, both of which may negatively affect patient convenience and cost. In addition, the pharmacokinetics of 5-FU is subject to significant variability (5) . Protracted 5-FU infusion results in interindividual and intraindividual variations in plasma 5-FU concentrations, mainly because of differing levels of DPD, the primary catabolic enzyme of 5-FU (6 , 7) . In addition, DPD activity displays circadian rhythms (8) . The variability of DPD levels in the gastrointestinal tract precludes the achievement of consistent 5-FU plasma concentrations, thus making oral administration of 5-FU ineffective. Inhibition or inactivation of DPD has emerged as a potential strategy to reduce the pharmacokinetic variability and improve the efficacy of 5-FU (5 , 9) .

Tegafur [5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione] is a fluoropyrimidine that is well absorbed after oral ingestion and is transformed into 5-FU by the hepatic microsomal system (10) . The combination of tegafur with the DPD inhibitor uracil is known as UFT. Extensive investigation of UFT in Japan and, more recently, in North America and Europe has demonstrated its promising activity in colorectal cancer (11) . Preliminary results from recent Phase III trials have shown similar response rates and overall survival for patients with colorectal cancer treated with UFT or with bolus 5-FU plus leucovorin (12 , 13) . However, UFT had a more favorable toxicity profile, with significantly less hematological and gastrointestinal toxicity.

S-1 is a novel oral fluoropyrimidine combination developed in Japan. S-1 consists of tegafur combined with two 5-FU-modulating chemicals, CDHP and potassium oxonate [potassium 1,3,5-triazine 2,4(1H,3H)-dione-6-carboxylate], at a molar ratio of 1:0.4:1 (14) . CDHP is a competitive inhibitor of 5-FU catabolism, being about 200 times more potent than uracil in inhibiting DPD (15) . When tegafur is combined with CDHP, the resulting 5-FU levels are maintained in both plasma and tumor (14) . Potassium oxonate inhibits orotate phosphoribosyltransferase, the enzyme that phosphorylates (i.e., activates) 5-FU in the gastrointestinal tract. Thus, potassium oxonate may reduce the gastrointestinal toxicity of 5-FU without interfering with its antitumor activity (16) . The cytotoxic action of S-1 is ultimately exerted by 5-FU through its antimetabolic effects on DNA (through thymidylate synthase inhibition) and RNA levels.

S-1 has undergone preclinical evaluation in Japan. The optimal molar ratio for the three components was determined after experiments in sarcoma-bearing rats and human gastric cancer xenografts (14) . The activity of S-1 was demonstrated in experimental solid tumor models, including rodent tumors and human xenografts (14 , 17, 18, 19) . In animal studies, S-1 showed superior activity against human gastric, colon, and breast cancer xenografts compared with UFT (20) . In addition, a comparison with continuous 5-FU infusion suggested that S-1 may be more active and less toxic than 5-FU (21) . Clinical studies of S-1 on a schedule of 28 days with twice-daily dosing, followed by a 14-day rest, were recommended, based on the Phase I trials (22 , 23) . In a Phase II study, S-1 demonstrated significant activity in patients with advanced gastric cancer (24) and has been approved for this indication in Japan. Preliminary favorable results have also been reported in Phase II studies in breast cancer and head and neck cancer (25 , 26) .

No previous Phase I studies of S-1 have been conducted in the United States. The primary objectives of the present study were to determine the MTD and DLT of S-1, and to determine its toxicity profile. The secondary objective was to determine the pharmacokinetic profiles of S-1 constituents in plasma after the administration of a single dose.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility.
Eligible patients had a pathologically confirmed, advanced solid tumor that was refractory to conventional treatment or for which no standard therapy existed. Eligibility criteria also included the following: age >=18 years; Zubrod performance status of 0 to 2; life expectancy of more than 12 weeks; absolute granulocyte count of >=1,500/µl; platelet count >=100,000/µl, bilirubin <=1.5 mg/dl, creatinine <=2.5 mg/dl, and measurable or evaluable disease. Patients were required to have discontinued chemotherapy, immunotherapy, and radiotherapy for at least 4 weeks before entry into the study (6 weeks for nitrosoureas or mitomycin C). Pregnant and breast-feeding women were excluded from this study, and fertile patients had to practice contraception. Patients with known brain metastasis or leptomeningeal disease were not eligible. Patients gave written informed consent as per institutional and federal regulatory requirements, and the protocol was approved by the institutional review board.

Study Treatment.
S-1 was supplied by Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan). Each capsule of S-1 contained 20 or 25 mg of tegafur. Individual doses were rounded as closely as possible to the calculated dose, given the available formulation. The study drug was administered p.o. twice daily. A course of therapy was defined as 28 consecutive treatment days followed by a 1-week rest (total course duration of 5 weeks). Days on which S-1 was held because of toxic effects were counted as treatment days. S-1 was given between 7 and 10 a.m. and again between 7 and 10 p.m. Because potassium oxonate is unstable under acidic conditions, patients were instructed to take the capsules within 1 h after a meal.

Study Design.
This was a Phase I, single-site, dose-finding study of S-1. Before starting the first course of treatment, each patient received a single dose of S-1 at that patient’s designated dose level to study the 24-hour pharmacokinetics of the S-1 constituents. Serial blood and urine samples were collected at specified time intervals (see Pharmacokinetic Studies) after this single dose. Three days later, the first course was begun. A starting dose of 30 mg/m2 twice daily (level 1) was selected based on the experience with S-1 in Japan (22 , 23) . The dose was based on actual body surface area, and intrapatient dose escalations were not permitted. Table 1Citation shows the dose levels used in this study.


View this table:
[in this window]
[in a new window]
  		Table 1 Dose levels for S-1

 
At least three patients were studied for one course at each dose level before additional patients received escalated doses. If none of the initial three treated patientstreated developed DLT, dose escalation continued. If one of the initial three treated patientstreated developed DLT, then three additional patients were to be entered on the same dose level. The MTD of S-1 was defined as the highest dose level that did not cause DLT during course 1 in more than ofone-third of the patients treated at that level. Hematological DLT was defined as grade 4 neutropenia lasting more than 5 days, febrile neutropenia, or grade 4 thrombocytopenia. Nonhematological DLT was defined as grade 3 or 4 nonhematological toxicity (excluding nausea/vomiting), inability of the patient to take >=75% of the planned chemotherapy dose during the treatment period, or grade 3 or 4 nausea/vomiting uncontrolled by aggressive antiemetic support. Grading of toxicity was done according to the NCIC CTC.

S-1 was held until recovery for nonhematological toxic effects grade <=2 and for granulocytopenia <=1,000/µl and thrombocytopenia <=50,000/µl. The protocol specified one level of dose reduction for patients with grade 3 or 4 toxicity. For patients with grade 2 toxic effects, S-1 was held until recovery to grade <=1 and then resumed at the same dose level.

All of the patients receiving any dose of S-1 were evaluable for toxicity. Patients receiving a minimum of two courses were evaluable for response, unless there was rapid disease progression after the first course, in which case, progression would be declared and patients would be removed from the study. Patients with a complete or partial remission of their disease continued to receive S-1 until documentation of disease progression. Patients with stable disease were allowed to continue on study, at the discretion of the treating physician, until the disease clearly progressed. Patients returned any unused capsules and their study calendars to the research nurse at each clinic visit, to verify compliance with the treatment.

Patient Evaluation.
All of the patients had a complete medical history and physical examination at the time of enrollment and a repeat physical examination at each clinic visit. Likewise, CBCs and serum chemistry profile, plain radiographs, computed tomography scans, and electrocardiogram were performed before enrollment. CBCs were obtained at least weekly while the patients were receiving S-1. The extent of disease was assessed every two cycles using the same radiographic method used initially to demonstrate measurable or evaluable disease. Responses were determined based on the WHO criteria (27) . All of the partial and complete responses were to be confirmed 4 weeks after their initial documentation.

Pharmacokinetic Studies.
Blood samples (15 ml) were collected in heparinized tubes before the single dosing of S-1 and at 30 min and 1, 2, 4, 8, 12, and 24 h thereafter. Samples were placed on ice and immediately transported to the laboratory, where the blood was centrifuged and the plasma was frozen at -80°C. Urine samples were collected 12 h before S-1 dosing and for the periods 0–6, 6–12, 12–18, and 18–24 h after administration. After estimation of the total urine volumes, 10-ml samples were frozen and stored at -80°C until analysis.

Plasma and urine concentrations of 5-FU, endogenous uracil, CDHP, potassium oxonate, and its metabolite, cyanuric acid, were determined using gas chromatography with mass spectrometric detection; tegafur concentrations were determined by performancehigh-performance liquid chromatography with UV detection (23 , 28) . The lower limits of quantification of tegafur, 5-FU, CDHP, and potassium oxonate were 10, 1, 2, and 1 ng/ml, respectively; the analytical method is considered to be approximately 90% accurate (28) . Pharmacokinetic analysis for the different compounds in plasma was performed using the Winnonlin software (version 1.5; SCI, NC) and included the determination of maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma T1/2.concentration-versus-time curve from time zero to last measurable plasma concentration (AUC0-t), area under the plasma concentration-versus-time curve from time zero to infinity (AUC0-{infty}), and plasma elimination half-life (T1/2). Pharmacokinetic analysis for the S-1 constituents in urine included the determination of the amount excreted at each collection interval and the cumulative amount excreted over a 24-hour period. In addition, oral clearance, volume of distribution, and the percentage of the dose excreted in urine were determined for tegafur, CDHP, and potassium oxonate.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Sixteen patients were enrolled in this trial; their demographic and clinical characteristics are listed in Table 2Citation . Most patients had gastrointestinal malignancies, performance status was 0 or 1, and median age was 61 years. Toxicity could be assessed for all of the patients and disease response in 15 patients. One patient had progressive disease after 17 days of beginning the first course and was, therefore, not evaluable for response. A total of 45 courses were administered, with a median of two courses per patient (range, 1–14).


View this table:
[in this window]
[in a new window]
  		Table 2 Patient characteristics (n = 16)

 
Three patients were initially entered on level 1 (30 mg/m2 twice daily). One patient developed grade 3 hyperbilirubinemia; therefore, three more patients were enrolled at this level. With no further DLT demonstrated in these three patients, escalation continued.

Three patients received S-1 at level 2 (40 mg/m2 twice daily). Two patients developed grade 4 diarrhea, and one patient developed grade 3 diarrhea. In addition, one of these patients also developed grade 3 granulocytopenia. The toxicity profile for this dose level is shown in Table 3Citation . Level 2 thereforewas, therefore, considered above the MTD, and the protocol was amended to include an intermediate dose level of 35 mg/m2 twice daily (level 3).


View this table:
[in this window]
[in a new window]
  		Table 3 Toxicity of S-1a

All of the doses were given twice daily. Dose levels 2 and 3 are shown in reversed order to illustrate increasing doses.

 
The first patient on level 3 had documented disease progression after 17 days on S-1 and was taken off the study. One patient had grade 3 diarrhea, and one had grade 3 hyperbilirubinemia (Table 3)Citation . A fourth patient was enrolled on this level. This patient developed grade 4 diarrhea, and this level thereforewas, therefore, considered above the MTD.

Level 1 was, thus, determined to be the MTD, and three additional patients received S-1 30 mg/m2 twice daily. Among these patients, one had grade 3 diarrhea and one had grade 3 hyperbilirubinemia. Nine patients were treated at this dose level, and the overall toxicity observed with 30 mg/m2 twice daily is shown in Table 3Citation . Severe toxic effects were restricted to the two cases of transient grade 3 hyperbilirubinemia and one patient with grade 3 diarrhea. The most common grade 1 and 2 toxic effects were diarrhea, nausea, vomiting, and asthenia. Our results indicate that the dose of 30 mg/m2 twice daily is the MTD for this agent and that diarrhea is the DLT. We found no evidence for cumulative toxicity among the patients treated on this study. Of the nine patients started on level 1, four received four or more courses. Three of these four patients eventually required dose reductions (to 20 mg/m2 twice daily) because of toxicity. Of the 37 courses administered at dose level 1, 20 were given at 30 mg/m2 twice daily, and 17 were given at 20 mg/m2 twice daily. allAmong all of the dose levels, there were 16 episodes of hyperbilirubinemia in 11 patients; these episodes were recorded during courses 1, 2, 3, and 4 in seven, six, two, and one case, respectively. All of the episodes were transient, and their distribution showed grade 2, 3, and 4 in eight, six, and two cases, respectively. Five patients had two episodes and six patients had only one episode. It should be noted that the grading of hyperbilirubinemia according to the system used in our study (NCIC CTC), is more stringent than the current United States National Cancer Institute CTC version 2.0. Using the latter grading system, we would have classified all of the episodes of hyperbilirubinemia in this trial one grade lower.

Fifteen patients were evaluable for response. There were no complete responses in this trial. One patient with colon cancer had a durable partial response lasting 14 months. Three years before entry into the study, this patient had been diagnosed with metastatic disease to regional lymph nodes and peritoneum that was completely resected; and afterward, the patient received 1 year of 5-FU/leucovorin chemotherapy. On the appearance of liver metastasis, the patient was enrolled on the current protocol. Three patients had disease stability lasting from 5 to 7 months, and 11 had progression of their disease at the first restaging.

Samples for pharmacokinetic analyses could be collected from seven patients on dose level 1, two patients on dose level 2, and four patients on dose level 3. The pharmacokinetic parameters of 5-FU, tegafur, CDHP, uracil, potassium oxonate, and cyanuric acid at the different dose levels are summarized in Table 4Citation .


View this table:
[in this window]
[in a new window]
  		Table 4 Summary data of S-1 pharmacokineticsa

 
5-FU, the active metabolite of tegafur, readily appeared in plasma, and the mean values for Cmax and AUC0-{infty} increased with increasing S-1 dose. 5-FU was eliminated from plasma with mean T1/2 values that did not markedly vary with the dose. Fig. 1Citation shows the mean plasma concentration of 5-FU and other S-1 constituents during the 24-hour period after the single-dose administration, according to dose level.



View larger version (26K):
[in this window]
[in a new window]
  		Fig. 1. Mean plasma concentrations (in ng/ml) of selected S-1 constituents. A–D, plasma concentrations of 5-FU, tegafur, CDHP, and uracil during the 24-hour period after a single-dose administration of S-1, according to dose level.

 
Tegafur was rapidly absorbed and slowly eliminated after oral administration. The mean values for tegafur Cmax and AUC0-{infty} were ~7–20 times higher than the corresponding mean values for 5-FU (Fig. 1)Citation .

Plasma levels of endogenous uracil steadily increased after the administration of S-1, with the mean Cmax at the different dose levels being 70- to 80-fold higher than the baseline (pre-dose) levels. The increased plasma concentrations of uracil after S-1 administration serve as a measure of effective DPD inhibition by CDHP. After reaching maximum concentration, plasma uracil concentrations steadily declined and were close to baseline values 24 h after dosing, which suggested that the functional DPD inhibition by CDHP is reversible (Fig. 1)Citation .

We investigated the correlation between S-1 toxicity and pharmacokinetic parameters. Spearman’s rank correlation coefficients were calculated for various adverse events. Significant correlations (P < 0.05) were found between higher 5-FU AUC and increased severity of diarrhea.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The DLT of S-1 was reached at the dose of 35 mg/m2 given twice daily. Other grade 3 or 4 toxic effects observed with doses of 35 or 40 mg/m2 twice daily included nausea/vomiting, hyperbilirubinemia, and granulocytopenia. On the basis of these findings, we recommend 30 mg/m2 twice daily as the starting dose for future studies. At this dose level, two cases of grade 3 hyperbilirubinemia and one case of grade 3 diarrhea occurred in the nine patients treated.

Our findings differ from those of the Japanese studies, in which S-1 was given for 28 consecutive days followed by a 14-day rest period. Taguchi et al. (22) reported a Phase I study investigating two different schedules of S-1, given either once or twice daily. Fixed doses of 75–100 mg twice daily or 150–200 mg once daily were found to be the MTD. The DLT was mainly hematological, and stomatitis and diarrhea were only grade 1 in severity. In a second Phase I study, Hirata et al. (23) treated 12 patients with fixed doses prespecified according to ranges of body surface area. Thus, patients with a body surface area of <1.25 m2 received 40 mg twice daily; patients with a body surface area from 1.25 to 1.5 m2 received 50 mg twice daily; and patients with a body surface area of >1.5 m2 received 60 mg twice daily. The average dose of S-1 received was 35.9 mg/m2 twice daily. The primary objective in the study by Hirata et al. was to investigate the pharmacokinetics of S-1, and dose escalation was not planned. Only three patients developed grade 3 or 4 toxic effects, all of which were hematological. This dose system was used in other studies from Japan. To make comparisons with the schedule used in our study, we calculated the ranges of doses (in mg/m2) actually given to Japanese patients, according to the ranges of body surface area specified (Table 5)Citation . The doses used in the Japanese studies were fairly similar to the dose range that we used but, on average, were higher than our recommended dose of 30 mg/m2 twice daily.


View this table:
[in this window]
[in a new window]
  		Table 5 Relationship between fixed and individualized doses of S-1a

 
Two Phase II trials of S-1 in patients with advanced gastric cancer have been reported, both using the same fixed-dose schedule according to ranges of body surface area. Sakata et al. (24) treated 51 patients and observed an objective response rate of 49%. Toxicity was mainly hematological, and only one case of grade 3 diarrhea and five cases of grade 1 diarrhea occurred. Other gastrointestinal toxicities were mild, with stomatitis observed in 12 patients and nausea/vomiting in 6. A second study was reported in abstract form, with 50 patients evaluable for drug safety and efficacy (29) . An overall response rate of 40% confirmed the activity of S-1 in patients with advanced gastric cancer. Grade 3 or 4 toxic effects were mainly hematological, with only one case of grade 3 diarrhea. In a Phase II study in patients with previously untreated advanced colorectal cancer, S-1 that was given in the same schedule based on body surface area ranges produced an overall response rate of 35.5% in 62 patients (30) . The toxicity profile was similar to that of previous Japanese studies, with hematological side effects predominating, and with one case of grade 3 diarrhea.

More recently, another Japanese Phase II trial of S-1 in patients with advanced gastric and colorectal cancer was reported (31) . Response rates were 53.6 and 16.7% for patients with gastric and colorectal cancer, respectively. Approximately one-third of these patients had received prior chemotherapy. Patients received the fixed doses of 50 mg or 75 mg twice daily for 28 days followed by a 2-week rest. Once more, grade 3 or 4 toxicity was mainly hematological, with 19% of patients having neutropenia and 8.6% having anemia or leukopenia. In this study, however, 24.1% of patients had diarrhea of any grade (8.6% with grade 3 or 4), compared with 11.7% of 51 patients in the other study by the same group (24) .

The EORTC reported the results of a Phase I study of S-1 conducted in Europe (32) . Twenty-eight patients with advanced solid tumors received S-1 for 28 days, followed by a 7-day rest. The starting dose was 25 mg/m2 twice daily, and DLT occurred at 45 mg/m2 twice daily. As was true for our study, grade 3 or 4 diarrhea was the most important DLT, occurring in three of five patients receiving 45 mg/m2 twice daily. EORTC investigators were able to demonstrate a difference in the incidence of diarrhea according to the extent of previous exposure to chemotherapy among patients who received 40 mg/m2 twice daily. The pharmacokinetic results in that study are comparable with ours, with linear 5-FU kinetics and a correlation between 5-FU parameters and the occurrence of diarrhea. On the basis of their findings, the EORTC investigators suggested 40 mg/m2 twice daily as the starting dose for Phase II studies in patients with no heavy previous exposure to chemotherapy. For patients with extensive prior chemotherapy, the dose of 35 mg/m2 twice daily was suggested.

We cannot explain the differences in the toxicity profile observed among the Japanese trials (22, 23, 24, 25, 26 , 29, 30, 31) and the EORTC (32) and the present study. Whereas hematological toxic effects predominated in the studies conducted in Japan, diarrhea was the DLT in Europe and the United States. Potassium oxonate decreased the gastrointestinal toxicity of 5-FU in animal models (16) . In our trial, diarrhea was the most significant toxic effect, but we were not able to ascertain whether potassium oxonate helped reduce the frequency or severity of diarrhea because we did not have a control group receiving tegafur and CDHP alone.

A comparison can be made between our pharmacokinetic results and those in the study by Hirata et al. (23 ; Table 6Citation ). At equivalent dose levels, the AUC for 5-FU in our patients are similar to those in Japanese patients. On the other hand, our patients had lower AUC for tegafur, suggesting a higher rate of conversion from the latter compound to 5-FU in our patients. Cytochrome P450 enzymes are involved in the oxidation of a number of drugs, and both interindividual and racial variations in the expression of P450 isozymes have been reported. Shimada et al. (33) have shown that Japanese individuals have lower expression of the cytochrome P4502A6 (CYP2A6) isozyme, compared with Caucasian individuals. Using human liver microsomes, it has been suggested that CYP2A6 is the main enzyme for the biotransformation of tegafur to 5-FU (34) . Whether pharmacogenetic variability could explain the quantitative and qualitative differences in the toxicity profile between the Japanese and Western studies of S-1 remains speculative at this time.


View this table:
[in this window]
[in a new window]
  		Table 6 Comparison of selected pharmacokinetic parameters, after single-dose administration, between the present study and the Japanese studya

 
The relatively similar uracil pharmacokinetic parameters in these two patient samples suggest that the degree of DPD inhibition may not explain the higher incidence of diarrhea in our patients. Our data suggest that CDHP inhibits DPD in a reversible manner, confirming the findings of other investigators (23 , 32) .

The oral treatment of cancer is an attractive modality, providing convenience for patients and health care staff (35 , 36) . Oral fluoropyrimidines such as UFT (12) , capecitabine (37) , and S-1 may in the future prove to be viable alternatives to i.v. 5-FU. S-1 is a rationally developed oral fluoropyrimidine combination deserving further investigation in Phase II trials of gastrointestinal malignancies. Results, thus far, suggest that S-1 may have a role in the treatment of metastatic gastric cancer (24 , 29 , 31 , 38) , and additional Phase II studies in this setting seem warranted (39) . Establishing the definitive role and the comparative efficacy of this fluoropyrimidine compared with other agents in this class will require additional studies. We recommend a starting dose of 30 mg/m2 given twice daily for 28 days, every 5 weeks. However, the relatively long half-life of the active compound (5-FU) may allow for once daily dosing, and this possibility should be evaluated in future studies.


   ACKNOWLEDGMENTS
 
We thank Michael S. Worley, ELS, for editorial assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by a contract from Taiho Pharmaceutical Co., Ltd., Tokyo, Japan. Back

2 To whom requests for reprints should be addressed, at Núcleo de Estudos Clínicos em Câncer, Hospital Israelita Albert Einstein, Av. Albert Einstein 627/701-2SS, 05651-901, Sao Paulo, Brazil. Phone: 55-11-37470491; Fax: 55-11-37471483; E-mail: necc{at}einstein.br Back

3 Present address: Department of Oncology, Albert Einstein Hospital, 05651-901 Sao Paulo, Brazil. Back

4 Present address: Covance Clinical Development Services, Princeton, NJ 08540. Back

5 Present address: Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20850. Back

6 The abbreviations used are: 5-FU, fluorouracil; DPD, dihydropyrimidine dehydrogenase; CDHP, 5-chloro-2,4-dihydroxypyridine; MTD, maximum tolerated dose; DLT, dose-limiting toxicity; CBC, complete blood plasma count; EORTC, European Organization for the Research and Treatment of Cancer; CTC, Common Toxicity Criteria; NCIC, National Cancer Institute of Canada; AUC, area under the curve. Back

Received 9/25/01; revised 7/ 9/02; accepted 7/27/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Heidelberger C., Chaudhuri N. K., Dannenberg P., Mooren D., Griesbach L., Duchinsky R., Schnitzer R. J., Pleven E., Scheiner J. Fluorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature (Lond.), 179: 663-666, 1957.[CrossRef][Medline]
  2. Lokich J. J., Ahlgren J. D., Gullo J. J., Philips J. A., Fryer J. G. 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., 7: 425-432, 1989.[Abstract]
  3. Leichman C. G., Fleming T. R., Muggia F. M., Tangen C. M., Ardalan B., Doroshow J. H., Meyers F. J., Holcombe R. F., Weiss G. R., Mangalik A. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J. Clin. Oncol., 13: 1303-1311, 1995.[Abstract]
  4. 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.[Abstract/Free Full Text]
  5. Iyer L., Ratain M. J. 5-Fluorouracil pharmacokinetics: causes for variability and strategies for modulation in cancer chemotherapy. Cancer Investig., 17: 494-506, 1999.[Medline]
  6. Diasio R. B., Harris B. E. Clinical pharmacology of 5-fluorouracil. Clin. Pharmacokinetics, 16: 215-237, 1989.[Medline]
  7. Diasio R. B., Lu Z., Zhang R., Shahinian H. S. Fluoropyrimidine catabolism. Cancer Treat. Res., 78: 71-93, 1995.[Medline]
  8. Harris B. E., Song R., Soong S-J., Diasio R. B. Relation between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma levels in patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res., 50: 197-201, 1990.[Abstract/Free Full Text]
  9. Schilsky R. L., Hohneker J., Ratain M. J., Janisch L., Smetzer L., Lucas V. S., Khor S. P., Diasio R., Von Hoff D. D., Burris H. A., III Phase I and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J. Clin. Oncol., 16: 1450-1457, 1998.[Abstract/Free Full Text]
  10. Hiller S. A., Zhuk R. A., Lidak M. Y. Analogs of pyridine nucleosides. Dokl. Akad. Nauk., 176: 332-335, 1967.[Medline]
  11. Hoff P. M., Pazdur R., Benner S. E., Canetta R. UFT and leucovorin: A review of its clinical development and therapeutic potential in the oral treatment of cancer. Anticancer Drugs, 9: 479-490, 1998.[Medline]
  12. Pazdur R., Douillard J-Y., Skillings J. R., Eisenberg P. D., Davidson N., Harper P., Vincent M. D., Lembersky B. C., Benner S. E. Multicenter Phase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin (LV) in patients with metastatic colorectal cancer. Proc. Am. Soc. Clin. Oncol., 18: 263a 1999.
  13. Carmichael J., Popiela T., Radsonte D., Falk S., Fey M., Oza A., Skovsgaard T., Martin C. Randomized comparative study of ORZEL (oral uracil/tegafur (UFT) plus leucovorin (LV) Proc. Am. Soc. Clin. Oncol., 18: 264a 1999.
  14. Shirasaka T., Shimamato Y., Ohshimo H., Yamaguchi M., Kato T., Yonekura K., Fukushima M. Development of a novel form of an 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.[Medline]
  15. Tatsumi K., Fukushima M., Shirasaka T., Fujii S. Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn. J. Cancer Res., 78: 748-755, 1987.[Medline]
  16. 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.[Abstract/Free Full Text]
  17. Takechi T., Nakano K., Uchida J., Mita A., Toko K., Takeda S., Unemi N., Shirasaka T. Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother. Pharmacol., 39: 205-211, 1997.[CrossRef][Medline]
  18. Shirasaka T., Nakano K., Takechi T., Satake H., Uchida J., Fujioka A., Saito H., Okabe H., Oyama K., Takeda S., Unemi N., Fukushima M. Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res., 56: 2602-2606, 1996.[Abstract/Free Full Text]
  19. Konno H., Tanaka T., Baba M., Kanai T., Matsumoto K., Kamiya K., Nakamura S. Therapeutic effect of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) on liver metastasis of xenotransplanted human colon carcinoma. Jpn. J. Cancer Res., 90: 448-453, 1999.[Medline]
  20. Fukushima M., Satake H., Uchida J., Shimamoto Y., Kato T., Takechi T., Okabe H., Fujioka A., Nakano K., Ohshimo H., Takeda S., Shirasaka T. Preclinical antitumor efficacy of S-1: A new oral formulation of 5-fluorouracil on human tumor xenografts. Int. J. Oncol., 13: 693-698, 1998.[Medline]
  21. Fukushima M., Shimamoto Y., Kato T., Uchida J., Yonekura R., Ohshimo H., Shirasaka T. Anticancer activity and toxicity of S-1, an oral combination of tegafur and two biochemical modulators, compared with continuous i.v. infusion of 5-fluorouracil. Anticancer Drugs, 9: 817-823, 1998.[CrossRef][Medline]
  22. Taguchi T., Inuyama Y., Kanamaru R., Hasegawa K., Akazawa S., Niitani H., Furue H., Kurihara M., Ota K., Suga S., Ariyoshi Y., Takai S., Shimoyama T., Toge T., Takashima S., Sugimachi K., Hara Y., Fujita H., Kimura K., Saito T., Tsukagoshi S., Nakao I. Phase I study of S-1. S-1 Study Group (in Japanese, with English abstract). Gan To Kagaku Ryoho (Jpn. J. Cancer Chemother.), 24: 2253-2264, 1997.[Medline]
  23. Hirata K., Horikoshi N., Aiba K., Okazaki M., Denno R., Sasaki K., Nakano Y., Ishizuka H., Yamada Y., Uno S., Taguchi T., Shirasaka T. Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug. Clin. Cancer Res., 5: 2000-2005, 1999.[Abstract/Free Full Text]
  24. Sakata Y., Ohtsu A., Horikoshi N., Sugimachi K., Mitachi Y., Taguchi T. Late Phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur. J. Cancer, 34: 15-1715-1720, 1998.[Medline]
  25. Taguchi T., Horikoshi N., Kinoshita H., Toge T., Takashima S. Early Phase II study of S-1 in patients with advanced breast cancer. Proc. Am. Soc. Clin. Oncol., 15: 121a 1996.
  26. Fujii M., Kanzaki J., Satake B., Baba S., Inuyama Y. Early Phase II study of S-1 in patients with advanced head and neck cancer. Proc. Am. Soc. Clin. Oncol., 15: 316a 1996.
  27. World Health Organization. . WHO Handbook for Reporting Results of Cancer Treatment, WHO Offset Publ. No. 48, World Health Organization Geneva 1979.
  28. Matsushima E., Yoshida K., Kitamura R., Yoshida K. Determination of S-1 (combined drug of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate) and 5-fluorouracil in human plasma and urine using high-performance liquid chromatography and gas chromatography-negative ion chemical ionization mass spectrometry. J. Chromatogr. B. Biomed. Sci. Appl., 691: 95-104, 1997.[CrossRef][Medline]
  29. Kurihara M., Koizumi W., Hasegawa K., Nakano K. Late Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with advanced gastric cancer. Proc. Am. Soc. Clin. Oncol., 17: 262a 1998.
  30. Ohtsu A., Baba H., Sakata Y., Mitachi Y., Horikoshi N., Sugimachi K., Taguchi T. Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with metastatic colorectal carcinoma. Br. J. Cancer, 83: 141-145, 2000.[CrossRef][Medline]
  31. Sugimachi K., Maehara Y., Horikoshi N., Shimada Y., Sakata Y., Mitachi Y., Taguchi T. An early Phase II study of oral S-1, a newly developed 5-fluorouracil derivative for advanced and recurrent gastrointestinal cancers. Oncology, 57: 202-210, 1999.[CrossRef][Medline]
  32. Van Groeningen C. J., Peters G. J., Schornagel J. H., Gall H., Noordhuis P., de Vries M. J., Turner S. L., Swart M. S., Pinedo H. M., Hanauske A. R., Giaccone G. Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. J Clin. Oncol., 18: 2772-2779, 2000.[Abstract/Free Full Text]
  33. Shimada T., Yamazaki H., Guengerich F. P. Ethnic-related differences in coumarin 7-hydroxylation activities catalyzed by cytochrome P4502A6 in liver microsomes of Japanese and Caucasian populations. Xenobiotica, 26: 395-403, 1996.[Medline]
  34. Nagayama S., Ikeda K., Matsushima E., Toko T., Kawaguchi Y. Drug-drug interaction between tegafur and fadrozole. Proc. Am. Assoc. Cancer Res., 41: 700 2000.
  35. Liu G., Franssen E., Fitch M. I., Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J. Clin. Oncol., 15: 110-115, 1997.[Abstract/Free Full Text]
  36. DeMario M. D., Ratain M. J. Oral chemotherapy: rationale and future directions. J. Clin. Oncol., 16: 2557-2567, 1998.[Abstract]
  37. Hoff P. M., Ansari R., Batist G., Cox J., Kocha W., Kuperminc M., Maroun J., Walde D., Weaver C., Harrison E., Burger H. U., Osterwalder B., Wong A. O., Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized Phase III study. J. Clin. Oncol., 19: 2282-2292, 2001.[Abstract/Free Full Text]
  38. Schoffski P., Chollet P., Ganser A., Wiese K. H., Rambusch E., de Vries M. J., Hanauske A. Complete response of a gastric primary after a short but toxic course of "S-1.". Ann. Oncol., 10: 1117-1120, 1999.[Abstract/Free Full Text]
  39. Schoffski P., Vermoken J., Schellens J., Aapro M., Bruntsh U., Wanders J., De Boer R., Hanauske A. R. Safety, toxiciy and antitumor efficacy of the modulated oral fluoro-pyrimidine derivative S-1 in patients with metastatic colorectal cancer: preliminary results of an early Phase II study. Clin. Cancer Res., 5 (Suppl.): 3772s 1999.



This article has been cited by other articles:


Home page
 The OncologistHome page
H.-C. Jeung, S. Y. Rha, H. K. Kim, H. Y. Lim, S. Kim, S. Y. Kim, S. J. Gong, C. H. Park, J. B. Ahn, S. H. Noh, et al.
Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations
Oncologist, May 1, 2007; 12(5): 543 - 554.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
A. Goto, Y. Yamada, H. Yasui, K. Kato, T. Hamaguchi, K. Muro, Y. Shimada, and K. Shirao
Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer
Ann. Onc., June 1, 2006; 17(6): 968 - 973.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. A. Ajani, J. Faust, K. Ikeda, J. C. Yao, H. Anbe, K. L. Carr, M. Houghton, and P. Urrea
Phase I Pharmacokinetic Study of S-1 Plus Cisplatin in Patients With Advanced Gastric Carcinoma
J. Clin. Oncol., October 1, 2005; 23(28): 6957 - 6965.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
T. A. Rich, R. C. Shepard, and S. T. Mosley
Four Decades of Continuing Innovation With Fluorouracil: Current and Future Approaches to Fluorouracil Chemoradiation Therapy
J. Clin. Oncol., June 1, 2004; 22(11): 2214 - 2232.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hoff, P. M.
Right arrow Articles by Pazdur, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hoff, P. M.
Right arrow Articles by Pazdur, R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online