|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2002 American Society for Clinical Oncology Randomized Comparative Study of Tegafur/Uracil and Oral Leucovorin Versus Parenteral Fluorouracil and Leucovorin in Patients With Previously Untreated Metastatic Colorectal Cancer
From the City Hospital, Nottingham; Weston Park Hospital, Sheffield; Bristol Oncology Center, Bristol, United-Kingdom; Jagiellonian University, Krakow, Poland; Inselspital Bern, Bern, Switzerland; Princess Margaret Hospital, Toronto, Canada; Herlev Amt Hospital, Copenhagen, Denmark; and Bristol-Myers Squibb Company, Waterloo, Belgium. Address reprint requests to James Carmichael, MD, City Hospital NHS Trust Hucknall Road, NG5 1PB Nottingham, United-Kingdom; email: james.carmichael{at}nottingham.ac.uk.
Purpose: This phase III study compared the time to progression (TTP) of an oral regimen of dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine composed of a fixed combination of tegafur and uracil in a 1:4 molar ratio (UFT) and leucovorin (LV) to intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma (CRC) patients. Secondary end points were survival, tumor response, safety, and quality of life. Patients and Methods: Between May 1996 and July 1997, 380 patients were randomized to receive either UFT (300 mg/m2/d) and LV (90 mg/d), administered for 28 days every 35 days, or 5-FU (425 mg/m2/d) and LV (20 mg/m2/d), given IV for 5 days every 35 days. Results: No statistically significant difference in TTP was observed between treatments. With 320 events assessed, the median TTP was 3.4 months (95% Confidence interval [CI], 2.6 to 3.8) on UFT/LV and 3.3 months (95% CI, 2.5 to 3.7) on 5-FU/LV (P = .591, stratified log-rank test). There were no statistically significant differences in survival, tumor response, duration of response, and time to response. Substantial safety benefits were observed in patients treated with UFT/LV. They experienced significantly less stomatitis/mucositis (P < .001) and myelosuppression, resulting in fewer episodes of febrile neutropenia (P < .001) and less documented infection (P = .04). Concomitant medication usage was significantly greater on 5-FU/LV (P = .010). With respect to quality of life, after correcting for baseline imbalances, there were no significant differences between treatments for any scale, except diarrhea. Conclusion: The oral UFT/LV regimen failed to achieve improved TTP; however, the study confirms significant safety improvements compared with bolus IV 5-FU/LV for the first-line treatment of metastatic CRC.
IN WESTERN COUNTRIES, colorectal cancer (CRC) remains the second leading cause of cancer death after lung cancer in men and breast cancer in women. In the United States, an incidence of 129,400 new cases and 56,600 deaths are the most recent projections for 1999.1 In Europe, the average annual incidence of colon cancer was 50,657 for women and 42,255 for men (years 1978 to 1982).2 The average annual mortality for colon cancer was 30,869 for women and 24,687 for men (years 1980 to 1984).2 Approximately 30% of CRC patients present with advanced disease, and an additional 25% will develop a recurrence after initial resection. Systemic treatment of CRC prolongs survival and also provides substantial symptom palliation.3–11 The combination of irinotecan with fluorouracil (5-FU) ± leucovorin (LV) as an initial treatment for metastatic disease is increasingly used because of demonstrated improved survival12,13; however, recent concern has been raised regarding the toxicity of this combination.14 The most widely used chemotherapy drug in the first-line treatment of metastatic CRC is 5-FU, with the daily x 5 schedule emerging as the preferred bolus regimen. The biomodulation of 5-FU by LV has been shown to significantly improve response rates and prolong survival with both high-dose and low-dose LV schedules.8–11 In addition, prolonged exposure to 5-FU improved the response rate to 5-FU and reduced the associated toxicity.15,16 However, the need for central venous catheters and infusion pumps has limited the use of these regimens because of a significant complication rate and increased costs. Therefore, intravenous bolus regimens of 5-FU/LV remain widely used in clinical practice and are frequently used as the comparator arm in clinical investigations. Although several 5-FU/LV regimens are currently in use, the regimen developed by the Mayo Clinic and the North Central Cancer Treatment Group remains the standard comparator arm for multinational phase III trials in metastatic CRC12,13,17–22 and is the most widely approved regimen worldwide. This dose and schedule (5-FU 425 mg/m2/d and LV 20 mg/m2/d every 4 or 4 to 5 weeks) is associated with considerable toxicity with an intolerability rate of 45.9% (95% confidence interval [CI], 41.1% to 50.8%).23 In the clinical trials leading to the adoption of the 5-day 5FU/LV schedule, 5-FU doses were most commonly in the range of 370 to 400 mg/m2, with LV doses of 20 to 200 mg/m2.8–11 The cycle length has varied from 3 weeks,11 to 4 weeks,9,10 to 4 to 5 weeks.8 It does not seem that dose-intensification results in higher response rates or longer survival. In an attempt to improve the therapeutic index of 5-FU, research has focused on the study of 5-FU prodrugs, competitors of enzymes involved in 5-FU catabolism, and the selection of drugs with a better bioavailability profile, the aim being to increase drug treatment duration and tumor exposure and to reduce the complexity involved with continuous intravenous (IV) infusion administration. UFT is an orally administered dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine composed of a fixed combination of tegafur and uracil in a 1:4 molar ratio. Tegafur is an orally bioavailable prodrug of 5-FU, and uracil reversibly inhibits the primary catabolic enzyme for 5-FU, which is dihydropyrimidine dehydrogenase. Both tegafur and uracil are very well absorbed after oral administration.24,25 Phase II results of single-agent UFT in patients with metastatic CRC demonstrated the efficacy and safety of oral UFT at doses between 400 and 800 mg/d in studies conducted in Japan,26 the United Kingdom,27 and in Spain.28 The development of an oral regimen of UFT in combination with oral leucovorin followed experimental data demonstrating increased efficacy for UFT when given in combination with leucovorin.29–31 Phase I/II studies32–40 using varying regimens of UFT and leucovorin showed that this combination resulted in impressive objective response rates with an acceptable safety profile. In the largest phase I/II study, conducted at M.D. Anderson Cancer Center,40 dose-limiting gastrointestinal toxicities were seen at UFT doses around 350 mg/m2 per day plus LV 150 mg/d orally for 28 days followed by 7 days rest. A UFT dose of 300 mg/m2/d with oral LV was safe, and the response rate in the 38 patients treated at these two dose levels was 42.2%. In view of the high response rates in the phase II studies and the favorable safety profile, this multicenter, randomized phase III trial was designed to compare the safety and efficacy of a regimen of UFT and oral leucovorin to the IV Mayo Clinic regimen of bolus 5-FU and LV in previously untreated metastatic CRC. The original regimen developed by the Mayo Clinic administered chemotherapy on weeks 4 and 8 and then every 4 to 5 weeks until progression. This study was designed to test UFT/LV over a 5-weekly 5-FU/LV regimen for superiority in time to progression (TTP) and evaluate any significant advantages in terms of the safety profile for the oral treatment.
Patient Selection Patients enrolled onto the study had histologically confirmed metastatic CRC and assessable or bidimensionally measurable disease. Prior adjuvant treatment for CRC was allowed if completed at least 6 months before study enrollment. Prior treatment for metastatic disease was not allowed. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, gave written informed consent, and were older than 18 years of age. Adequate bone marrow, liver, and renal function (creatinine grade 0 or 1) were required. Women of childbearing potential were required to have a negative baseline pregnancy test. Patients with psychiatric or medical problems rendering them unable to give informed consent or with a serious concurrent, uncontrolled medical condition were ineligible. With the exception of patients with previous basal cell skin cancer or carcinoma-in-situ of the cervix, patients with a history of prior malignant neoplasms were to be excluded. The protocol was approved by institutional review boards including central national institutional review boards (in France, for example).
Treatment UFT/LV was to be administered as follows: UFT, 300 mg/m2/d, plus LV, 90 mg/d, both divided into three separate doses and administered orally every 8 hours for 28 consecutive days. 5-FU/LV treatment was to be 5-FU, 425 mg/m2/d, plus LV, 20 mg/m2/d, given by rapid IV injection for 5 consecutive days. On both treatment arms, treatment cycles were to be repeated every 35 days. Subsequent cycles were continued at the starting dose levels unless toxicity necessitated dose reduction. During a cycle, therapy was withheld after development of grade 3 and 4 hematologic toxicity (ie, granulocytes < 1,000/mm3 or platelets < 50,000/mm3) or grade 2 to 4 nonhematologic toxicity. Days when therapy was withheld because of toxicity were counted as treatment days. Therapy was to be resumed if the toxicity resolved during the patient’s treatment window (ie, 5 days for 5-FU/LV or 28 days for UFT/LV); the remaining days of the treatment course were to be completed at the same fluoropyrimidine dose level. Patients were to be taken off study if treatment delays more than 2 weeks were required. The UFT dose was to be decreased by 50 mg/m2/d for all grade 3 to 4 hematologic and nonhematologic toxicities. The 5-FU dose was to be decreased to 80% of the preceding dose for grade 3 to 4 hematologic and nonhematologic toxicities. Doses of oral or IV LV remained unchanged for all cycles. Treatment with either regimen was withheld in subsequent cycles until evidence of hematologic recovery (granulocyte count > 1,500/mm3 and platelet count > 100,000/mm3) and until complete recovery of all nonhematologic toxicities to baseline or grade 1. The nadir counts during the previous cycle were used to adjust dose levels of subsequent cycles of UFT and 5-FU. Dose escalations were not allowed in this study. While on treatment, weekly complete blood cell count with differential and platelet count was to be obtained with serum chemistry before each cycle. Before each cycle, a physical examination was to be performed and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire was completed. Tumor reassessment, by computed tomography scan, was repeated after every two cycles, with an additional computed tomography scan at week 15. Monitoring for adverse events was continuous throughout the trial, with National Cancer Institute common toxicity criteria used to grade the severity of adverse events. After going off treatment, patients were observed for TTP and survival. Efficacy was evaluated locally with data subsequently centrally reviewed.
Statistical Methods For the primary study end point of TTP, a stratified log-rank test41 was used for the primary comparison of treatment arms. A two-sided 95% CI of the hazard ratio (5-FU/LV:UFT/LV) was calculated. A second comparison was a stratified Cox regression,41 adjusted for prespecified prognostic factors. Kaplan-Meier curve42 and 95% CI43 for median survival, by treatment arm, were prepared. The same methods were applied for the analysis of survival. The modified criteria of the World Health Organization were used to assess objective response. The response rate was compared between treatment arms using a Cochran-Mantel-Haenszel (CMH) test.44 Secondary comparisons were performed with a stratified logistic regression model.44 Duration of response was compared between treatment arms using a log-rank test41 and time to response using a Wilcoxon test45. All efficacy analyses have been presented by treatment arm as randomized, and all comparisons between treatment arms were carried out using a two-sided test at an alpha level of 5%. Longitudinal comparisons between treatment arms on the EORTC Quality of Life Questionnaire (five functional scales, nine symptom scales, and global health status) were made using the Wei-Johnson46 type stochastic ordering test; baseline differences between treatment arms were assessed using the Wilcoxon test.
Patient Characteristics Between May 1996 and July 1997, 380 patients with metastatic CRC were enrolled and randomized at 47 sites. Most patients (n = 291) were entered at European sites. The remaining patients were entered in Canada (n = 55), Australia (n = 24), New Zealand (n = 5), and Israel (n = 5). One hundred ninety patients were randomized to receive UFT/LV, and 190 patients were randomized to receive 5-FU/LV. Stratification criteria at randomization included: PS (ECOG 0 v 1 to 2), prior adjuvant therapy (yes v no), and study site.
Pretreatment characteristics were well balanced between treatment arms (Table 1
Standard baseline disease characteristics were well balanced between treatment arms (Table 2  ), although differences in baseline quality of life were seen. Most patients had no prior adjuvant therapy and had bidimensionally measurable disease. The median number of disease sites was two in both treatment arms. Patients generally had widespread disease, with the most frequent distant sites including the liver, abdominal lymph nodes, and lung.
Study Therapy Data Three hundred eighty patients were randomized, of whom a total of 373 patients were appropriately treated (188 UFT/LV; 185 5-FU/LV). Seven patients (2%) received no treatment: three patients randomized to UFT/LV and four patients randomized to 5-FU/LV. One patient was randomized to receive 5-FU/LV but was treated with UFT/LV instead. There was no difference in the median number of courses administered (three courses) in both treatment groups. The range in the number of courses given was one to 10 for UFT/LV and one to 13 for 5-FU/LV. The median treatment duration was 17.2 weeks (range, 1.3 to 51.1 weeks) for patients receiving UFT/LV and 15.1 weeks (range, 0.3 to 67.1 weeks) for patients receiving 5-FU/LV.
Dose Escalations and Reductions Between Courses
For each course and both drugs, the prescribed dose was defined as the maximum of the total daily dose on days 1 and 2 of each course. To identify dose reductions for a course, the prescribed doses per course were predefined according to the dose levels as follows: a UFT dose
Dose-Intensity and Relative Dose-Intensity
Concomitant Medications
Antiemetic use was significantly higher (P < .001) in patients treated with 5-FU/LV (65%) than in patients treated with UFT/LV (38%). There was also significantly more use of anxiolytic medications among patients receiving 5-FU/LV (24%) compared with those receiving UFT/LV (15%, P = .026). The use of antidiarrhea, systemic anti-infective, and analgesic medications was similar in the two arms.
Efficacy Data
At the time of this analysis, 320 (84%) of the 380 randomized patients had evidence of tumor progression (317 patients) or had died without progression (three patients). The median TTP was 3.4 months (95% CI, 2.6 to 3.8) with a range of 0.03+ to 15.6+ months for patients treated with UFT/LV versus 3.3 months (95% CI, 2.5 to 3.7) with a range of 0.03+ to 15.8+ months for patients treated with 5-FU/LV (P = .591, stratified log-rank). The hazard ratio for 5-FU/LV over UFT/LV was 0.94 (95% CI, 0.75 to 1.18) (Fig 1
The overall tumor response rate (ie, complete response [CR] and partial response [PR]) among all randomized patients was 10.5% (20 of 190 patients) in the UFT/LV treatment arm and 9.0% (17 of 190 patients) in the 5-FU/LV treatment arm. There was no statistically significant difference in response rate between the two treatment arms (P = .593, CMH). A complete tumor response was observed in two patients (1%) in each treatment arm.
With 326 events in the 380 randomized patients, the median survival was similar in both treatment arms: 12.2 months in the UFT/LV treatment arm and 10.3 months in the 5-FU/LV treatment arm (P = .226, stratified log-rank test) (Fig 2
Secondary chemotherapy was administered to 41% (78 of 190) of patients receiving UFT/LV, and 39% (75 of 190) of patients receiving 5-FU/LV. The most frequently administered secondary chemotherapy was fluoropyrimidines only, in 49% of the 78 UFT/LV patients and in 47% of the 75 5-FU/LV patients who took secondary chemotherapy, followed by irinotecan only (28% in each arm). In patients receiving secondary chemotherapy, oxaliplatin alone or in combination with irinotecan was given to 13% (10 of 78) of UFT/LV treated patients and 16% (12 of 75) of 5-FU/LV treated patients. A Cox proportional hazard model, with secondary chemotherapy as a time-dependent covariate and an interaction term with treatment, showed that the effect on survival of using secondary chemotherapy was similar in both treatment arms.
Quality-of-Life Data
Safety Data
Hematologic Toxicity
The incidence of thrombocytopenia was low; however, patients treated with UFT/LV experienced less thrombocytopenia of any grade than the patients treated with 5-FU/LV. There were statistically significantly fewer patients with any grade anemia in the UFT/LV-treated patients compared with the 5-FU/LV–treated patients (76% v 89%, respectively); however, severe anemia was infrequent and did not differ between treatment arms (5% v 4%, respectively).
Nonhematologic Toxicity
The most frequently reported skin/appendage toxicities in this category were alopecia and rash. There were four cases (2%) of hand-foot syndrome reported in the 5-FU/LV treatment arm, whereas no were reported in the UFT/LV treatment arm.
There were no significant differences between the treatment arms in the incidence of liver function elevations (Table 6
An additional analysis of worst hematologic (excluding anemia) and nonhematologic toxicity in the subset of patients with a calculated creatinine clearance less than 80 mL/min at baseline showed no apparent increased toxicity for UFT/LV in association with abnormal renal function. A total of 127 patients were hospitalized during the study, 59 (31%) in the UFT/LV arm and 68 (37%) in the FU/LV arm. Patients could have multiple reasons for hospitalization, so the incidence is difficult to compare between the two arms. However, five patients, all in the FU/LV treatment group, had febrile neutropenia as a reason for hospitalization. Thirty-six patients died within 30 days of the last study drug administration, 19 in the UFT/LV arm and 17 in the 5-FU/LV arm. Death in the UFT/LV arm was a result of disease in all 19 cases. In the 5-FU/LV arm, death was a result of toxicity, partly or entirely, in four patients, to disease in 10 patients, and to other reasons in three patients.
Chemotherapy in metastatic CRC is palliative, and therefore, convenience, quality of life, and safety are very important benefits of chemotherapy. The results of this phase III trial in patients with previously untreated metastatic CRC failed to demonstrate superiority between oral UFT/LV and IV 5-FU/LV in the primary end point, TTP. The median TTP was 3.4 months in the UFT/LV treatment group and 3.3 months in the 5-FU/LV–treated patients, and the hazard ratio for 5-FU/LV over UFT/LV was 0.94 (95% CI, 0.75 to 1.18). This difference was not statistically significant (P = .591, stratified log-rank test). There were also no statistically significant differences between the treatment arms in any of the secondary efficacy end points, in particular, survival (median survival: UFT/LV, 12.2 months; 5-FU/LV, 10.3 months; with a hazard ratio for 5-FU/LV over UFT/LV of 1.14 [95% CI, 0.92 to 1.42], P = .226, stratified log-rank test) and objective response rate (UFT/LV, 10.5%; 5-FU/LV, 9.0%; P = .593, CMH) In this study, the choice of the Mayo Clinic regimen, every 5 weeks from course 1 was made to avoid the effect of an assessment bias on the primary study end point of TTP by allowing patients to be assessed on both arms every 5 weeks before each course. The original regimen developed by the Mayo Clinic is to be administered at weeks 4 and 8 and then every 4 to 5 weeks until patients develop progressive disease. In study CA 146-011,47 where 5-FU/LV was administered using the 4-week dosing Mayo Clinic regimen, the median dose-intensity for 5-FU was 452 mg/m2/wk, whereas it was 418 mg/m2/wk in the present study, a difference of only 8%. Thus, it seems unlikely that the schedule difference of the control arm resulted in any substantial difference in efficacy. In addition, the median survival reported for the 5-FU/LV arm in this trial (10.3 months; 95% CI, 8.2 to 13.0) and in study CA 146-011 (13.4 months; 95% CI, 11.6 to 15.4) are within the range (8 to 15 months) of many of the trials used to establish 5-FU/LV as a superior treatment to 5-FU alone.8–11,48–53 Median survival with 5-FU/LV has been greater than 12 months in recent larger trials.12,20 A 5-FU dose of 425 mg/m2 combined with LV 20 mg/m2 was selected for the control arm of this study. This dose of 5-FU is reported to be associated with considerable toxicity requiring frequent dose reductions.23 In this study, 26% of patients receiving 5-FU/LV were dose reduced for grade 3 or 4 toxicity; however, four patients treated with 5-FU/LV died within 30 days of study therapy partly or entirely because of 5-FU/LV treatment. The safety of this dose of 5-FU in clinical trials and in general oncology practice continues to be questioned.54 The response rates were low in both arms of the study. Although there was no independent response assessment, a central review according to the protocol response definitions took place. All the efficacy measures, including response rate, were assessed using an intent-to-treat analysis. Further analysis of response by patient pretreatment characteristics showed lower response rates in patients with worse PS and prior adjuvant chemotherapy. It is possible that patient selection factors may have played a role because the response rate for both UFT/LV, and 5-FU/LV was much lower than observed in phase II or other studies. However, the survival data was in keeping with other large trials. Safety results from this study confirmed the frequent occurrence of myelosuppression, mucositis, nausea, vomiting, and diarrhea associated with 5-FU/LV therapy and revealed a substantial safety advantage for UFT/LV. There was no statistically significant difference between the treatment arms in the overall incidence of any or severe diarrhea, the most common side effect associated with UFT/LV. The UFT/LV regimen led to a statistically significant reduction in myelosuppression, especially severe leukopenia and neutropenia, but also thrombocytopenia and anemia. The incidence of severe stomatitis/mucositis was one-eighth of that for 5-FU/LV, and the incidence and duration of any grade stomatitis/mucositis was also statistically significantly lower in the UFT/LV treatment arm. Severe neutropenia and leukopenia place patients at significant risk. In the setting of bolus IV 5-FU treatment, the risks of infection associated with neutropenia are increased by the effects of treatment-related mucositis and stomatitis because of disruption of the normal mucosal barriers. In this study, the clinical relevance of neutropenia and leukopenia was demonstrated by the significantly higher incidence of documented infection associated with the 5-FU/LV regimen. The reduction of severe stomatitis is of clear benefit to patients preventing severe pain and, on occasion, hospitalization. This study of 380 patients confirms the superior safety of oral UFT/LV compared with IV 5-FU/LV for the treatment of metastatic CRC. UFT/LV-treated patients experienced significantly lower rates of severe toxicity, especially neutropenia, leukopenia, and stomatitis, with a decrease in the use of concomitant medications and a reduction in episodes of febrile neutropenia and documented infection. The safety advantages of UFT/LV surprisingly did not lead to demonstrable improvement in quality of life. A direct comparison of quality-of-life scores recorded on study showed statistically significant differences favoring the 5-FU/LV treatment arm in four quality-of-life scales. A sensitivity analysis in which the on-study data were adjusted for baseline levels revealed that only diarrhea remained statistically significantly different in favor of 5-FU/LV. However, this difference should be interpreted with caution, as the quality-of-life questionnaires were completed 4 weeks after 5-FU/LV chemotherapy but only 7 days after dosing in patients given UFT/LV. The study failed to demonstrate superiority in TTP of UFT/LV over 5-FU/LV. However, the results are consistent with the other study comparing oral UFT/LV with 5-FU/LV (CA 146-011).47 Indeed, although survival in UFT/LV was shown to be noninferior compared with 5-FU/LV in the CA 146-011 study, the survival hazard ratio estimate for 5-FU/LV over UFT/LV in the present study was larger than 1.0, although this difference was not statistically significant. Regarding TTP, in the CA 146-011 study, there was a statistically significant difference between the treatment arms in favor of 5-FU/LV. However, this difference was 9 days and, of note, disease assessments were performed on cycle completion, with timings that differed for the two treatment arms in this study (5-week cycle of UFT/LV and 4-week cycle of 5-FU/LV). The high level of consistency between the UFT/LV results for this trial, compared with the CA 146-011 study, is also confirmed by the overall survival results. The median survival time was 12.2 months in the present study and 12.4 months in CA 146-011 study. The median TTP was 3.4 months in the present study and 3.5 months in CA 146-011 study. Finally, the response rate was 11% in the present study and 12% in CA 146-011 study. This study also adds to the growing experience with oral fluoropyrimidines and is consistent with larger studies showing similar survival18,20 between oral and parenteral fluoropyrimidine monotherapy. Among the novel oral fluoropyrimidines, capecitabine has also been found to be as effective as 5-FU/LV (Mayo Clinic regimen) in terms of TTP and survival in two large, randomized, phase III studies in patients with metastatic CRC.55–56 In the pooled analysis57 of data from these trials, oral capecitabine produced superior response rates (25.7% v 16.7%, P < .0002) with similar TTP (4.6 v 4.7 months) to the control arm. Similar to UFT/LV, capecitabine did not improve median survival compared with 5-FU/LV and was shown to be well tolerated as monotherapy. Further studies including UFT/LV in combination with other active agents such as oxaliplatin or irinotecan are ongoing to confirm the increased activity and explore the impact on survival of combination chemotherapy based on oral fluoropyrimidines for metastatic CRC.58,59
Complete listing of participating institutions: Institute of Oncology, Warsaw; Jagiellonian University, Krakow, Poland; Shaare-Zedek Medical Center, Jerusalem; Kaplan Hospital, Rehovot, Israel; Fondation Bergonie, Bordeaux; Centre Antoine Lacassagne, Nice; Institut Paoli Calmettes, Marseille; Centre Régional de Lutte contre le Cancer, Montpeiller; Centre Catherine de Sienne, Nantes, France; Bristol Oncology Center, Bristol; Weston Park Hospital, Sheffield; City Hospital, Nottingham, United Kingdom; Herlev Amt Hospital. Finsen Center, Copenhagen; Roskilde Amt Hospital, Roskilde, Denmark; Helsinborgs Lasarett, Stockholm, Sweden; Notre-Dame Hospital, Montreal, Quebec; Princess Margaret Hospital, Toronto; Credit Valley Hospital, Mississauga; York County Hospital, Newmarket; Oshawa General Hospital, Oshawa, Ontario, Canada; Academic Medical Center, Amsterdam, The Netherlands; Klinikum Rechts der Isal, Klinikum Grosshadern, Munich; Universitaetsklinikum Charite, Berlin; St. Johannes Hospital, Duisburg; Mutterhaus der Borromaeerinnen, Trier; Zentralklinikum Augsburg, Augsburg, Germany; Kantonsspital Basel, Basel; University Hospital, Zurich; Centre Hospitalier Universitaire, Lausanne; Ospedale San Giovanni, Bellinzona; Kantonsspital, St. Gallen; Hospital Cantonal Universitaire, Geneva; Inselspital Bern, Bern, Switzerland; Ospedale San Gerardo Nuovo, Monza; Ospedale San Carlo Borromeo, Ospedale San Paola, Milan; Istituto Regina Elena, Rome; Ospedale San Giovanni Vecchio, Turin, Italy; Kuopia University Hospital, Kuopia, Finland; Waikato Hospital, Hamilton, New Zealand; Peter MacCallum Cancer Institute, East Melbourne; Sir Charles Gardiner Hospital, Nedlands; Royal Adelaide Hospital, Adelaide, Australia; Université Catholique de Louvain, Institut Jules Bordet, Brussels, Belgium.
Supported by the Taiho Pharmaceutical Company, Tokyo, Japan, and the Bristol-Myers Squibb Company, Princeton, NJ.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49:8–31, 1999 2. Moller Jensen O, Esteve J, Moller H, et al: Cancer in the European community and its member states. Eur J Cancer 26:1167–1256, 1990[Medline] 3. Van Triest B, van Groeningen CJ, Pinedo HM: Current chemotherapeutic possibilities in the treatment of colorectal cancer. Eur J Cancer 31A:1193–1197, 1995[Medline] 4. Beretta G, Bollina R, Cozzi C, et al: Should we consider the weekly chemotherapy with fluorouracil + racemic folinic acid a standard treatment for advanced/metastatic carcinoma of digestive tract in elderly patients? Proc Am Soc Clin Oncol 16:259a, 1997 (abstr 920)
5. Scheithauer W, Rosen H, Kornek G-V, et al: Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306:752–755, 1993
6. Glimelius B, Hoffman K, Graf W, et al: Cost-effectiveness of palliative chemotherapy in advanced gastrointestinal cancer. Ann Oncol 6:267–274, 1995 7. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10:896–903, 1992[Abstract] 8. Poon MA, O’Connell MJ, Moertel CM: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407–1418, 1989[Abstract] 9. Babbio-Pallavicini E, Porta C, Moroni M, et al: Folinic acid does improve 5-fluorouracil activity in vivo: Results of a phase III study comparing 5-fluorouracil to 5-fluorouracil and folinic acid in advanced colon cancer patients. J Chemother 5:52–55, 1993[Medline]
10. Borner MM, Castiglione M, Bacchi M, et al: The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: Results of phase III trial. Ann Oncol 9:535–541, 1998 11. Petrioli R, Lorenzi M, Qauio A, et al: Treatment of advanced colorectal cancer with high-dose intensity folinic acid and 5-fluorouracil plus supportive care. Eur J Cancer 31A:2105–2108, 1995[Medline]
12. Saltz L, Cox J, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905–914, 2000 13. Douillard JY, Cunningham D, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041–1047, 2000[CrossRef][Medline]
14. Sargent D, Niedzwiecki D, O’Connell M, et al: Recommendation for caution with irinotecan: Fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 345:144–145, 2001
15. Meta-analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301–308, 1998
16. Aranda E, Diaz-Rubio E, Cervantes A, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol 9:727–731, 1998 17. Cunningham D: Mature results from three large controlled studies with raltitrexed (Tomudex). Br J Cancer 77:15–21, 1998 (suppl 2)[Medline] 18. Pazdur R, Doulliard J-Y, Skillings J, et al: Multicenter phase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin (LV) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:263a, 1999 (abstr 1009)
19. Hoff P, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282–2292, 2001 20. Twelves C, Harper R, Van Cutsem E, et al: A phase III trial (S014796) of XELODA (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:263a, 1999 (abstr 1010) 21. Kalofonos HP, Nikolaides C, Samantas E, et al: A phase III study of 5-fluorouracil (5FU) versus 5FU plus leucovorin (LV) versus 5FU plus interferon A-2ß (IFN) in patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol 18:255a, 1999 (abstr 981)
22. Aranda E, Diaz-Rubio E, Cervantes A, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol 9:727–731, 1998 23. Vincent M, Whiston F, Tomiak A: Mini-meta-analysis of toxicity of full dose Mayo regimen (FUFA) from two randomized controlled trials (RCTs): A concern about dose. Proc Am Soc Clin Oncol 18:242a, 1999 (abstr 930) 24. Maehara Y, Kakeji Y, Ohno S, et al: Scientific basis for the combination of tegafur with uracil. Oncology (PRR) 11:14–21, 1997 (suppl 10) 25. Rustum YM: Mechanism-based improvement in the therapeutic selectivity of 5-FU prodrug alone and under conditions of metabolic modulation. Oncology (Karger) 54:7–11, 1997 (suppl 1)[Medline] 26. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmcol 22:333–338, 1988[Medline] 27. Malik STA, Talbot D, Clarke PI, et al: Phase II trial of UFT in advanced colorectal and gastric cancer. Br J Cancer 62:1023–1025, 1990[Medline] 28. Sanchiz F, Milla A: Tegafur (UFT) in advanced colorectal cancer, a phase II study. Anticancer Res 5:1122, 1988 (Part B) 29. Okabe H, Toko T, Saito H, et al: Augmentation of the chemotherapeutic effectiveness of UFT, a combination of tegafur [1-(2-tetrahydrofuryl)-5-fluorouracil] with uracil, by oral l-leucovorin. Anticancer Res 17:157–164, 1997[Medline] 30. Cao S, Frank C, Shirasaka T, et al: 5-Fluorouracil prodrug: Role of anabolic and catabolic pathway modulation in therapy of colorectal cancer. Clin Cancer Res 1:839–845, 1995[Abstract] 31. Rustum YM: Mechanism-based improvement in the therapeutic selectivity of 5-FU prodrug alone and under conditions of metabolic modulation. Oncology 54:7–11, 1997 (suppl 1)[Medline] 32. González-Barón M, Feliu J, de la Gándara I, et al: Efficacy of oral tegafur modulation by uracil and leucovorin in advanced colorectal cancer: A phase II study. Eur J Cancer 31A:2215–2219, 1995[Medline] 33. González-Barón M, Feliu J, Garcia Girón C, et al: UFT modulated with leucovorin in advanced colorectal cancer: Oncopaz experience. Oncology 54:24–29, 1997 (suppl 1) 34. Feliu J, González-Barón M, Espinosa E, et al: Uracil and tegafur modulated with leucovorin: An effective regimen with low toxicity for the treatment of colorectal cancer. Cancer 79:1884–1889, 1997[CrossRef][Medline] 35. Abad A, Navarro M, Sastre J, et al: UFT plus oral folinic acid as therapy for metastatic colorectal cancer in older patients. Oncology (PRR) 11:53–57, 1997 (suppl 10)[Medline]
36. Sanchiz F, Milla A: Tegafur-uracil (UFT) plus folinic acid in advanced rectal cancer. Jpn J Clin Oncol 24:322–326, 1994 37. Meropol NJ, Rustum YM, Petrelli NJ, et al: A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin in patients with advanced cancer. Cancer Chemother Pharmacol 37:581–586, 1996[CrossRef][Medline] 38. Pazdur R, Lassere Y, Diaz-Canton E, et al: Phase I trial of uracil-tegafur (UFT) plus oral leucovorin: 14-day schedule. Invest New Drugs 15:123–128, 1997[CrossRef][Medline] 39. Saltz LB, Leichman CG, Young CW, et al: A fixed-ratio combination of uracil and ftorafur (UFT) with low dose leucovorin. Cancer 75:782–785, 1995[CrossRef][Medline]
40. Pazdur R, Lassere Y, Rhodes V, et al: Phase II study of uracil and tegafur plus oral leucovorin: An effective oral regimen in the treatment of metastatic colorectal cancer. J Clin Oncol 12:2296–2300, 1994 41. Kalbfleisch JD, Prentice RL: The statistical analysis of failure time data. New York, NY, Wiley and Sons, 1980 42. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 43. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38:29–41, 1982[CrossRef] 44. Alan Agresti: Categorical Data Analysis. New York, NY, Wiley and Sons, 1990 45. Lehmann EL: Nonparametrics. San Francisco, CA, McGraw-Hill, 1975
46. Wei LJ, Johnson WE: Combining dependent tests with incomplete repeated measurements. Biometrika 72:359–364, 1985
47. Douillard JY, Hoff PM, Skillings JR, et al: Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3605–3616, 2002 48. Erlichman C, Fine S, Wong A, et al: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6:469–475, 1988[Abstract]
49. Di Costanzo F, Bartolucci R, Calabresi F, et al: Fluorouracil-alone versus high-dose folinic acid and fluorouracil in advanced colorectal cancer: A randomized trial of the Italian Oncology Group for Clinical Research (GOIRC). Ann Oncol 3:371–376, 1992 50. Doroshow J, Multhauf P, Leong L, et al: Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 8:491–501, 1990[Abstract] 51. Leichman C, Fleming T, Muggia F, et al: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: A Southwest Oncology Group study. J Clin Oncol 13:1303–1311, 1995[Abstract]
52. Labianca R, Pancera G, Aitini E, et al: Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: Phase III study of ‘GISCAD’ (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol 2:673–679, 1991 53. Löffler T, Korsten F, Reis H, et al: Fluorouracil as monotherapy or in combination with folic acid in the treatment of metastatic colorectal carcinoma. Dtsch Med Wschr 117:1007–1011, 1999[CrossRef] 54. Tomiak A, Vincent M, Kocha W, et al: Standard dose (Mayo regimen) 5-fluorouracil and low dose folinic acid: Prohibitive toxicity? Am J Clin Oncol 23:94–98, 2000[CrossRef][Medline]
55. Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous 5-fluorouracil plus leucovorin (Mayo Clinic regimen) in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097–4106, 2001
56. Hoff PM, Ansari R, Batisti G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282–2292, 2001 57. Twelves C: Capecitabine as first-line treatment in colorectal cancer: Pooled data from two large, phase III trials. Eur J Cancer 38:S15–S20, 2002 58. Douillard J, Seitz J: A phase I study of oral uracil/tegafur (UFT) plus leucovorin (LV) combined with oxaliplatin in patients with metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol 20:144a, 2001 (abstr 572) 59. Hill M, Mackay H, Cunningham D, et al: Phase I/II study of oral uracil/tegafur (UFT) leucovorin and irinotecan in patients with advanced colorectal cancer. Ann Oncol 11:45, 2000 (suppl 4, abstr 193P) Submitted October 25, 2001; accepted June 6, 2002.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
275 mg/m
90% of the recommended dose. Thirty-nine patients (21%) receiving UFT/LV and 15 patients (8%) receiving 5-FU/LV received less than 80% of the protocol-defined fluoropyrimidine dose-intensity. The median ftorafur dose-intensity for patients receiving UFT/LV was 1,542 mg/m
