The Oral Fluoropyrimidines in Cancer Chemotherapy

Vol. 5, 2289–2296, September 1999 Clinical Cancer Research 2289

Minireview The Oral Fluoropyrimidines in Cancer Chemotherapy

Elizabeth B. Lamont and Richard L. Schilsky1 i.v. because of problems with oral dosing. Orally-administered Division of Hematology and Oncology [E. B. L., R. L. S.], 5-FU is associated with erratic and unpredictable plasma levels Department of Medicine, the Robert Wood Johnson Clinical Scholars with extensive interpatient and intrapatient variability (3). The Program [E. B. L.], and the Cancer Research Center [R. L. S.], variability in plasma levels results primarily from extensive first University of Chicago, Chicago, Illinois 60637 pass metabolism of 5-FU in the gut wall and the liver coupled with variable and schedule-dependent clearance. The primary Abstract and rate-limiting enzyme involved in 5-FU metabolism is di- A classic example of a rationally developed class of hydropyrimidine dehydrogenase (DPD). The role of DPD in the anticancer drugs, the fluoropyrimidines are now the focus of catabolism of 5-FU is depicted in Fig. 1. Although present in further rational approaches to cancer chemotherapy as they tissues throughout the body, DPD has its highest concentration are transformed into oral formulations. Given alone, oral in the liver, and hepatic metabolism of the drug by DPD ac- 5-fluorouracil (5-FU) has erratic absorption and nonlinear counts for most of the clearance of 5-FU; only 5–10% of an pharmacokinetics. However, when oral 5-FU is given as a administered dose is eliminated unchanged in the urine (2). The prodrug and/or paired with a dihydropyrimidine dehydro- observed intrapatient variability in plasma levels of 5-FU may genase inhibitor, the resultant 5-FU has linear pharmacoki- be due in part to the observed circadian variation of DPD netics that may approximate the less myelosuppressive con- activity in humans that results in variable plasma concentrations tinuous i.v. infusion schedule of 5-FU administration of the drug throughout the day during prolonged i.v. infusion without the use of infusion catheters and pumps. We review (4). The interpatient variability in elimination may relate to the preclinical and clinical experience of several of the oral genetic polymorphism in DPD activity, with 2–4% of the pop- fluoropyrimidines. ulation estimated to be deficient in the enzyme (5, 6). Given the unpredictable pharmacokinetics of orally-admin- Introduction istered 5-FU, the drug has traditionally been administered al- A classic example of a rationally developed class of anti- most exclusively via the i.v. route, although hepatic arterial cancer drugs, the fluoropyrimidines are now the focus of further infusion and i.p. instillation have been used in special clinical rational approaches to cancer chemotherapy as they are trans- circumstances. 5-FU may be administered by bolus, rapid infu- formed into oral formulations. Modestly effective in the treat- sion over minutes to hours, or prolonged infusion over hours to ment of solid tumors, the fluoropyrimidines are now being weeks. Several studies have shown that the schedule of admin- refashioned into oral preparations in an attempt to both improve istration may result in different antitumor efficacy and different their anticancer activity and minimize their toxicity. This article toxicity profiles. A recent meta-analysis examined data from describes the efforts toward refashioning the most common 1219 patients with advanced colorectal cancer treated on one of fluoropyrimidine, 5-FU,2 into pharmacokinetically predictable seven Phase III randomized trials of bolus infusion versus oral forms and describes the preclinical and clinical outcomes of continuous infusion of 5-FU. A small survival advantage (ap- those efforts. proximately 24 days) and a large toxicity advantage were reported for continuous infusion over bolus infusion (7). Specif- ically, continuous infusion was associated with far less 5-FU Pharmacokinetics myelosuppression than bolus administration (4% compared to First synthesized by Heidelberger in the 1950s in an at- 31%), but continuous infusion was associated with more hand- tempt to exploit the increased avidity of tumor cells for uracil, foot syndrome than bolus administration (34% compared to the antimetabolite 5-FU exerts its antitumor effects through 13%). Because orally-administered agents have pharmacokinet- several mechanisms including inhibition of RNA synthesis and ics that approximate those of continuous infusion without the function, inhibition of thymidylate synthase activity, and incor- patient inconvenience and morbidity associated with indwelling poration into DNA, leading to DNA strand breaks (1, 2). Until catheters and infusion pumps, investigators have renewed inter- recently, the primary route of administration of 5-FU has been est in developing oral preparations of fluoropyrimidines that may result in equivalent or greater tumor response rates and less toxicity.

Received 3/19/99; revised 5/27/99; accepted 6/8/99. The costs of publication of this article were defrayed in part by the The Oral Fluoropyrimidines payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to The oral fluoropyrimidines may be divided into three indicate this fact. groups: (a) 5-FU prodrugs; (b) 5-FU combined with a DPD 1 To whom requests for reprints should be addressed, at University of inhibitor, and (c) 5-FU prodrugs combined with a DPD inhibi- Chicago, Biological Sciences Division, 5841 South Maryland Avenue, tor. We discuss the rationale for each type of agent, and then we MC 1000, Chicago, IL 60637. 2 The abbreviations used are: 5-FU, 5-fluorouracil; DPD, dihydropyri- discuss specific agents within each group, summarizing both the midine dehydrogenase; GI, gastrointestinal; UFT, uracil and ftorafur; preclinical and clinical experience. Oral coadministration of CDHP, chloro-2,4-dihydroxypyridine; CNS, central nervous system. leucovorin is being evaluated for possible synergy with each of Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 1999 American Association for Cancer Research. 2290 Oral 5-FU

Fig. 1 The role of DPD in the catabolism of 5-FU.

may manifest itself as change in mental status, cerebellar ataxia, and coma and is felt to result from the accumulation of a psychoactive 5-FU degradation product, ␥-hydroxybutryrate (2). Oral ftorafur has been used in the treatment of adenocarci- nomas and appears to have an efficacy similar to that of i.v. 5-FU, but its associated neurological toxicities have limited enthusiasm for the drug (13–17). Recently, however, a new formulation combining ftorafur with uracil (UFT) in a 1:4 molar ratio has been developed and evaluated extensively in Japan and the United States. UFT is discussed below in more detail.

Capecitabine Capecitabine (n4-pentyloxycarbonyl-5Ј-deoxy-5-fluorocy- tidine; Xeloda) is itself a prodrug of another 5-FU prodrug (doxifluridine) and was designed to minimize the substantial local GI toxicity of doxifluridine without compromising its antitumor efficacy (18). The pharmacologically inactive capecitabine is reliably absorbed unchanged from the GI tract and then converted through three enzymatic reactions to 5-FU. The metabolism of capecitabine is depicted in Fig. 3. It is first converted to 5Јdeoxyfluorocytidine in the liver by carboxyles- terase and then converted to doxifluridine by cytidine deami- Fig. 2 The activation steps of ftorafur. nase, a ubiquitous enzyme found in liver, plasma, and tumor tissue. The toxic intermediary doxifluridine is then converted to 5-FU by thymidine phosphorylase, an enzyme that may be more abundant in tumors than in normal tissue, thus potentially re- these agents, based on its well-documented ability to enhance sulting in tumor 5-FU concentrations that far exceed plasma tumor response to 5-FU (8, 9). levels and produce greater antineoplastic effects with lower toxicity (19, 20). Indeed, investigators have reported that cape- 5-FU Prodrugs citabine administration results in tumor concentrations of 5-FU Prodrugs of 5-FU have been developed that are not sub- more than 127 times those attained with i.v. dosing of 5-FU strates for DPD and are therefore absorbed intact through the GI (21). In preclinical studies, capecitabine showed activity against mucosa. These agents must then undergo enzymatic activation a number of human tumor xenografts (22, 23). Subsequent by one or more enzyme systems to liberate 5-FU intracellularly. clinical trials have revealed the drug to be well-tolerated (24– The extent to which these reactions occur in normal versus 27). From a recent Phase I clinical trial in advanced solid tumor tumor tissue has the potential to provide some tumor selectivity patients, investigators recommended 2510 mg/m2/day capecit- for these agents. abine in two divided doses for 2 weeks followed by a 1-week rest for Phase II testing (28). The dose-limiting toxicities were Ftorafur diarrhea, stomatitis, abdominal pain, and hand-foot syndrome. Ftorafur (Tegafur) is a prodrug [R,S-1–1(tetrahydrofuran- When paired with leucovorin (60 mg/day), the recommended 2-yl)-5-FU] that is slowly metabolized to 5-FU through two Phase II dose of capecitabine is substantially lower, 1650 mg/ separate pathways, hepatic cytochrome P-450 enzymes and sys- m2/day, although the toxicities are similar (29). temic soluble enzymes (10, 11). Fig. 2 depicts the activation Several Phase II studies have tested the efficacy of cape- steps of ftorafur. It is reliably absorbed and has a half-life of citabine against specific solid tumors. In a randomized Phase II 5–12 h in the circulation (12). This drug has been extensively study of previously untreated advanced breast cancer patients, evaluated in Japan and Russia during the past 20 years. The 2510 mg/m2/day capecitabine (given in two divided doses daily primary toxicities of the drug are neurological and GI (nausea, for 2 weeks followed by a 1-week rest) had an efficacy similar vomiting, diarrhea, and mucositis). The neurological toxicity to that of traditional cyclophosphamide, methotrexate, 5-flu-

Fig. 3 The metabolism of capecitabine.

orouracil (CMF) therapy (given every 21–28 days; Ref. 30). The gression-free survival (capecitabine, 5.3 months; 5-FU/leucov- same group of investigators also performed a randomized Phase orin, 4.8 months) were not significant. The grade 3/4 toxicities II study of capecitabine and paclitaxel in patients with anthra- produced by capecitabine were hand-foot syndrome (16.2%) cycline-resistant advanced breast cancer. Capecitabine (given on and diarrhea (10.8%), whereas the grade 3/4 toxicities related to the same schedule noted above) was similar to paclitaxel (175 5-FU/leucovorin were neutropenia (19.7%), stomatitis (13.4%), mg/m2 every 21 days) with respect to response rate and median and diarrhea (10%). In the second trial of 605 patients, the time to disease progression (31). Whereas the results of these response rate of patients treated with capecitabine (23.2%) was and other studies have led the Food and Drug Administration to again superior to that of patients treated with 5-FU/leucovorin grant accelerated approval to capecitabine for use in patients (15.5%; P ϭ 0.02; Ref. 34). The differences in duration of with advanced breast cancer, results will need to be replicated in response (capecitabine, 9.1 months; 5-FU/leucovorin, 9.7 an adequately powered randomized Phase III trial before defin- months) and duration of progression-free survival (capecitabine, itive conclusions about efficacy can be made. 4.4 months; 5-FU/leucovorin, 5.1 months) were also not signif- The drug has also been studied in patients with advanced icant in this study. The grade 3/4 toxicities produced by cape- colorectal cancer. Three doses and schedules that were deter- citabine were hand-foot syndrome (17.7%) and diarrhea mined in Phase I trials were tested in the Phase II setting as (15.1%), whereas the grade 3/4 toxicities resulting from 5-FU/ first-line therapy for patients with advanced colorectal cancer leucovorin were neutropenia (25.9%), stomatitis (16.3%), and 2 (32). The investigators reported that 2510 mg/m /day capecit- diarrhea (13.9%). Survival data have not yet been reported from abine given in two divided doses for 14 days followed by a these studies, although it is unlikely that significant differences 1-week rest was associated with the highest response rate (9 of will emerge. At this point, it seems reasonable to conclude that 36 patients, 25%) and the longest time to tumor progression (30 oral capecitabine is similar to monthly i.v. 5-FU/leucovorin in weeks) of the three schedules. This dose and schedule became tumor efficacy and produces a toxicity profile that may be the basis for two Phase III randomized trials of capecitabine preferred by some patients. However, patients unlikely to be 2 (2500 mg/m /day) versus the standard monthly bolus of 5-FU/ compliant with an oral regimen are probably best treated with 2 2 leucovorin (450 mg/m /day 5-FU and 20 mg/m /day leucovo- i.v. chemotherapy. rin) in the first-line treatment of advanced colorectal cancer. Preliminary results from both Phase III trials suggest that capecitabine is superior to the traditional bolus 5-FU/leucovorin DPD-targeted Therapies with respect to both response rates and the incidence of life- As noted previously, DPD is a ubiquitous enzyme that is threatening neutropenia. In a trial of 602 patients, the response the immediate rate-limiting step in the degradation of 5-FU. rate of patients treated with capecitabine was 26.6% compared Both preclinical and clinical studies have shown repeatedly that to 17.9% for those treated with 5-FU/leucovorin (P ϭ 0.013; inhibition of DPD is associated with a prolongation of the Ref. 33). The differences in duration of response (capecitabine, half-life of 5-FU in plasma (35–37). Patients genetically defi- 7.3 months; 5-FU/leucovorin, 9.6 months) and duration of pro- cient in DPD are natural examples of this phenomenon because

after receiving standard doses of 5-FU, they have prolonged circulation of the drug and may experience life-threatening toxicity (38, 39). Studies in head and neck and colorectal cancers suggest that patients whose tumors overexpress DPD maybe less likely to respond to standard 5-FU therapy (40, 41). Agents that inhibit DPD activity have been developed and are now increasingly studied in the treatment of cancer because they facilitate oral absorption of 5-FU and prolong its half-life in plasma and may circumvent 5-FU resistance due to tumor overexpression of DPD, which may translate into improved antitumor efficacy. There are two types of DPD-targeted therapies, those that Fig. 4 The molecular structure of S-1. irreversibly inactivate DPD and those that reversibly inhibit DPD. A uracil analogue, eniluracil (ethynyluracil, BW776, GW776, 776C85), has been shown to irreversibly inactivate DPD both in vitro (42) and in vivo (43). The preclinical and yielded promising results. Mani et al. (46) studied the effects of clinical studies showed that eniluracil inhibited Ͼ96% of DPD oral eniluracil (10 mg/m2) and 5-FU (1–1.15 mg/m2/day) given activity for up to 6 h after a single dose (35, 43). The reversible daily for 28 days as a first-line agent in the treatment of patients inhibitors of DPD that have been studied in clinical trials are with advanced colorectal cancer. They reported a response rate uracil, CDHP, and 3-cyano-2,6-dihydroxypyridine (CNDP). of 24% (11 of 45 patients) and rare grade 3 or 4 toxicities. This dose and schedule are the basis for a recently completed Phase Combination Therapies III trial comparing eniluracil/fluorouracil to a conventional i.v. Given the reliable inhibition of DPD produced by these 5-FU/leucovorin regimen in patients with metastatic colorectal agents, the next logical step was to pair the DPD-targeted cancer. therapies with fluoropyrimidines in an attempt to facilitate oral absorption and prolong the half-life of 5-FU. The other potential S-1 benefits of using DPD inhibitors are elimination of 5-FU me- S-1 is a combination of the 5-FU prodrug ftorafur and two tabolites, which may be responsible for some of the toxic effects 5-FU modulators, CDHP and oxonic acid, in a molar ratio of of the drug, and inhibition of intratumoral DPD that may in- 1:0.4:1 (see Fig. 4). As noted above, ftorafur is converted to crease sensitivity to 5-FU (44). 5-FU through hepatic cytochrome P-450s and through cytosolic enzymes, and CDHP is a competitive, reversible DPD inhibitor Eniluracil/5-FU that prolongs the half-life of 5-FU. Oxonic acid is a pyrimidine The combination of oral 5-FU with the oral DPD inhibitor phosphoribosyltransferase inhibitor that is intended to mitigate eniluracil holds great promise as a potent antineoplastic therapy. 5-FU-related GI toxicity by preventing the phosphorylation of In preclinical animal trials, pretreatment with eniluracil resulted 5-FU in the digestive tract. After preclinical studies revealed the in 100% oral bioavailability of 5-FU and extended its half-life drug to have antitumor effects in human tumor xenografts in from 9 min to 100 min (35). In humans, Baker et al. noted nude mice (47), early Phase I clinical testing determined that the complete and reliable oral bioavailability of 5-FU after exposure 5-FU generated from the ftorafur component had linear phar- to eniluracil and a prolongation of the half-life of 5-FU (36). macokinetics and a half-life of 2–7 h (48). The dose-limiting These investigators found that in the setting of complete DPD toxicity was myelosuppression (neutropenia), and the recom- inhibition with eniluracil, 5-FU had linear pharmacokinetics mended Phase II dose was 75 mg twice daily (49). Additional with clearance dependent primarily on creatinine clearance, toxicities were GI (anorexia, vomiting, diarrhea, and stomatitis) consistent with renal excretion of 5-FU rather than hepatic and dermatological (rash). Phase II studies in a variety of metabolism. Indeed, a subsequent Phase I trial found a Ͼ10-fold advanced solid tumors (gastric, colorectal, breast, and head and increase in renal 5-FU excretion after exposure to eniluracil neck tumors) report high response rates (35–50%) with few Ͻ (45). In a larger Phase I clinical trial, combinations of eniluracil patients ( 10%) experiencing major toxicities (grade 3), which and 5-FU with or without leucovorin were administered on a were primarily hematological (neutropenia, anemia, and throm- daily ϫ 5 schedule to 65 patients with advanced solid tumors bocytopenia; Refs. 50–53). (37). These investigators confirmed the pharmacokinetics de- scribed in the previous trials and reported that in the setting of BOF A-2 complete DPD inhibition by eniluracil, 5-FU had a maximally BOF A-2 (Emitefur) is a second example of a 5-FU pro- tolerated dose that was dramatically lower than that seen in drug combined with a DPD inhibitor. In this case, the 5-FU conventional 5-FU regimens. The dose-limiting toxicity on this prodrug is 1-ethoxymethyl 5-FU, and the DPD inhibitor is schedule was myelosuppression (neutropenia) without infec- 3-cyano-2,6-dihydroxypyridine (combined in a 1:1 molar ratio; tious complications, and the investigators recorded only infre- Ref. 54). Preclinical studies revealed that the compound resulted quent episodes of severe GI toxicity. in a prolonged 5-FU half-life and produced antitumor responses The combination of 5-FU and eniluracil has been evaluated in murine models (55–57). Subsequent Phase I clinical testing in the Phase II setting against specific solid tumors and has reported the maximally tolerated dose to be 400 mg/m2 daily for

Table 1 Advantages and toxicities of various drugs Drug 5-FU prodrug DPD inhibitor Potential advantages Toxicities Ftorafur Yes No Reliable absorption GI, neurological toxicity (CNS) Capecitabine Yes No Reliable absorption GI, hand-foot syndrome Tumor selective EU/5-FUa No Yes Reliable absorption Neutropenia (5-day schedule)

Prolonged 5-FU t1/2 Diarrhea (28-day schedule) Increased tumor sensitivity UFT Yes Yes Reliable absorption Diarrhea

Prolonged 5-FU t1/2 Increased tumor sensitivity S-1 Yes Yes Reliable absorption Neutropenia

Prolonged 5-FU t1/2 Increased tumor sensitivity Decreased GI toxicity BOF A-2 Yes Yes Reliable absorption GI, hematological toxicity

Prolonged 5-FU t1/2 Increased tumor sensitivity a EU/5-FU, eniluracil/5-FU.

4 weeks, and the dose-limiting toxicities were reported to be GI 400 mg/m2/day UFT, leading to a recommended Phase II dose (anorexia, diarrhea, and stomatitis) and hematological (leuko- of 300 mg/m2/day with 150 mg/day leucovorin. This dose was penia and thrombocytopenia; Ref. 58). Early Phase II studies then tested in a Phase II trial of patients with advanced colo- report antitumor effects in several solid tumors including breast, rectal cancer and was associated with a 42% tumor response rate colorectal, gastric, non-small cell lung, and pancreatic tumors and a 24% rate of grade 3 GI toxicities (diarrhea, vomiting, and (59, 60). abdominal cramping) and fatigue (68). Results of two randomized Phase III studies comparing traditional 5-day bolus 5-FU UFT (425 mg/m2/day) and leucovorin (20 mg/m2/day) given every 35 2 UFT is a 1:4 molar combination of the 5-FU prodrug days with oral UFT (300 mg/m /day) and oral leucovorin (75 or ftorafur and the DPD inhibitor uracil that was developed over 20 90 mg/day) for 28 days every 35 days in previously untreated years ago in Asia. Preclinical studies revealed that the combi- patients with metastatic colorectal cancer have recently been nation of ftorafur with uracil was associated with higher tumor: reported (69, 70). In both studies, the oral and i.v. regimens had blood levels of 5-FU than ftorafur alone, and the difference was similar response rates, times to disease progression, and sur- associated with greater antitumor activity (61, 62). Combining vival. However, in both studies, the oral regimen was associated uracil with ftorafur also appears to change the drug’s toxicity with far fewer episodes of severe neutropenia compared to the Ͻ profile, with a substantial reduction of the CNS toxicity and a i.v. regimen [3% compared with 31% (P 0.001) in one study Ͻ mitigation of the GI toxicity that results when ftorafur is given (69), and 1% compared with 56% (P 0.001) in the other study alone (63). The CNS toxicity of ftorafur is felt to be mediated by (70)]. UFT/leucovorin therefore appears to be an acceptable hepatic degradation of 5-FU to ␣-fluoro-␤-alanine by DPD, and alternative to i.v. 5-FU/leucovorin for treatment of metastatic uracil blocks this process. In Phase I trials in the United States, colorectal cancer. The National Surgical Adjuvant Breast and UFT has been studied in different schedules (5-day and 28-day Bowel Project is currently testing a similar dose and schedule of schedules) and with and without leucovorin. Pazdur et al. (64) UFT/leucovorin against a traditional i.v. 5-FU regimen in a found that the dose-limiting toxicity on the 5-day schedule was Phase III study (C-06) of adjuvant therapy for colon cancer granulocytopenia at 900 mg/m2/day, leading to a recommended patients. Phase II dose of 800 mg/m2/day. On the 28-day schedule, however, the dose-limiting toxicity was diarrhea at 450 mg/m2/ Clinical Application day, leading to a recommended Phase II dose of 360 mg/m2/day. The choice of which oral fluoropyrimidine to use must be In other early trials from the same group, the pharmacokinetics guided both by the patient’s physiological profile and by their of oral UFT at 375 mg/m2/day on the 28-day schedule were tumor’s biochemical profile. Whereas the use of DPD inhibitors compared with those of 5-FU at 250 mg/m2/day on a continuous requires a reduction in 5-FU dose to avoid severe toxicity, there infusion 5-day schedule (65). The results revealed similar 5-FU may be special clinical circumstances where the risks of therapy areas under the concentration curve but higher maximal 5-FU are further increased by DPD inhibition. For example, patients concentrations with UFT. with renal insufficiency should not be treated with 5-FU and Given the enhanced antitumor effect conferred by the ad- DPD inhibitors because in the face of DPD inhibition, 5-FU dition of leucovorin to 5-FU therapy (66), Pazdur et al. (67) then clearance is almost entirely renal. Such patients could experi- tested the combination of UFT with oral leucovorin in the Phase ence life-threatening 5-FU toxicity due to inability to eliminate I setting. They reported a dose-limiting toxicity of diarrhea at the drug by either metabolic or renal clearance. It is also

theoretically possible that DPD inhibitors could reduce the 3. Fraile, R. J., Baker, L. H., Buroker, T. R., Horwitz, J., and Vaitkevi- frequency of certain unusual toxicities of 5-FU. As mentioned cius, V. K. Pharmacokinetics of 5-fluorouracil administered orally, by previously, UFT is associated with less neurological toxicity rapid intravenous and by slow infusion. Cancer Res., 40: 2223–2228, 1980. than ftorafur, perhaps due to the inhibition of formation of toxic 4. Daher, G. C., Harris, B. E., Willard, E. M., and Diasio, R. B. 5-FU metabolites. Similarly, it is of interest that hand-foot Biochemical basis for circadian-dependent metabolism of fluoropyrimi- syndrome appears to be rare with those oral fluoropyrimidines dines. Ann. N. Y. Acad. Sci., 618: 350–361, 1991. that include a DPD inhibitor, whereas it occurs commonly after 5. McMurrough, J., and McLeod, H. L. 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Elizabeth B. Lamont and Richard L. Schilsky

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