Other Fluorinated Pyrimidines in the Treatment of Solid Tumors
Researchers, primarily in Japan, Europe, and the United States, have evaluated several new fluorinated pyrimidines in recent years. Most of these drugs are orally active prodrugs of fluorouracil (5-FU), and some also
ABSTRACT: Researchers, primarily in Japan, Europe, and the United States,have evaluated several new fluorinated pyrimidines in recent years. Most ofthese drugs are orally active prodrugs of fluorouracil (5-FU), and some alsocontain modulators of its pharmacological properties. S-1 is a rationallydeveloped combination of tegafur, a prodrug of 5-FU; CDHP, an inhibitor of 5-FUcatabolism; and potassium oxonate, an inhibitor of 5-FU-induced diarrhea. S-1underwent phase I and II trials in Japan, where it is now approved for use inthe treatment of advanced gastric cancer. Two phase I studies conducted recentlyin Europe and the United States identified diarrhea as the dose-limitingtoxicity of S-1. BOF-A2, which contains a 5-FU prodrug and CNDP, an inhibitor of5-FU catabolism, demonstrated clinical activity in preliminary studies in Japan.This article summarizes the preclinical and clinical development of S-1 andBOF-A2. [ONCOLOGY 15(Suppl 2):65-68, 2001]
Introduction
Since its introduction in 1957,fluorouracil (5-FU) has been usedin the treatment of breast, head and neck, and gastrointestinal malignancies.[1]The prototype fluorinated pyrimidine, 5-FU works as an antimetabolite to disruptnucleic acid synthesis and thus kill cells.[2] Over the past few years,researchers have developed and tested several new oral fluorinated pyrimidines,which are starting to gain wider application. Most of these agents are oralprodrugs of 5-FU, and some also contain biochemical modulators of 5-FU. Two ofthese prodrugs, S-1 and BOF-A2, have shown promising preliminary results. Thisarticle summarizes the preclinical and clinical development of S-1 and BOF-A2.
S-1
Pharmacology and Preclinical Evaluation of S-1
S-1 is a combination of tegafur, 5-chloro-2,4-dihydroxypyridine(CDHP) and potassium oxonate (potassium1,3,5-triazine-2,4(1H,3H)-dione-6-carboxylate) at a fixed molar ratio of1:0.4:1. Tegafur(5-fluoro-1-(tetrahydro-2-furanyl)-2,4-(1H,3H)-pyrimidinedione), a prodrug of5-FU, was developed in the former Soviet Union and introduced in 1967.[3]Evaluation of tegafur in the 1970s by the United States National CancerInstitute revealed that, when administered by short intravenous infusion, thedrug caused significant gastrointestinal and neurologic toxicity despitedemonstrated activity in a variety of solid tumors.[4,5] Because tegafur is wellabsorbed via the oral route, Japanese investigators pursued an alternativestrategy of prolonged oral administration. Further development of tegafur tookplace mainly in Japan, although researchers in the United States conductedadditional phase I and II studies of oral tegafur.[6,7]
The development of S-1 represents a rational approach to thepharmacologic modulation of fluoropyrimidines.[8] After being absorbed by thegastrointestinal tract, tegafur is converted to 5-FU by the hepatic microsomalenzyme system.[9] CDHP reversibly inhibits dihydropyrimidine dehydrogenase(DPD), the chief enzyme regulating 5-FU degradation. In vitro, CDHP is almost200 times more potent than uracil, another reversible inhibitor of DPD.[10] WhenCDHP is combined with tegafur, the resulting 5-FU levels are maintained both inplasma and in tumor tissue.[8]
Gastrointestinal Toxicity
Early research attributed the gastrointestinal toxicity of 5-FUto its phosphorylation.[11] In animal models, potassium oxonate inhibits theactivity of orotate phosphoribosyltransferase, the enzyme that catalyzes 5-FUphosphorylation in the gastrointestinal tract, thus leading to decreasedgastrointestinal toxicity without loss of antitumor activity.[12]
Researchers in Japan conducted preclinical evaluation of S-1 anddemonstrated its antitumor activity in experimental models of rodent tumors andhuman xenografts. S-1 significantly inhibited tumor growth in rats withsubcutaneous Yoshida sarcoma[13], and in rats and nude mice orthotopicallyimplanted with human colon cancer cell lines.[14,15] The animal studies alsoconfirmed that the gastrointestinal toxicity of S-1 is low, most likely becauseof the protection afforded by potassium oxonate.[13]
Pharmacological data derived from these studies indicated highconcentrations of 5-FU in the plasma and tumor tissue of animals treated withoral S-1. In addition, S-1 compared favorably with intravenous 5-FU, showingsimilar levels of tumor inhibitory activity and gastrointestinal toxicity.[16]
Phase I Studies of S-1
Phase I trials of S-1 have been conducted in Japan, Europe, andthe United States. Japanese investigators administered S-1 for 28 consecutivedays, followed by a 14-day rest period. In a phase I study using two dosingschedules of S-1, Taguchi et al identified the maximum tolerated doses as 75 to100 mg twice daily or 150 to 200 mg once daily.[17] Toxicity was mainlyhematologic, and gastrointestinal side effects were generally mild.
In another phase I study, Hirata et al treated 12 patients withfixed doses prespecified according to body surface area.[18] Patients with abody surface area < 1.25 m2 received 40 mg twice daily; those with a bodysurface area of 1.25 to 1.5 m2 received 50 mg twice daily; and those with a bodysurface area > 1.5 m2 received 60 mg twice daily. Dose escalation was notincluded in the protocol of this study; rather the primary objective was toinvestigate the pharmacokinetics of S-1. The only grade 3 or 4 toxicity washematologic and occurred in three patients.
Dosing Based on Actual Measurement vs Body Surface Area
Phase I studies of S-1 conducted in Europe and the United Statesemployed a dosing schedule based on actual body surface areas. The EuropeanOrganization for the Research and Treatment of Cancer (EORTC) reported thepreliminary findings of a phase I study of S-1. Fifteen patients received thedrug for 28 days, followed by a 7-day rest period. The starting dose was 25 mg/m2 twice daily, and dose-limiting toxicity was reached, at 45mg/m2 twicedaily. Although the Japanese study reported only mild gastrointestinal sideeffects, the EORTC data identified grade 3 or 4 diarrhea as the primarydose-limiting toxicity.[19] An analysis of 13 of 28 patients receiving 25, 35,40, or 45 mg/m2 once daily showed linear pharmacokinetics for S-1 components,such as 5-FU and CDHP, and for endogenous uracil.[20]
We, at The University of Texas M. D. Anderson Cancer Center,conducted a phase I study of S-1 administered for 28 days, followed by a 7-dayrest period.[21] Consecutive cohorts of patients received escalating doses ofS-1. The starting dose of 30 mg/m2 twice daily was found to be the maximumtolerated dose, and, as in the EORTC study, diarrhea was the dose-limitingtoxicity. In contrast to the findings of the Japanese study, our studydocumented infrequent hematologic toxicity. The pharmacokinetic profiles of S-1constituents suggested linear kinetics, and measurement of endogenous uracilconfirmed the transient nature of DPD inhibition.
Phase II Studies of S-1
Phase II studies of S-1 conducted in Japan used a fixed-doseschedule adjusted to the ranges of body surface areas. Three trials amongpatients with advanced gastric cancer were reported. In a study of 51 patientswith no history of previous chemotherapy, Sakata et al documented an objectiveresponse rate of 49%.[22] In a second study, reported in abstract form, 50patients evaluable for efficacy demonstrated an overall response rate of 40%,confirming the activity of S-1 in advanced gastric cancer.[23]
Sugimachi et al treated 28 patients, of whom 9 had receivedprevious chemotherapy. Objective responses, documented in 12 of 23 patients(52%) with measurable disease, did not differ, irregardless of whether patientshad or had not received prior chemotherapy.[24] Based on the good resultsobserved in patients with advanced gastric cancer treated with S-1, the drugreceived approval for this indication in Japan.
The EORTC Early Clinical Studies Group has launched an earlyphase II study of S-1 in patients with advanced/metastatic gastric andcolorectal cancer. It recently reported that a patient with gastric cancer whocould only tolerate only one cycle of S-1 therapy experienced a durable completepathologic response in the primary tumor, with stable metastatic disease.[25]Although anecdotal, the experience with this patient clearly illustrates theactivity of the drug and suggests that it should be evaluated further indisease-specific settings.
Phase II studies of S-1 in patients with other types of solidtumors have yielded promising results. S-1 produced an overall response rate of36% in 62 patients with previously untreated, advanced colorectal cancer.[26] Inanother trial of S-1 in 29 patients with measurable advanced colorectal cancer,only 4 (14%) responded. However, in the latter study, 25% of patients (4 of 16),who had not received prior chemotherapy, achieved a partial response.[24] S-1produced objective responses in 41% of 27 evaluable patients with advancedbreast cancer,[27] and in 46% of 26 evaluable patients with advanced head andneck tumors.[28]
Predominant Toxicities
In all the phase II studies summarized above, the predominanttoxicities were hematologic and included anemia and neutropenia. These studiesreport only a few cases of grade 3 or 4 diarrhea or stomatitis, and infrequentincidences of other gastrointestinal toxicities. However, diarrhea of any gradewas documented in 24.1% of the 144 patients participating in the studies.[24] Inanother study, grade 1 or 2 stomatitis was seen in 23.5% of patients, and grade1 nausea/vomiting occurred in 11.7%.[22]
The differences between the toxicity profiles observed in theJapanese studies (in which toxicity was chiefly hematologic) and the EORTC andthe M. D. Anderson Cancer Center studies (in which diarrhea was thedose-limiting toxicity and hematologic toxicity was mild) remain unexplained.Evidence suggests that the conversion of tegafur to 5-FU occurs more slowly inAsians than in other ethnic groups, a finding that seems to be confirmed by acomparison of our pharmacokinetic data with the data obtained from the Japanesetrials.[18,21]
BOF-A2
In the search for biochemical modulators of the activity of5-FU, Japanese investigators have described the activity of1-ethoxymethyl-5-fluorouracil (EM-FU), another prodrug of 5-FU, and3-cyano-2,6-dihydroxypyridine (CNDP), a potent inhibitor of DPD.[29] Liketegafur, EM-FU is converted to 5-FU by the hepatic microsomal enzyme system.[30]In vitro, CNDP is approximately 300 times more potent than uracil in inhibitingDPD.[10] BOF-A2, a molecule that combines EM-FU and CNDP in equimolar ratios,spontaneously degrades to the parent compounds in vivo.
Early preclinical data suggested the presence of long-lastingserum levels of 5-FU after oral administration of BOF-A2 to rats. In addition,these animals had high concentrations of 5-FU in tumor tissue.[30] The antitumoractivity of oral BOF-A2 was demonstrated in rodent sarcoma models[30] and inseveral human cancer xenografts.[31-33]
In a phase II study of BOF-A2 conducted in Japan, the drug wasadministered orally at a dose of 200 mg twice a day for 2 weeks, followed by a2-week rest period.[34] Sixty-five patients with non-small-cell lung cancerwere treated and evaluated for toxicity, and more than 90% of the planned doseswere delivered. Reported rates of side effects with this regimen were modest,with grade 3 or higher complications seen in less than 7% of patients.
The incidence of grade 2 or higher diarrhea was 9%; stomatitis,11%; anemia, 6%; leukopenia, 8%; and thrombocytopenia, 8%. Two additionalpatients discontinued therapy during the first cycle due to grade 1 or 2gastrointestinal symptoms. Among the 62 patients evaluable for efficacy, 11patients (18%) demonstrated partial responses, and 34 patients (55%) achievedstable disease.
Conclusions
Oral fluorinated pyrimidines are an attractive alternative tointravenous 5-FU. Pharmacologic modulation offers not only patient convenience,but also the potential for enhanced efficacy of the parent compound. S-1 andBOF-A2 are two active agents with demonstrated activities under evaluation inpreclinical solid tumor models and in early clinical studies.
Questions and Answers
Peter O’Dwyer, MD: For the S1, that ethnic difference intoxicity is pretty interesting. Is there any evidence that oxonic acid is lesseffective in European populations than in the Japanese population?
Paulo Hoff, MD: This is obviously a subject of great debate.Comparing the data that we have from Japan and our own pharmacogenetics, oxonicacid absorption, at least, does not seem to be significantly different. Dr.Tagouchi has been very interested in this, and he believes that the differenceis in the hepatic microsomal system, that the Japanese will have a differentrate of conversion from tegafur to the 5-FU and this will allow them to get ahigher dose and less toxicity.
Peter Danenberg: Bob Diasio found that there are a certainnumber of patients with very low DPD to whom 5-FU is very toxic, and when theyadd these DPD inhibitors, they’re just thrown in indiscriminately withoutknowing the DPD levels in the patient. So with somebody who was low to beginwith, do you ever see an occurrence of [AU: UNCLEAR, BUT SOUNDS LIKE "DPDINHIBITION IN REVERSE."].
Dr. Hoff: No. We don’t.
Robert Diasio, MD: There’s a theory that basically you couldlevel the playing field by making everybody essentially DPD deficient byadministering a small dose of 5-FU.
Leonard Saltz, MD: It’s somewhat equivalent to the concept ofthe higher dose of leucovorin. It’s leveled the playing field by gettingeverybody up to a certain higher saturated level of these folates. [AU:"FOLATES" CORRECT?] Effectively, what we’re doing is makingeverybody into a DPD deficient patient; that’s okay, as long as you know thatin advance and dose accordingly.
Dr. Hoff: It’s interesting to note that with these largetrials, we haven’t had anybody die from DPD deficiency. So the theoreticalconcern is there, but the practical point is if you have a 3% incidence of DPDdeficiency, you would have probably seen a problem in the large trials.
Dr. Saltz: It’s a little hard to know.
Dr. Diasio: The issue of oral drugs in upper GI malignanciesseems like a confounding problem in terms of people taking things orally. Thisconcept of oral drugs and the lack of knowledge of their absorption isespecially true with pancreatic cancer, for example, where you have a hard timegetting patients to eat.
Dr. Hoff: We know that the drugs are absorbed in the duodenumand proximal jejunum. So, I guess as long as you have small bowel intact, youcan use them, and they get through. Obviously, the issue of the pancreaticcancer is an interesting one.
Dr. Saltz: In the Japanese gastric studies, what were thecriteria for response?
Dr. Hoff: They used the standard Japanese criteria, which arevery different than oursusing a combination of endoscopies and scans. The 53%response rate they had was using the Japanese definition of response, not theconventional Western definition, and that’s why it’s so hard to understandand apply their data here.
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