UFT and leucovorin (Orzel) is a combination of tegafur and uracil in a molar ratio of 1:4. Tegafur, a prodrug of 5-fluorouracil (5-FU), is converted to 5-FU by the hepatic cytochrome P450 pathway, whereas uracil enhances the
ABSTRACT: UFT and leucovorin (Orzel) is a combination of tegafur anduracil in a molar ratio of 1:4. Tegafur, a prodrug of 5-fluorouracil (5-FU), isconverted to 5-FU by the hepatic cytochrome P450 pathway, whereas uracilenhances the half-life of converted 5-FU leading to prolonged exposure andhigher intracellular concentration of 5-FU by inhibiting dihydropyrimidinedehydrogenase (DPD), a rate-limiting enzyme in 5-fluorouracil catabolism. UFThas broad antitumor activity against colorectal and breast cancer, and has beenstudied extensively worldwide. Trials conducted in the United States have mainlyfocused on the combination of UFT and leucovorin (Orzel). Compared with anintravenous 5-fluorouracil plus leucovorin regimen in advanced colorectal cancertreatment, UFT plus leucovorin appears to have equivalent antitumor efficacywith less toxicity. UFT may also provide a more convenient protracted treatmentmethod with fewer complications, compared to intravenous programs. Theapplication for FDA approval of UFT with leucovorin as a first-line treatmentregimen for advanced colorectal cancer is pending. Administered as a singleagent or in combination with other chemotherapy agents and hormones, UFT mayalso be effective in treating breast cancer, either as a primary adjuvanttreatment or as palliative treatment for metastatic disease. [ONCOLOGY 15(Suppl2):49-56, 2001]
Breast cancer is the most common malignancy in women inthe United States and second only to lung cancer as a cause of cancer death.Based on American Cancer Society estimates, there were 180,300 new cases ofbreast cancer and 43,900 deaths from breast cancer in 1998 in the United Statesalone. Colorectal cancer is the third leading cause of cancer mortality both inmale and females in the United States, with an estimated 131,600 new cases and55,500 deaths in 1998.
The pyrimidine analogue 5-fluorouracil (5-FU) has been amainstay of chemotherapy for breast cancer, colorectal cancer, and othermalignancies for more than 30 years since its initial synthesis by Heidelberger.Combination regimens such as CAF (cyclophosphamide, doxorubicin [adriamycin],and 5-FU) and CMF (cyclophosphamide, methotrexate and 5-FU) are among thestandard therapies for breast cancer. 5-FU is the most widely prescribed therapyfor the treatment of advanced colorectal cancer and, combined with leucovorin,is the only currently recommended regimen for use as adjuvant therapy.
An understanding of the mechanism of action of 5-FU has resultedin significant therapeutic advances in the past 10 years, including synergy withleucovorin and low-dose continuous infusion for improving both the antitumoractivity and the toxicity profile.
The cytotoxic effects of 5-FU are a result of interference withboth RNA and DNA structure and function. 5-FU is converted intracellularly toFdUMP (5-fluoro-2’-deoxyuridine monophosphate) and FUTP (5-fluorouridinetriphosphate). FUTP is incorporated into RNA as a fraudulent base causing errorsduring RNA processing. FdUMP binds to thymidylate synthetase (TS) withgreater affinity than the natural substrate and inhibits production of thymidinemonophosphate (dTMP), and thus DNA synthesis. 5-FU is catabolized rapidly inthe liver by dihydropyrimidine dehydrogenase (DPD) and subsequently excreted inthe urine as a-fluoro--alanine (FBAL). Dihydro- pyrimidine dehydrogenaseis the initial rate-limiting enzymatic step in the catabolism ofpyrimidines,[5,6] and is widely distributed in many tissues, including theliver, lung, gastrointestinal tract, kidney, and many tumors. DPD occupies animportant position in the overall metabolism of 5-FU, converting over 85% ofclinically administered 5-FU to 5-FUH2, then FBAL. There is a broad variation inDPD activity from person to person, which is partly responsible for greatvariation in the t1/2 and bioavailability of 5-FU. DPD activity in theintestinal mucosa and liver also contributes to the limited and erraticbioavailability of orally administered 5-FU, and clearance of the drug. Thevariable DPD activity level of different tumors may contribute to the variabletumor response to 5-FU. In addition, elevated levels of DPD in many tumors after5-FU treatment may contribute to the development of drug resistance.
When the value of low-dose continuous infusion of 5-FU wasconfirmed, it was recognized that the requirement for surgically-implantedvenous access and need for a constant-infusion pump may impose serious financialand quality of life constraints. Accordingly, the potential for oraladministration as a substitute for continuous exposure of fluoropyrimidines hasbeen re-examined.
The oral chemotherapy agent UFT is a combination of uracil andtegafur in 4:1 molar ratio. Tegafur (1-[2-tetra hydrofuranyl]-5-FU, ftorafur,BMS-200604) acts as a prodrug of 5-FU, being rapidly and completely absorbedafter oral administration, and slowly metabolized by cytochrome P450.[11-13]Uracil is a normal substrate for DPD, which competitively inhibits themetabolism of 5-FU, thereby reducing 5-FU clearance and increasing plasma andintratumor 5-FU concentration. In preclinical studies, the antitumoractivity of tegafur is enhanced by co-administration of uracil and this effectis maximized at a uracil:tegafur molar ratio of 4:1. The ratio of 5-FU in tumortissue compared with plasma or normal tissue is enhanced.[15,16]
In a further effect to maximize the therapeutic efficacy oftegafur, UFT in the United States has been developed in combination with oralleucovorin (calcium folinate), a derivative of tetrahydrofolic acid. Leucovorinincreases the reduced folate concentration, stabilizing the FdUMP-TS complex andtherefore further enhancing 5-FU effects to mimic the biochemical modulation of5-FU with leucovorin.
Phase I studies of UFT in the United States have examined twoschedules: 5 days of drug administration repeated every 21 days, and 28 daysrepeated every 35 days. The daily dose of UFT is given in 3 daily doses, every 8hours.[18,19] Granulocytopenia is dose-limiting with the 5-day schedule, whilediarrhea is the principal toxicity seen with 28-day dosing. The dose of 350-400mg/m2/day in a 28-day schedule has been recommended for phase II trials as asingle agent. Further phase I studies have concentrated on UFT plus leucovorin(Orzel). Four large institutions in the United States conducted similar phase Itrials of UFT plus leucovorin on 14-day and 28-day schedules, at 8 hourintervals (Table 1).[18-22] Diarrhea, nausea, and vomiting are dose-limiting.These investigators have recommended a UFT dose of 350 mg/m2/day with variousdoses of leucovorin (15-150 mg/day) for further combination studies.
Phase II Studies of UFT in Colorectal Cancer
Starting in 1993, several phase II trials of UFT(tegafur/uracil) and leucovorin have been conducted in the United States. Allpatients enrolled in these trials had measurable diseases and no priorchemotherapy for metastatic colorectal cancer.
With the initial regimen of UFT 350 mg/m2/d and leucovorin 150mg/d, five of the first seven patients at the M. D. Anderson Cancer Centerdeveloped grade 3 diarrhea. Subsequently, 39 patients were treated with UFT at300 mg/m2/d and leucovorin at 150 mg/d. The lower dose was associated withless grade 3 diarrhea. No significant neutropenia, thrombocytopenia, hand-footsyndrome, mucositis, or alopecia was seen. Another phase II trial at theUniversity of Southern California and Memorial Sloan-Kettering Cancer Centertreated 21 patients with advanced colorectal cancer with UFT 350 mg/m2/d plus 15mg/d of leucovorin. The toxic effects of these two doses of UFT arepresented in Table 2.
One complete response (CR) and 15 partial responses (PR) wereachieved in the 39 patients treated with the 300 mg/m2/d regimen; the mediansurvival was 16 months. The overall response rates of these phase II trialsranged from 26% to 44% (Table 3).
Subsequent trials of UFT and leucovorin have used a leucovorindose of 75 or 90 mg/d (25 mg or 30 mg every 8 hours), because of the saturableoral absorption of leucovorin when the dose exceeds 25 mg.
A phase II trial of UFT and leucovorin was conducted in Europewith UFT at 390 mg/m2/d and leucovorin (either 30 mg/day oral for 14 days or 500mg/m2 IV on day 1) in 75 advanced colorectal cancer patients. This regimenresulted in an overall response rate of 39%. The patients in the phase IIstudies from Europe and the United States are compared in Table4.
In Spain, the Oncopaz clinical trial evaluated UFT plusleucovorin in elderly patients with advanced colorectal cancer (median age 74years). They observed an overall response rate of 29%, with diarrhea as themajor toxicity. UFT plus leucovorin was felt to be both well-tolerated andfeasible as outpatient treatment for elderly patients.
The efficacy of UFT with leucovorin was demonstrated in aseparate phase II study in patients with metastatic rectal carcinoma.Patients were treated with UFT at 600 mg/m2/d and leucovorin at 90 mg/d for 14days in a 28-day schedule. Of the 52 evaluable patients, 50% had livermetastases, and 62% had received treatment for advanced disease prior to thetrial. Overall response was 70% in patients without previous chemotherapy, and22% in patients who had had previous treatment. The median time to progressionfor all patients was 8.2 months, but was 19.6 months in patients without priorchemotherapy.
Phase III Trials inColorectal Cancer
Based on the results from phase II trials, two large phase IIItrials were conducted of UFT/leucovorin (Orzel) as first-line treatment formetastatic colorectal cancerStudy 011 in the United States, Canada, andEurope, and Study 012 in Europe.[28,29] These trials compared oral UFT plusleucovorin vs a 5-day intravenous bolus regimen of 5-FU (Mayo Regimen)at 425mg/m2/d and leucovorin at 20 mg/m2/d every 4 or 5 weeksevery 4 weeks fortrial 011 and every 5 weeks for trial 012. The trials used UFT at 300 mg/m2/dwith leucovorin at 75 to 90 mg/d (in Canada and Europe, the leucovorin dose was90 mg/d), with both drugs given in three daily doses at 8-hour intervals for 28days in a 35-day schedule. The trials were stratified for performance status,measurability, prior adjuvant therapy, and institution. The primary end point ofeach trial was survival, and the secondary end point was time to progression(TTP).
Trial 011: The results of 011 trial were first presented atthe 1999 annual meeting of the American Society of Clinical Oncology (ASCO). Of816 patients accrued, 409 were randomized to the UFT/leucovorin arm, and 407 tothe 5-FU/leucovorin arm. The pretreatment characteristics were equivalent (Table5). Treatment with UFT/leucovorin produced comparable efficacy to the IV5-FU/leucovorin (Mayo) regimen. The median survival was 12.4 months (95% CI,11.2-13.6 months) in the UFT/leucovorin arm and 13.4 (95% CI, 11.6-15.4months) in the 5-FU/leucovorin arm (P = 0.65). The overall response rate was 12%(48/409) in the UFT/leucovorin arm and 15% (59/407) in the 5-FU/leucovorin arm (P = 0.232).
UFT/leucovorin was associated with significant improvements insafety compared with the 5-FU/leucovorin regimen. UFT treatment resulted infewer and less severe toxicities, both hematologic and nonhematologic, includinggastrointestinal and hand-foot syndrome (Table 6 andTable 7). The study also showedfewer concomitant medications were needed for side effects in the UFT/leucovorinarm (Table 8). Dose reduction and dose delays were necessary less often in theUFT/leucovorin arm than in the IV 5-FU/leucovorin arm (Table9).
Since UFT was administered orally, compliance was evaluated inthe study. More than 89% of patients were compliant at a level of 90% or higher,and more than 99% of patients complied at a level greater than 80%.
Trial 012: In the 012 study, 380 patients were accrued with190 patients in each arm. The median survival was 12.3 months (95% CI, 10.4-13.8months) in the oral UFT/leucovorin arm and 10.3 months (8.2-13.0 months) inthe IV 5-FU/leucovorin arm. The overall response rate was 11% (20/190) in theUFT/LV arm and 9% (17/190) in the 5-FU/leucovorin arm (P = 0.593). The toxicityprofile was similar to that of the 011 study.
Both large phase III trials demonstrated that oralUFT/leucovorin as initial treatment for metastatic colorectal cancer producesequivalent survival to intravenous 5-FU and leucovorin (Mayo regimen).Clinically, oral UFT and leucovorin appears to have significant safetyadvantages including less severe myelosuppression, febrile neutropenia,infection, severe stomatitis/mucositis, diarrhea and nausea/vomiting, hand-footsyndrome, and concomitant medication use.
Adjuvant Treatmentin Colorectal Cancer
Efficacy of UFT as adjuvant chemotherapy has been studied inJapan for patients with curatively resected colorectal cancer. In one study,476 patients were randomized to receive mitomycin C (6 mg/m2) 1 day prior to and1 day following surgery with or without oral UFT (400 mg/day) for 1 year. Aftera median 3-year follow-up period, the disease-free survival rate increasedsignificantly in the UFT treatment arm compared with the mitomycin alone arm (P= 0.026). These preliminary results suggest that UFT may be valuable as anadjuvant chemotherapy agent in prolonging disease-free survival in resectablecolorectal cancer patients.
In the United States, the National Surgical Adjuvant Breast andBowel Project (NSABP) has completed protocol C-06, which examined a 28-dayschedule of UFT/leucovorin vs a weekly regimen of intravenous 5FU/leucovorin asadjuvant therapy in stage II/III colon carcinoma. UFT was given at 300 mg/m2/dwith oral leucovorin at 90 mg/d for 5 cycles. The intravenous regimenadministered was as follows: 5-FU at 500 mg/m2 IV bolus and leucovorin at 500mg/m2 IV over 2 hours weekly for 6 weeks out of 8, for 3 cycles. Accrual wascompleted by December of 1999, and results are pending.
UFT Approval as a First-line Treatment for AdvancedColorectal Cancer
UFT/leucovorin (Orzel) has been submitted to the United StatesFood and Drug Administration (FDA) for approval as a first-line treatment ofadvanced colorectal cancer. On September 16, 1999, the FDA’s Oncologic DrugAdvisory Committee unanimously agreed that the oral therapy with UFT capsulesplus leucovorin calcium tablets was equivalent to the Mayo Clinic regimen of5-FU/LV in terms of survival in the treatment of metastatic colorectal cancer,as documented in the two clinical trials presented.
As of this writing, approval by the FDA is still pending, withtwo issues needing resolution. First, there is concern at the FDA that the drugwas not truly equivalent to the Mayo Clinic regimen of 5-FU/LV. Although boththe 011 and 012 trials are comparable, the schedule of the 012 trial was every 5weeks instead of the standard Mayo regimen of every 4 weeks initially for 2cycles, followed by 5-week cycles. Second, there is also a question about thecontribution of uracil to the fixed combination of uracil and tegafur, whichcomprises Orzel.
From the perspective of a medical oncologist, neither issueseems pivotal. Equivalency cannot always be generalized, and may depend on thetype and stage of disease, goal(s) of treatment, and type of treatment.Oncologists and patients may need alternative treatments, especially oral and/orless toxic regimens for many reasons (eg, economic issues, patient selection,and patient’s preference).
Uracil is a natural occurring, nontoxic substance in UFT thatinhibits DPD and prolongs the concentration of 5-FU in plasma and tumor cells.The mechanism, toxicity, and molar ratio of uracil combined with tegafur hasbeen well studied [15,16], and there seems to be little reason to go back torepeat these studies.
A more global and relevant issue is that, since the first-linetherapy of advanced colorectal cancer is changing to the combination of5-FU/leucovorin and CPT-11(Camptosar), the overall role of UFT and leucovorinalone remains to be established in standard practice. Phase I/II trials arebeing conducted in which UFT/leucovorin is being combined with CPT-11 oroxaliplatin and other agents to find more effective regimens foradvanced/metastatic colorectal cancer that incorporate both intravenous and oraldrugs.
UFT also has been studied extensively for breast cancer as anadjuvant for primary cancer and as palliative treatment for metastatic disease.These trials were based on the antitumor efficacy of 5-FU in breast cancertreatment.
UFT/Leucovorin in theTreatment of Advanced/Metastatic Breast Cancer
The prognosis for patients with advanced breast cancer who faila first-line chemotherapy regimen remains poor. Currently, second-linemanagement with various combination regimens seems to be primarily palliative,with response rates of 20% to 40%. These regimens are not curative and may beassociated with considerable toxicity.
Pooled data from a Japanese phase II study showed the responserate of UFT in a subset of patients with advanced breast cancer was 32%. Theefficacy of UFT as a single agent has also been demonstrated in several otherphase II studies in patients with advanced metastatic breast cancer. OneJapanese study compared the efficacy of UFT vs tegafur in 56 patients (UFT 400mg/day vs tegafur 800mg/day, 28 patients in each arm). The overall responserate in the UFT arm was 40% (CR 11%, PR 29%) and 21% (CR 7%, PR 14%) in thetegafur arm.
In a study conducted by Daniels et al, 70 heavily pretreatedpatients were given UFT 10 mg/kg/d. Overall response rate was 24% (2% of CR and22% of PR). Another study evaluated UFT plus leucovorin in 29 heavilypretreated (including anthracycline, paclitaxel, and vinorelbine) advancedbreast cancer patients. Doses of 300 mg/m2/d of UFT and 45 mg/d of leucovorinwere given every 12 hours. This combination achieved a 25% response rate (8% CR,and 17% PR).
A randomized trial compared the efficacy of UFT vs intravenous5-FU, given in combination with AC (Adriamycin and cyclophosphamide) at thePhilippines General Hospital. In this study, patients received either oralUFT (350 mg/m2/d, days 1 to 14, n = 31) or IV 5-FU (500mg/m2/d 1 and day 8, n =31), in combination with doxorubicin (50 mg/m2 IV day 1) and cyclophosphamide(500 mg/m2 IV day 1). The overall response rate was 48.4% in UFT plus AC arm and35.5% in 5-FU plus AC arm (P = 0.30).
The median response duration was 16 weeks (range 4 to 30 weeks)for both arms. The median overall survival was 12 months for the UFT plus AC armand 11 months for the 5-FU plus AC arm. Anemia and stomatitis were significantlymore common in the 5-FU arm (P = 0.02). This trial shows that the responserates, duration of response, and survival with oral UFT are comparable to thosewith intravenous 5-FU in a combination chemotherapy regimen for advanced breastcancer.
A study combining cyclophosphamide (65 mg/m2 orally on days1-14), doxorubicin (30 mg/m2 IV on day1), and tamoxifen 20 mg/d orally on days1-21 with UFT (300 mg/m2 on days 1-14) for 20 patients with recurrent breastcancer produced an overall response rate of 58% (95% CI, 29% to 87%). Adverseevents (> CTC grade 3) included leukopenia in six patients, anemia in onepatient, and generalized malaise in one patient. There are several ongoingstudies evaluating UFT/leucovorin combined with paclitaxel/vinorelbine.[38,39]
All of these studies have shown promising evidence of theactivity of UFT in treating advanced breast cancer. However, most have beenconducted by single institutions, and with relatively few patients. Large andmulticenter studies are needed to definitively prove efficacy.
UFT in Stage II Breast Cancer
Two large studies have evaluated UFT as adjuvant treatment forstage II breast cancer. Hokkaido Adjuvant Chemoendocrine Therapy for BreastCancer (ACETBC) Study Group randomized stage II estrogen-receptor (ER) positivepatients to two treatments. All patients received mitomycin intravenously at13 mg/m2 on the day of surgery. In arm A, patients received oral tamoxifen only,at 20 mg/d, 14 days after surgery for 2 years (n = 219). In arm B, patientsreceived UFT 400 mg/d plus tamoxifen 20 mg/d (n = 225). There was no differencein the 5-year survival rate (93% in arm A vs 95.4% in arm B). However, the5-year relapse-free survival rates were 83.1% for arm A and 90.7% for arm B, asignificant advantage for the UFT plus tamoxifen arm (P = 0.02).
The Nishinihon Cooperative Study Group of Adjuvant Therapy forBreast Cancer evaluated a similar regimen. A benefit from the mitomycin, UFT,and tamoxifen combination was suggested in premenopausal ER-positivepatients.
UFT in the neoadjuvant setting for Stage IIIb breast cancer hasalso been investigated. In an ongoing phase I/II trial, 11 patients with stageIIIb disease have been enrolled, with a fixed dose of doxorubicin (60 mg/m2 IVbolus) and paclitaxel (200 mg/m2 IV 3-hour infusion) with escalating UFT dosesof 200, 250, 300, 350 mg/m2/d in a 21-day schedule. With nine evaluablepatients, two patients have had complete responses, and the other seven hadpartial responses. A mastectomy was performed in eight patients, and one had apathological response.
UFT plus leucovorin has been shown to be a convenient,well-tolerated, and effective treatment regimen for advanced colorectal cancer.It has also shown promise in the treatment of breast cancer as both adjuvant orpalliative therapy. Although the combination of oral UFT/leucovorin had shownequivalent efficacy for advanced colorectal cancer in comparison with5-FU/leucovorin, its advantages may be in ease of administration, reducedneutropenia, fewer hospitalizations for toxicity, less oral mucositis, fewerclinic visits, and fewer laboratory tests. There is also less infusion-relatedside effects, including infection and bleeding. Trials of UFT/leucovorincombined with other cytotoxic agents (eg, CPT-11, oxaliplatin) will providefurther information about future optimal treatments for colorectal cancer.Protracted venous infusion of 5-FU is superior to bolus 5-FU when combined withexternal beam radiation for treating localized rectal cancer. For thisreason, UFT is also being studied in patients with rectal adenocarcinoma, as apotential substitute for protracted venous infusion of fluorouracil.
Jean Grem, MD: Dr. Haller, in the intergroup study, the monthlyscheduled 5-FU-leucovorin was for six cycles and the Roswell Park regimen wasfour cycles, which ended up being longer than 6 months. My experience is thateverybody looks at the abstract, which concludes that approximately 6 months oftherapy with 5-FU-leucovorin is the standard. But a lot of people have just beengetting three cycles.
Daniel Haller, MD: Actually, it’s 30 weeks, about 7 months. Itcould be that, in truth, the number of cycles is irrelevant; that the length oftime is important.
John Marshall, MD: Why do you think European colon cancer isworse than colon cancer in the United States in regard to response rates? Theyjust always seem to be about 5% to 10% points lower.
Dr. Haller: It partly has to do with how the protocol is writtenand how people interpret the protocol in terms of taking people off studies. Thesurvivorship doesn’t change a great deal. If your pretest probability is thatsomething’s not working, you look for every excuse to take someone off a trialfaster than you will if you believe they’re going to respond. Most peoplereview the responders, but they don’t review the nonresponders who were takenoff the study. So it would be interesting, if the finances were there, to goback and look at patients who might have been taken off study prematurely. Ithink a lot of patients are actually taken off treatments too soon. They arestill getting benefit and we take them off for regulatory purposes. So inclinical trials, the time-to-tumor progression is very short, compared to whatwe typically see in our own practices.
I’m not sure we have the best model for evaluating efficacy. Istill think progression-free survival is the most sensitive end point, but it’sa misery for drug development, because you’re looking at relatively smallintervals. Thus, most companies are unwilling to pick up the cost of the monthlyCT scans, which adds another $10,000 per patient. Few, if any, insurancecarriers are willing to pay for these frequent markers of response. It’s easyto screen for markers of death or toxicity, but response maintenance or failureof progression is very, very hard.
Leonard Saltz, MD: I’d like to go back to the development ofUFT (uracil and tegafur). Basically, M. D. Anderson and Roswell Park togetherlooked at the high-dose schedule and came up with 350 mg/m2/d. Then it was cutback to 300 mg/m2. And when you consider the exquisite sensitivity of leucovorinin terms of infusional regimens, there’s probably an enormous drop in theintensity of the regimen and that may be why we have a very nontoxic regimen.
Paulo Hoff, MD: The dose was not dropped to 300 mg/m2 just outof the hat. We did start the phase II trial at 350 mg/m2 and seven out of eightpatients had intolerable diarrhea. So that’s when the dose was dropped. Thedrop of the leucovorin was based on preclinical data showing that if you goabove 25 mg of leucovorin, patients are really not absorbing any more.
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