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Originally published as JCO Early Release 10.1200/JCO.2002.04.123 on July 9 2002 © 2002 American Society for Clinical Oncology Multicenter Phase III Study of Uracil/Tegafur and Oral Leucovorin Versus Fluorouracil and Leucovorin in Patients With Previously Untreated Metastatic Colorectal CancerByFrom the Centre René Gauducheau, Nantes, France; University of Texas, M.D. Anderson Cancer Center, Houston, TX; Nova Scotia Cancer Center, Halifax, Canada; California Healthcare, Greenbrae, CA; North Middlesex and Guy’s Hospital, London, United Kingdom; London Regional Cancer Center, London, Canada; University of Pittsburgh Cancer Center, Pittsburgh, PA; and Bristol-Myers Squibb Company, Wallingford, CT. Address reprint requests to Prof Jean-Yves Douillard, Centre René Gauducheau, Site Hospitalier Nord, Bld J. Monod, 44805 Saint Herblain Cedex, France; email: jy-douillard{at}nantes.fnclcc.fr
PURPOSE: This phase III study was designed to demonstrate equivalence in survival of oral uracil/tegafur (UFT) and oral leucovorin (LV) to conventional intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma. Safety was also compared. PATIENTS AND METHODS: Eight hundred sixteen patients were randomized to receive either UFT (300 mg/m2/d) and LV (75 or 90 mg/d) for 28 days every 35 days or IV bolus 5-FU (425 mg/m2/d) and LV (20 mg/m2/d) for 5 days every 28 days. RESULTS: UFT/LV produced survival comparable to the IV 5-FU/LV regimen. Median survival was 12.4 months (95% confidence interval [CI], 11.2 to 13.6 months) with UFT/LV and 13.4 months (95% CI, 11.6 to 15.4 months) with 5-FU/LV (P = .630). The hazard ratio for survival was 0.964 (95.6% CI, 0.826 to 1.125), supporting equivalent survival. The overall response rate did not differ between treatment arms (UFT/LV, 11.7%; 5-FU/LV, 14.5%; P = .232). Median time to progression favored 5-FU/LV (UFT/LV, 3.5 months; 5-FU/LV, 3.8 months; P = .011), but tumor assessment schedules differed between arms. UFT/LV significantly improved safety compared with 5-FU/LV. Diarrhea, nausea and vomiting, and stomatitis and mucositis were significantly less frequent with UFT/LV, as was myelosuppression. Patients treated with UFT/LV had fewer episodes of febrile neutropenia (P < .001) and documented infections (P < .05). Increased bilirubin, without other liver function abnormalities, was observed more often with UFT/LV (P < .001). Concomitant medications were more frequent with 5-FU/LV, including use of antibiotics, growth factors, and antiemetics. CONCLUSION: UFT/LV provided a safer, more convenient oral alternative to a standard bolus IV 5-FU/LV regimen for metastatic colorectal cancer while producing equivalent survival.
CARCINOMA OF THE colon and of the rectum (colorectal cancer) is one of the most common tumor types, affecting approximately one person in 20 in the United States and in most European countries. In the Western world, colorectal cancer is the second leading cause of cancer deaths. In the United States, the most recent projections for the year 2001 estimate an incidence of 135,400 new cases and 56,700 deaths.1 Unfortunately, approximately half of all patients with colorectal cancer will develop distant metastases sometime during the course of their illness, and in this population, median duration of survival for patients treated with supportive care alone is approximately 4 to 6 months.2 The adoption of effective chemotherapy for metastatic disease produces median survival figures ranging from 17 months to 21 months.3,4 The standard treatments for metastatic colorectal cancer in the United States are based on intravenous (IV) fluorouracil (5-FU) given in combination with leucovorin (LV), with increasing use of 5-FU and LV combined with irinotecan based on improved survival.3-5 While 5-FU and LV remains the backbone of treatment for metastatic colorectal cancer, there continues to be significant debate regarding the proper dosing and schedule for 5-FU. With the exception of continuous IV infusions, however, 5-FU is invariably given with LV for the treatment of this disease. Of recently reported phase III trials in metastatic colorectal cancer, all used 5-FU in combination with LV as the comparator arm, and in approximately two thirds of these trials, the 5-FU/LV was administered using the Mayo Clinic regimen (a 5-day schedule of 5-FU 370 to 425 mg/m2/d and LV 20 mg/m2/d repeated every 4 to 5 weeks).5-12 Until March 2000, the Mayo Clinic regimen was an accepted standard worldwide based on approval by most regulatory authorities, including the United States Food and Drug Administration. Although investigators failed to demonstrate a survival advantage against 5-FU in the first meta-analysis published in 1992,13 5-FU/LV combinations in several large studies published after the first meta-analysis have demonstrated a statistically significant improvement in survival compared with 5-FU alone.14-16 The 1992 meta-analysis also did not include a positive study from the North Central Cancer Treatment Group, since these data were not made available.17 Currently, capecitabine is the only oral regimen approved in the United States for the treatment of this disease. A dose of 2,500 mg/m2/d administered intermittently (2 weeks on/1 week off) was selected based on a randomized phase II study18 and was compared in a randomized phase III trial to the 5-FU/LV Mayo Clinic regimen. Treatment with capecitabine was associated with a significantly higher response rate (24.8% v 15.5%, P = .005) without improvement in median overall survival (12.5 months capecitabine, 13.3 months 5-FU/LV; P = .974).8 In another trial, the response rate, time to progression, and survival were identical for capecitabine compared to 5-FU-LV.10 UFT is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (ftorafur [FT] or tegafur) and uracil in a molar ratio of 1:4. FT was synthesized by Hiller et al19 and is converted to 5-FU in vivo. Fujii et al20 found that the coadministration of uracil enhanced the concentration of 5-FU in tumors and the resulting antitumor activity of FT. In in vitro studies, uracil strongly inhibited the degradation of 5-FU to 2-fluoro-beta-alanine through reversible dihydropyrimidine dehydrogenase inhibition. After oral administration of UFT, uracil and FT are rapidly absorbed into the systemic circulation, with maximum plasma concentrations being achieved at approximately 1 hour.21-23 After the maximum plasma concentration was reached, both uracil and 5-FU decline rapidly while FT is eliminated from plasma at a significantly slower rate, consistent with its longer elimination half-life. Once absorbed, FT is metabolized to 5-FU by one of two different pathways and enzyme systems, thereby behaving as a prodrug to 5-FU.23,24 FT undergoes either hepatic microsomal oxidation at the C5' position to release 5-FU and succinaldehyde or cytosolic cleavage of the C2'-N1' bond to form 5-FU and 4-hydroxybutanal.24 The succinaldehyde and 4-hydroxybutanal moieties are subsequently converted to succinic acid or butyrolactone and hydroxybutyric acid, respectively.23,24 Other stable metabolic products of FT include 3'OH-ftorafor and 4'OH-ftorafur, both of which are eliminated in the urine and are not converted to 5-FU.25,26 UFT is commonly used in Japan. The Japanese experience has demonstrated that UFT administered at doses of 300 to 600 mg/d is extremely well tolerated and shows evidence of antitumor activity in a wide variety of solid tumors.27 The Japanese UFT regimen was evaluated by Malik et al28 in the United Kingdom in a phase II study of patients with gastric and colorectal cancer. UFT was administered in three divided doses daily, with most patients receiving 600 mg/d. Forty patients with colorectal cancer were enrolled, and 36 of these patients were assessable. The response rate in this population was 16.6% (95% confidence interval [CI], 6.4% to 32.8%). The overall toxicity of the treatment was low. These results were consistent with the Japanese experience demonstrating that the regimen was both active and well tolerated. LV is known to modulate the activity of 5-FU by stabilization of the fluorodeoxyuridine monophosphate–enzyme folate ternary complex. Japanese experiments performed in animal models demonstrated that UFT in combination with LV seemed to be more efficacious than UFT alone.29 Additional data from two experiments by Cao et al30 and Rustum31 support this conclusion. In a rat colon cancer model, the complete remission rate for UFT alone was 38%; it increased to 75% when high-dose LV was added. In this experiment, 5-FU and FT produced no complete responses..31 Until recently, Spain was the only country in Western Europe in which UFT was approved and in clinical use. Spanish investigators have developed UFT as a treatment for colorectal cancer and other solid tumors. In Spain, UFT has been administered in combination with oral LV. The Oncopaz Cooperative Group has reported their phase II experience with 75 colorectal cancer patients treated with a UFT and LV regimen.32 The overall response rate was 39% (95% CI, 27.8% to 50%). The most frequent side effect of this regimen was diarrhea, with 9% of the patients experiencing World Health Organization grade 3 or 4 diarrhea. Other severe (ie, grade 3 or 4) toxicities included nausea and vomiting (4%), mucositis (4%), gastric pain (3%), and leukopenia (3%). The Spanish experience, as illustrated by the Oncopaz study, suggested that the efficacy of the combination of UFT plus oral LV for colorectal cancer, based on the surrogate end point of response rate, seemed higher than historical comparisons using UFT alone.32,33 This approach offered the advantage of an apparent improvement in activity while maintaining an excellent safety profile. In the recent Spanish literature, the standard approach for UFT therapy in the treatment of colorectal cancer is administration of UFT in combination with oral LV.34-44 Through phase I and II studies initiated in the United States, UFT and oral LV treatment administration schedules were developed, and the side effects of this therapy were characterized.39-42 Four phase II studies combining UFT and oral LV for the treatment of previously untreated metastatic colorectal cancer were initiated in the United States starting in 1993. The largest of these studies was conducted at the M.D. Anderson Cancer Center (Houston, TX).41 The study was designed to administer UFT at a dose of 350 mg/m2/d plus LV 150 mg/d, both given three times daily, for 28 consecutive days with cycles repeated every 35 days; however, because of the gastrointestinal side effects observed in the first seven patients, the starting dose of UFT was reduced to 300 mg/m2/d in the remaining 39 patients enrolled. An overall response rate of 43% was observed among all 46 patients; among the 39 patients treated at the UFT dose of 300 mg/m2/d, the overall response rate was 44%. Five of the seven patients treated at a UFT dose of 350 mg/m2/d experienced grade 3 toxicity, whereas only seven of the 39 patients treated at the UFT dose of 300 mg/m2/d developed severe toxicity. At both doses, severe toxicity was primarily gastrointestinal. Based on excellent response rates and a favorable toxicity profile reported in phase II, the present phase III randomized trial was conducted to compare a combination regimen of UFT and oral LV to a standard bolus IV 5-FU and IV LV regimen. This multicenter, randomized trial was designed to compare the efficacy and safety of oral UFT and LV therapy to a combination of IV 5-FU and IV LV. Therapy was administered to patients with previously untreated metastatic colorectal carcinoma. The primary objective of the trial was to demonstrate that in patients assigned to receive UFT and LV, survival was equivalent to patients randomized to receive treatment with IV 5-FU and LV. The trial also evaluated the safety of UFT and LV therapy in comparison with IV 5-FU and LV.
Patient Selection All patients were required to have histologically confirmed metastatic colorectal cancer unsuitable for definitive surgical resection. Patients were to have assessable or bidimensionally measurable disease. Prior adjuvant treatment for colorectal cancer must have been completed at least 6 months before study enrollment, and prior treatment for metastatic disease was not allowed. Patients were to be enrolled at least 4 weeks after major surgery and were to have fully recovered from prior procedures. All patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, to give signed informed consent, and to be older than 18 years of age. Adequate bone marrow (absolute granulocyte count  2,000/mm3 and platelet count 100,000/mm3), liver (bilirubin within institution’s upper limit of normal), and renal (creatinine within institution’s upper limit of normal) function was required. Women of childbearing potential were required to have a negative baseline pregnancy test. Patients were excluded if they showed evidence of a concurrent serious infection, had a psychiatric or medical problem rendering them unable to give written informed consent, or had unstable medical conditions.
Treatment In the UFT/LV treatment arm, UFT 300 mg/m2/d and LV 75 or 90 mg/d were divided into three separate doses administered every 8 hours for 28 consecutive days with cycles repeated every 35 days. In the United States, patients received LV 75 mg/d, and in other countries, patients received LV 90 mg/d because of differences in the available dosages of LV (25-mg or 15-mg tablets, respectively). In the 5-FU/LV treatment arm, 5-FU 425 mg/m2/d plus LV 20 mg/m2/d were given by rapid IV injection for 5 consecutive days with cycles repeated every 28 days. Treatment courses were to be repeated at the starting dose levels unless toxicity necessitated a dose modification. During a treatment course, therapy was withheld for the development of grades 3 and 4 hematologic toxicity (ie, granulocyte count < 1,000/mm3 or platelet count < 50,000/mm3) or grades 2 to 4 nonhematologic toxicity. Days when therapy was withheld because of toxicity were counted as treatment days. Therapy was resumed if the toxicity resolved during the patient’s treatment window (ie, 5 days for 5-FU/LV or 28 days for UFT/LV); however, the remaining days of the treatment course were completed at a decreased fluoropyrimidine dose level. The UFT dose was decreased by 50 mg/m2/d for all grade 3 or 4 hematologic and nonhematologic toxicities. The 5-FU dose was decreased to 80% of the preceding dose for grade 3 hematologic or grade 2 nonhematologic toxicities and to 70% of the preceding dose for grade 4 hematologic or grade 3 or 4 nonhematologic toxicities. For subsequent courses, treatment was withheld until evidence of hematologic recovery (granulocyte count > 1,500/mm3 and platelet count > 100,000/mm3) and complete recovery of all nonhematologic toxicities to baseline or grade 1. The nadir counts during the previous course were used to adjust UFT and 5-FU dose levels as described above for subsequent cycles. Patients were taken off study for toxicity, necessitating treatment delays of greater than 2 weeks. Dose escalations were allowed for both UFT and 5-FU for those patients who experienced no hematologic or nonhematologic toxicities greater than grade 0 (UFT treatment arm) or greater than grade 1 (5-FU treatment arm) after a completed course of therapy. UFT dose was escalated in 50-mg/m2/d increments up to 400 mg/m2/d, and 5-FU dose was escalated in 10% increments up to 514 mg/m2/d. Throughout the study, the doses of oral or IV LV remained unchanged regardless of the grade of toxicity observed. However, if treatment with UFT or 5-FU was discontinued or doses were missed, LV was not given. During treatment, a complete blood count with differential and platelet count was obtained weekly. Before each course of therapy, a physical examination, complete blood count with differential and platelet count, and serum chemistry tests were performed, and the Functional Living Index-Cancer (FLIC) quality-of-life questionnaire consisting of 22 items43 was completed. Tumor reassessment, including tumor measurements and a computed tomography scan of the abdomen and pelvis, was repeated after every two courses with a repeat computed tomography scan 4 weeks after a response was noted for confirmation. Objective response was evaluated using modified criteria of the World Health Organization. Responses were assigned according to the protocol definitions by the sponsor (a Bristol-Myers Squibb oncologist); responses were required to be confirmed at 4 weeks. Monitoring for adverse events continued throughout the trial. The severity of adverse reactions was graded using the common toxicity criteria. Patients were to be followed off treatment for survival.
Statistical Methods Longitudinal comparisons (change from baseline up to course 6) on the FLIC quality-of-life questionnaire43 total and factor scores were made using the Wei-Lachin stochastic ordering test. If an item was missing, the score was prorated based on the answered questions. If 50% of the items that compose the factor were missing, the score was assigned a missing value.
Patient Characteristics Between June 1995 and August 1997, 816 patients with metastatic colorectal cancer were enrolled and randomized from 85 sites. Approximately two thirds of the patients (566 patients) were entered at sites in the United States and Puerto Rico (466 patients) and Canada (100 patients); the remaining third (250 patients) were entered at European sites. Four hundred nine patients were randomized to receive UFT/LV, and 407 patients were randomized to receive 5-FU/LV. Stratification criteria at the time of randomization included PS (ECOG 0 to 1 v 2), prior adjuvant therapy (yes v no), classification of disease (measurable v assessable), and study site. Pretreatment characteristics were well balanced between treatment arms (Table 1). Approximately two thirds of the patients were male, and the majority of patients were white. The median age overall was 64 years, and patients ranged in age from 22 to 90 years. At the start of treatment, the majority of patients had an ECOG PS of 0 or 1. Baseline lactate dehydrogenase levels were not obtained.
The disease characteristics of these patients were comparable between treatment arms (Table 2). Most patients had no prior adjuvant therapy for their disease (prior therapy for metastatic disease was not allowed by protocol), and at baseline, the majority of patients had bidimensionally measurable disease. The distribution of involved disease sites was similar between the two treatment arms. Patients in this study had widespread involvement with distant disease sites, including the liver, lungs, and abdominal lymph nodes.
Study Therapy Data Of the 816 patients randomized, 801 patients received their assigned treatment regimen. Of the remaining 15 patients, one patient was randomized to receive 5-FU/LV but received UFT/LV, and 14 patients (UFT/LV, four patients; 5-FU/LV, 10 patients) did not receive treatment. Seven patients randomized to the 5-FU/LV treatment arm were not treated at the patients’ request. Two patients, one on each treatment arm, experienced progressive disease before the initiation of therapy. For four patients, two on each treatment arm, medical complications prevented the initiation of study therapy. One patient, randomized to UFT/LV, was diagnosed with bone involvement after randomization and was never treated. The median number of courses administered was similar between treatment arms for this study. Patients in the UFT/LV treatment arm received a median of 3.5 courses (range, one to 24), and in the 5-FU/LV treatment arm, patients received a median of 4.0 courses (range, one to 16). The median treatment duration was 16.6 weeks (range, 0.7 to 120.0 weeks) for patients receiving UFT/LV and 16.7 weeks (range, 0.7 to 69.4 weeks) for patients receiving 5-FU/LV.
Dose Escalations and Reductions Between Courses More patients required dose escalation in the UFT/LV treatment arm than in the 5-FU/LV treatment arm. In the UFT/LV treatment arm, 17% required dose escalation, compared with 9% in the 5-FU/LV treatment arm. For both treatment arms, the percentage of patients receiving escalated doses remained stable during courses 2, 3, and 4 (UFT/LV, 13%, 16%, 17% and 5-FU/LV 7%, 8%, 7%, respectively), which suggests that patients whose doses were escalated were able to continue at the higher dose. Patients treated with 5-FU/LV required a greater number of dose reductions than the patients in the UFT/LV treatment arm. Twenty percent of patients treated with UFT/LV required dose reductions, compared with 66% on the 5-FU/LV treatment arm.
UFT Compliance
Dose-Intensity and Relative Dose-Intensity
Concomitant Medications
Efficacy Data Analyses of efficacy included all randomized patients based on the treatment arm as randomized. The primary measure of efficacy for this study was survival. Secondary assessments of efficacy included an assessment of the objective response rate and time to progression. A per-protocol final analysis occurred with a total of 640 deaths reported. The median survival time in the UFT/LV treatment group was 12.4 months (95% CI, 11.1 to 13.6 months), and the median survival time in the 5-FU/LV treatment group was 13.4 months (95% CI, 11.6 to 15.4 months). The hazard ratio for 5-FU/LV:UFT/LV was 0.93 (95.6% CI, 0.794 to 1.097). In an updated survival analysis, 60 additional deaths had occurred since the time of the per-protocol final analysis. With a total of 700 events reported, the median survival time in the UFT/LV treatment group was unchanged at 12.4 months (95% CI, 11.2 to 13.6 months), whereas the median survival time in the 5-FU/LV treatment group was also unchanged at 13.4 months (95% CI, 11.6 to 15.4 months). The hazard ratio for 5-FU/LV:UFT/LV was 0.964 (95.6% CI, 0.826 to 1.125). Since the lower bound of the CI exceeded 0.80, equivalence as noninferiority was established. There was no statistically significant difference in survival between the two treatment arms (P = .630, stratified log-rank). The Kaplan-Meier curve is presented in Fig 1.
Among all randomized patients, the overall tumor response rate (ie, complete response and partial response) for patients randomized to UFT/LV was 11.7% (48 of 409 patients), compared with 14.5% (59 of 407 patients) in the 5-FU/LV treatment group. There was no statistically significant difference in response rate between the two treatment arms (Cochran-Mantel-Haenszel, P = .232). A complete tumor response was observed in eight patients (2%) in each treatment arm. The median time to progression in the UFT/LV treatment arm was 3.5 months (95% CI, 3.0 to 4.4 months), and the median time to progression in the 5-FU/LV treatment arm was 3.8 months (95% CI, 3.6 to 5.0 months). There was a significant difference between the treatment arms in favor of 5-FU/LV (P = .011, stratified log-rank). The difference in median time to progression was 9 days. It should be noted that patients in this study were assessed for progressive disease at the completion of a cycle, which differed for the two treatment arms (5-week interval for UFT/LV and 4-week interval for 5-FU/LV). Secondary chemotherapy was administered to 52% of patients assigned to UFT/LV and 50% of patients assigned to 5-FU/LV. Information about the type of drugs included in subsequent chemotherapy was not collected. A survival analysis was performed in a Cox proportional hazards model with secondary chemotherapy (yes:no) as a time-dependent covariate, along with treatment and treatment x secondary chemotherapy interaction variables. The hazard ratio for secondary chemotherapy was greater than 1 (P = .002), but the interaction with treatment was found to be not significant (P = .74). This suggests that secondary chemotherapy is a risk factor associated with failure and is similar for both treatment groups.
Safety Data
Hematologic Toxicity
As a consequence of the more severe myelosuppression caused by the 5-FU/LV treatment, the number of patients developing febrile neutropenia (ie, investigator-reported febrile neutropenia or investigator-reported fever with associated grade 4 neutropenia) was significantly higher in the 5-FU/LV treatment arm than in the UFT/LV treatment arm (Table 4). There was no reported febrile neutropenia in the UFT/LV treatment arm, whereas febrile neutropenia was reported in 13% of the patients in the 5-FU/LV treatment arm (P < .001). Although thrombocytopenia occurred infrequently, the patients treated with UFT/LV experienced a significantly lower incidence of any and severe thrombocytopenia than the patients treated with 5-FU/LV (Table 4). There was no difference between the treatment arms with respect to the incidence of any grade anemia (UFT/LV, 83%; 5-FU/LV, 87%); however, the patients treated with UFT/LV experienced a significantly lower incidence of severe anemia than the patients treated with 5-FU/LV.
Nonhematologic Toxicity
The incidence of any grade and severe infection was lower in the patients receiving UFT/LV (2%) as compared with the patients receiving 5-FU/LV (7%) (P < .05). The significantly lower incidence of infection, as well as febrile neutropenia, in patients treated with UFT/LV was reflected in the reduced need for concomitant systemic anti-infectives in the patients receiving UFT/LV. The incidence of hand-foot syndrome was low in both treatment arms, and there were no cases of severe hand-foot syndrome reported in either treatment arm (Table 5). Any grade hand-foot syndrome was reported in only 2% of the patients treated with UFT/LV, whereas hand-foot syndrome was reported in 5% of the patients treated with 5-FU/LV (P < .05). There were no differences in the incidence of any grade alkaline phosphatase, AST, and ALT elevations between the treatment arms (Table 6). Total bilirubin (direct and indirect bilirubin were not measured) was the only liver function test for which there was a significant difference in incidence (Table 6). Thirty-nine percent of the patients treated with UFT/LV had grade 1 to 4 hyperbilirubinemia, whereas 22% treated with 5-FU/LV had grade 1 to 4 hyperbilirubinemia (P < .001). Grade 3 or 4 hyperbilirubinemia was observed in 15% of the patients in the UFT/LV treatment arm and 8% of the patients in the 5-FU/LV treatment arm (P < .05). Severe hyperbilirubinemia was not associated with a concurrent severe transaminase elevation in either treatment arm. For the majority of patients experiencing severe hyperbilirubinemia, AST and ALT elevations were grades 0 to 1 (UFT/LV, 71% and 82%, respectively; 5-FU/LV, 61% and 81%, respectively), with few patients experiencing severe concurrent AST and ALT elevations (UFT/LV, 9% and 2%, respectively; 5-FU/LV, 6% and 0%, respectively). Furthermore, it was not apparent that the increased incidence of hyperbilirubinemia resulted in an adverse outcome for patients in these studies.
In both arms of the study, the occurrence of hyperbilirubinemia required recovery to baseline or grade 1 before re-treatment. The majority of patients treated with UFT/LV could be re-treated after bilirubin elevation (78% after grade 2, 80% after grade 3, 60% after grade 4). Re-treatment was possible because the bilirubin declined in 81% of patients (92 of 113) after retesting. Re-treatment was possible for the majority of patients treated with 5-FU/LV experiencing grade 2 hyperbilirubinemia (71%) but was less common when more severe elevations occurred (46% after grade 3, 43% after grade 4). No other toxicities, either any grade or severe, were reported to be worse in patients treated with UFT/LV than in patients treated with 5-FU/LV. There were a total of 65 deaths (8%) that occurred within 30 days of the last administration of study drug. Of these, 42 deaths (10%) were reported on the UFT/LV treatment arm and 23 deaths (6%) on the 5-FU/LV treatment arm. Twenty-four patients (6%), 11 (3%) on the 5-FU/LV arm and 13 (3%) on the UFT/LV arm, died due to reasons other than progressive disease.
Quality-of-Life Data
The standard treatment for metastatic colorectal cancer is IV 5-FU, most often given in combination with LV calcium. Treatment of metastatic colorectal cancer with 5-FU–based chemotherapy provides palliation for these patients. For optimal palliation to occur, it is extremely important for patients to maintain or improve the outcome of survival associated with chemotherapy while minimizing the toxicities associated with treatment. In this phase III trial in patients with previously untreated metastatic colorectal cancer, treatment with UFT/LV produced equivalent survival compared with IV 5-FU/LV. While maintaining the efficacy observed with IV chemotherapy, UFT/LV was much safer, thus improving the therapeutic index for the treatment of metastatic colorectal cancer. The primary study end point of this phase III trial was survival, and the study was designed to demonstrate equivalence in survival. The protocol called for the first survival analysis to be performed after at least 630 deaths had occurred. With 700 deaths observed, the median survival time was 12.4 months in the UFT/LV treatment arm and 13.4 months in the 5-FU/LV treatment arm. The hazard ratio for 5-FU/LV:UFT/LV was 0.964 (95.6% CI, 0.826 to 1.125). The lower bound of the CI exceeded 0.80, supporting the conclusion of equivalence in survival. Determination of response rates was not a primary objective for this study. Patients were included with both measurable and assessable disease. All randomized patients were included in the denominator for the reported response rates. Patients with measurable disease were noted to have a higher response rate than nonmeasurable/assessable patients (UFT/LV: measurable, 13%, nonmeasurable/assessable, 5%; 5-FU/LV: measurable, 16%, nonmeasurable/assessable, 3%). Although there was no independent response assessment, an internal review was conducted according to protocol response definitions. The investigator responses (UFT/LV, 12.0%; 5-FU/LV, 15.0%) seem similar to the reviewed responses reported here (UFT/LV, 11.7%; 5-FU/LV, 14.5%). The lower response rate for UFT/LV in this study compared with the M.D. Anderson phase II study42 is likely to be related to patient selection including the addition of nonmeasurable patients. Bolus IV 5-FU/LV treatment of metastatic colorectal cancer is associated with significant toxicity. In this randomized phase III trial, UFT/LV produced greatly superior, clinically important safety advantages. One percent of the patients treated with UFT/LV experienced severe neutropenia, compared with 56% of the patients treated with 5-FU/LV. Severe neutropenia and leukopenia put patients at risk for serious opportunistic infections. In this study, the clinical impact of neutropenia and leukopenia was demonstrated by the significantly higher incidence of both documented infection and febrile neutropenia associated with the 5-FU/LV regimen. Additionally, the use of systemic anti-infectives and hematopoietic growth factors was also higher in patients treated with 5-FU/LV than in patients receiving UFT/LV. UFT/LV treatment was also associated with significant improvements in nonhematologic toxicity. The incidence of any and severe stomatitis and mucositis was significantly lower in the UFT/LV treatment arm as compared with the 5-FU/LV treatment arm. The clinical importance of reducing grade 3 and 4 stomatitis/mucositis is clear. Patients with this level of toxicity present with painful erythema, edema, or ulcers that prevent intake of solids (grade 3) or require parenteral or enteral support for alimentation (grade 4). These toxicities often lead to hospitalization. UFT/LV treatment was associated with a 10-fold decrease in this debilitating side effect. In addition to stomatitis and mucositis, other gastrointestinal toxicities are also important adverse effects of fluoropyrimidine therapy. Patients were much more likely to have received antiemetics, including 5-hydrocytryptamine-3 blockers, if they were receiving 5-FU/LV. The incidence of any diarrhea and any nausea and vomiting was lower for the patients receiving UFT/LV (P < .05). The incidences of toxicity were similar for hepatic function tests when 5-FU/LV was compared with UFT/LV, with the exception of the incidence of hyperbilirubinemia. It is not apparent, however, that this increased incidence of hyperbilirubinemia in patients treated with UFT/LV was associated with an adverse clinical outcome. The mechanism for hyperbilirubinemia is not known but clinically did not seem related to hemolysis. The incidence of abnormal liver function, jaundice, liver failure, and hepatomegaly was not different between the two treatment groups. Additionally, the on-study levels of alkaline phosphatase, AST, and ALT, which are usually more sensitive to drug-related insults, were comparable between the treatment arms. This phase III trial represented the first opportunity for most of the participating investigators to administer UFT/LV. That the safety advantages of UFT/LV were so striking in this setting attests to the safety of UFT/LV. In addition, the repeated oral dosing of UFT/LV provides an opportunity to interrupt treatment when a toxicity arises, before it worsens—an option that is not available with Mayo Clinic-like regimens. It was surprising that there was no observed difference between the treatment arms in quality of life, despite the clear reduction in toxicity with UFT/LV. Although quality of life may truly not have differed between treatment arms, the analysis could have been affected by the short interval from the completion of UFT/LV dosing (7 days) compared with 5-FU/LV dosing (23 days), which allowed patients a better recall of the effects of UFT/LV during completion of the quality-of-life questionnaire. Alternatively, the quality-of-life instruments may not be sensitive enough to show an improvement despite reduced toxicity. In this study, two different LV doses were used in the UFT/LV treatment group, 75 mg/d and 90 mg/d. In the United States, the 25-mg formulation was available; therefore, a daily dose of 75 mg was used. In other countries, the 15-mg formulation was available; therefore, a 90-mg daily dose was used. These doses were chosen to deliver LV above the point of complete absorption. It was expected that the clinical outcome for patients treated with these two LV doses would be the same. There was no evidence for any difference in toxicity associated with the two LV doses. There was also no statistically significant difference in survival, when comparing UFT/LV to 5-FU/LV, for the United States patients who received 75 mg, or for patients in other countries given oral LV 90 mg/d. Initially it was thought that the frequent oral dosing of UFT/LV might pharmacologically resemble a prolonged IV infusion of 5-FU. Subsequent pharmacokinetic data have shown that this UFT/LV dosing schedule results in 5-FU plasma concentrations that follow a repeated peak and trough profile, which is not consistent with the relatively constant 5-FU plasma concentrations that are observed for low-dose, prolonged-infusion 5-FU.44 As a result, this UFT/LV schedule is now thought to resemble a repeated mini-bolus profile and may help to explain the low incidence of hand-foot syndrome reported in this study (2%) relative to continuous-infusion 5-FU (9% to 46%).45-48 The incidence of hand-foot syndrome for the 5-FU/LV bolus treatment in this study was 5%, similar to the 6% reported for a similar 5-FU/LV regimen in the pooled analysis of the capecitabine studies.49 Randomized trials of low-dose and high-dose continuous infusion of 5-FU compared with bolus 5-FU/LV have shown a higher response rate for continuous infusion but no improvement in survival time.45-50 No randomized, clinical data are available comparing UFT/LV with infusional 5-FU with or without LV. This phase III study demonstrates that metastatic colorectal cancer patients were able to successfully comply with self-administered oral treatment. The majority of patients receiving UFT/LV did not require dose reductions. Twenty percent of patients treated with UFT/LV received dose reductions during the course of treatment, whereas 66% of the patients treated with 5-FU/LV required dose reductions during treatment, and 43% of patients had their doses reduced for course 2. This toxicity-related dose reduction is consistent with other randomized controlled trials and suggests that a 5-FU dose of 425 mg/m2 causes unacceptable toxicity.51 Overall, UFT/LV was effective and well tolerated in the palliation of patients with metastatic colorectal cancer. In this setting, UFT/LV provided superior safety compared with current standard bolus IV 5-FU/LV treatment. Patients treated with UFT/LV experienced significantly lower rates of severe toxicity, especially neutropenia, leukopenia, and stomatitis and mucositis. This reduction in toxicity was reflected in the decreased use of concomitant medications, as well as a reduction in the number of episodes of febrile neutropenia and documented infection for those patients treated with UFT/LV as compared with the bolus 5-FU/LV regimen. The substantial safety benefits were achieved while maintaining an efficacy equivalent to that of the 5-FU/LV regimen. In a phase I/II study of UFT/LV with irinotecan in metastatic colorectal cancer, and in a phase I study of UFT/LV with oxaliplatin in a similar population, a recommended phase II dose and schedule with acceptable toxicity has been demonstrated. Preliminary response data suggest that these combinations have a potential to be superior to monotherapy with 5-FU/LV or with an oral fluoropyrimidine.52,53 Consequently, UFT/LV produces an improvement in the therapeutic index of fluoropyrimidine chemotherapy of metastatic colorectal cancer. Importantly, UFT/LV will also provide patients with an additional oral chemotherapy for the treatment of this disease. Oral treatment results in fewer treatment-related visits and allows patients to exercise more control over their own lifestyles and to minimize visits related to treatment. This convenience and control of their own time will provide, in itself, an important palliative benefit for patients facing the burden of metastatic colorectal cancer.
APPENDIX
Supported by the Taiho Pharmaceutical Company, Tokyo, Japan, and the Bristol-Myers Squibb Company, Princeton, NJ.
This article was published ahead of print at www.jco.org.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
