Oral Leucovorin Research Articles

Integrated analysis of overall survival in two randomised studies comparing 5-fluorouracil/leucovorin with or without trimetrexate in advanced colorectal cancer

BackgroundTwo randomised studies were performed with trimetrexate (TMTX) as a biochemical modulator of 5-fluorouracil (5-FU)/leucovorin (LV) in advanced colorectal cancer (ACC), one in Europe and one in the United States. Both studies were similarly designed to detect a statistically significant difference in progression-free survival (PFS). Overall survival (OS), however, was later adopted as the primary outcome measure for approvability of agents for first-line treatment of ACC. Therefore, an integrated analysis of survival data from the European and USA trials was performed to detect a clinically relevant difference in survival. Patients and methodsThe experimental arm was identical in both studies and consisted of TMTX 110 mg/m2 intravenously (i.v.) followed 24 h later by i.v. LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. The 5-FU dose in the control arm was 600 mg/m2 in the European study and 500 mg/m2 in the USA study, and the USA study was placebo-controlled. Treatment was given weekly for 6 weeks every 8 weeks. ResultsA total of 746 patients were analysed. Median OS was 13.0 months for 5-FU/LV and 14.6 months for TMTX/5-FU/LV (P = 0.15; Wilcoxon). Median PFS was 4.4 months and 5.4 months, respectively (P = 0.07; Wilcoxon). ConclusionsThe addition of TMTX to a weekly regimen of 5-FU/LV does not improve the outcome for patients with ACC.

Trimetrexate as biochemical modulator of 5-fluorouracil/leucovorin in advanced colorectal cancer: final results of a randomised European study

BackgroundTrimetrexate (TMTX) is a biochemical modulator of 5-fluorouracil (5-FU) and leucovorin (LV). Phase II trials have shown promising activity of 5-FU/LV/TMTX in patients with advanced colorectal cancer (ACC). This trial evaluated the effect of TMTX in combination with 5-FU/LV as first-line treatment in ACC. Patients and methodsPatients with ACC were randomised to receive either intravenous LV 200 mg/m2/5-FU 600 mg/m2 or TMTX 110 mg/m2 followed 24 h later by LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumour response, quality of life (QoL) and toxicity. ResultsA total of 365 patients were randomised. A statistically significant prolongation of median PFS was seen in patients treated with TMTX/5-FU/LV compared with 5-FU/LV (5.4 months versus 4.1 months, respectively; P = 0.03), and a trend towards a significant benefit for OS (13.4 months versus 10.5 months, respectively; P = 0.08). Tumour response, QoL and toxicity were comparable between the two arms. Diarrhoea was the most frequently occurring grade 3 or 4 toxicity (22% and 30%, respectively). ConclusionsThe addition of TMTX to a weekly regimen of 5-FU/LV results in a small but significant improvement in PFS without adding toxicity or worsening QoL in patients with ACC.

Cisplatin-5-fluorouracil-leucovorin (PFL) as neoadjuvant therapy in patients with locally advanced squamous cell carcinoma of the head and neck. Results after long term follow-up

The objective of this study was to evaluate the activity, toxicity, and long-term survival of patients with locally advanced unresectable squamous cell carcinoma of the head and neck treated with neoadjuvant chemotherapy (cisplatin, 5-fluorouracil [5-FU] and leucovorin) followed by conventional radiation therapy.Twenty-six patients with stage III or IV squamous cell carcinoma of the head and neck were treated with four cycles of cisplatin 100 mg/m2, 5-FU mg/m2/day as a continuous infusion for five consecutive days, and oral leucovorin 120 mg/day for five days, administered every three weeks.After neoadjuvant treatment, patients underwent standard radiation therapy (50–70 Gy).The most remarkable toxic effects included mucositis (30.7%; grade: 3) and neutropenia (30.7%; grade: 3/4), although only one case of febrile neutropenia was recorded. Two toxic deaths were recorded. The major objective response achieved was 88.4% (23 patients), seven (26.9%) of which were complete. After local treatment, 57.7% of the patients achieved complete remission. With a mean follow-up of 50 months, the median period free of disease progression was 14 months, with a median overall survival of 20 months. The 2- and 4-year survival rates were 46.1% and 23%, respectively.In conclusion, these results seem to be no better than those reported with the traditional cisplatin plus 5-FU without leucovorin, although this issue can be clearly clarified only by carrying out randomized clinical trials.

The role of UFT and the combination of UFT/leucovorin in non-small cell lung cancer

Although 5-FU administered as a single agent in different intravenous bolus schedules has been shown to have minimal activity in non-small cell lung cancer (NSCLC), several lines of experimental evidence suggest that 5-FU in combination regimens may be synergistic with the ‘anchor’ drug of the combination. Moreover, the recent availability of oral formulations of 5-FU together with the ability to modulate the anabolic and catabolic metabolism of 5-FU with leucovorin and dihydropyrimidine dehydrogenase (DPD) inhibitors, respectively, may provide a substantial improvement in the ease of administration and the efficacy of fluoropyrimidine therapy. Several oral fluoropyrimidines are under investigation. Orzel [UFT (uracil:tegafur) plus oral leucovorin] is the first oral DPD-inhibitory fluoropyrimidine. Orzel administered daily achieves similar concentrations of 5-FU obtained with continuous-infusion 5-FU. This paper reviews the clinical experience with UFT and Orzel in the treatment of NSCLC.

A Phase II Trial of UFT-E and Oral Leucovorin in Advanced Colorectal Cancer.

To determine the efficacy and toxicity of UFT-E plus oral calcium leucovorin in the treatment of patients with advanced colorectal cancer. Forty-three patients with advanced, bidimensionally measurable colorectal adenocarcinoma were enrolled in the trial. No patients had received prior palliative chemotherapy. The patients that had received previous adjuvant chemotherapy were enrolled when more than 6 months had elapsed after the completion of adjuvant therapy. Patients were treated with 300 mg/m2/day of UFT-E (tegafur-based) plus 90 mg/day of leucovorin administered orally in three divided daily doses, every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two or three courses of therapy. Thirty-six of forty-three patients were evaluable for response; seven dropped out due to infection, toxicity and patients' refusal. Ten patients had partial responses and one patient complete response (response rate, 31%; 95% confidence interval, 16~46%). The median response duration for the UFT-E plus leucovorin regimen was 28 weeks. Grade III toxicity was seen in one case, with diarrhea. This oral regimen proved effective and well tolerated. This schema also avoided inconveniences, such as hospitalization and the use of infusion pumps, which are associated with 5-FU infusion regimens. The regimen used showed minimal toxicity, especially in the upper digestive tract, with good patient compliance.

Preoperative chemoradiotherapy with oral doxifluridine plus low-dose oral leucovorin in unresectable primary rectal cancer

Purpose: The use of oral chemotherapeutic agents in chemoradiotherapy provides several advantages. Doxifluridine, an oral 5-FU prodrug, has been shown to be effective in colorectal cancer. We attempted a Phase II trial of preoperative chemoradiotherapy with doxifluridine plus a low-dose oral leucovorin in unresectable primary rectal cancer patients. In this study, toxicity and efficacy were evaluated. Methods and Materials: There were 23 patients with primary unresectable rectal cancer in this trial, 21 of whom were available for analysis. The patients were treated with oral doxifluridine (900 mg/day) plus oral leucovorin (30 mg/day) from days 1 to 35, and pelvic radiation of 45 Gy over 5 weeks. Surgical resection was performed 5–6 weeks after the treatment. Results: Acute toxicity involved thrombocytopenia, nausea/vomiting, diarrhea, and skin reaction. All were in Grade 1/2, except diarrhea, which was not only the most frequent (7 patients, 33.3%), but also the only toxicity of Grade 3 (2 patients). The clinical tumor response was shown in 5 patients (23.8%) as a complete response and 13 patients (61.9%) as a partial response. A complete resection with negative resection margin was done in 18 patients (85.7%), in 2 of whom a pathologic complete response was shown (9.5%). The overall downstaging rate in the T- and N-stage groupings was 71.4% (15 patients). Conclusion: This study demonstrated the efficacy and low toxicity of chemoradiotherapy with doxifluridine. Currently, a Phase III randomized trial of chemoradiotherapy is ongoing at our institute to compare the therapeutic efficacy of oral 5-FU with respect to i.v. 5-FU in locally advanced and unresectable rectal cancer.

Tegafur and Uracil plus Leucovorin in Advanced Colorectal Cancer: A Phase II Trial

The objective of this study was to evaluate the activity and toxicity of tegafur and uracil (UFT; 1:4 molar ratio) plus leucovorin (LV) in patients with advanced colorectal cancer. One hundred forty-one patients were entered into the study. The treatment schedule consisted of UFT 300 mg/m 2/day (in three divided doses) plus oral LV 150 mg/day (50 mg t.i.d.) over 28 days. The treatment cycle was repeated every 5 weeks until progression or unacceptable toxicity was observed. The treatment was interrupted if grade 3/4 toxicity appeared and was resumed at the same dosage on recovery. One hundred thirty-six patients were evaluable for response and 141 were evaluable for toxicity. The response rate was 19.9% (95% confidence interval: 12%-28%). The total number of patients without progression (objective response + stable disease) was 76 (55.9%). The median time to progression was 5.6 months, and the overall survival was 11.6 months. The toxicity profile was low, with 11% of patients experiencing grade 3/4 nausea and vomiting, while 17% had grade 3/4 diarrhea. Oral administration of UFT modulated with LV is a comfortable regimen of chemotherapy for patients with advanced colorectal cancer.

Bioavailability and phase II study of oral UFT plus leucovorin in patients with relapsed or refractory colorectal cancer

Bioavailability and phase II study of oral UFT plus leucovorin in patients with relapsed or refractory colorectal cancer

UFT plus oral leucovorin calcium (Orzel) and radiation in combined modality therapy: a comprehensive review.

5-fluorouracil (5-FU) has become the most commonly used drug in combination with radiation therapy. The recent availability of oral formulations of 5-FU in conjunction with the ability to modulate the anabolic and catabolic metabolism of 5-FU with leucovorin and dihydropyrimidine dehydrogenase (DPD) inhibitors, respectively, may provide a substantial improvement in the ease of administration and the efficacy of fluoropyrimidine therapy. Several oral fluoropyrimidines are under investigation. UFT (uracil:tegafur) plus oral leucovorin (Orzel) is the first oral DPD-inhibitory fluoropyrimidine. With daily administration, Orzel achieves similar concentrations of 5-FU obtained with continuous-infusion 5-FU. This paper summarizes the therapeutic rationale for Orzel and reviews the clinical experience with UFT and UFT/LV in combined modality therapy regimens.

Current Status and Perspectives in Cancer Chemotherapy.

New anticancer drugs with novel structures including paclitaxel, docetaxel, ilinotecan and gemcitabine have shown significant activity against various solid tumors in phase II trials. Phase II trials of combination regimens containing these drugs are currently in progress. Some combinations such as paclitaxel pluscisplatin in ovarian cancer have shown superiority over the past standard regimen. Not surprisingly, several analogues of these drugs have been developed and currently phase II trials are in progress. ET-743 may has some hope to become thefirst anticancer drug from a marine product. Oral chemotherapy is useful for treatment of outpatients. A combination regimen of UFT plus oral leucovorin has shown equivalent activity to 5-fluorouracil and leucovorin in advanced colorectal cancer, and capecitabine has shown superior activity and less toxicity than 5-fluorouracil and leucovorin in advanced colorectal cancer. Monoclonal antibody therapy has been successful in patients with breast cancer overexpressing HER2 and in patients with B-cell lymphoma. Currently clinical trials of 17-1A for colorectal cancer and HUM195 for acute myelogeneous leukemia are in progress. Recently presented results of angiogenesis inhibitors are discussed.

Phase II study of radiochemotherapy with uft and low-dose oral leucovorin in patients with unresectable rectal cancer

Purpose: To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT) plus low-dose leucovorin administered concomitantly with pelvic irradiation in patients with unresectable or recurrent rectal cancer. Methods and Materials: Thirty-five patients (22 with primary unresectable tumors and 13 with locally recurrent tumors) were enrolled in the trial. Thirty-five patients were evaluable for toxicity and 32 of these were evaluable for clinical response. Patients received 300 mg/m 2/day UFT and 30 mg/day leucovorin on days 8–35 concomitantly with pelvic radiotherapy, to a total dose of 45 Gy. Results: Eight of the 35 (23%) patients developed Grade 3 diarrhea and were treated with radiotherapy alone after this event. Of the 22 patients with unresectable primary tumors, 17 underwent surgery, and resection was feasible in 15 cases (88%). Of the 32 patients evaluable for clinical response, 4 (13%) had a complete clinical response (CR) and 22 (69%) a partial response (PR). A complete pathologic response was observed in 3 cases (18%) and, a PR in 11 cases (65%). Conclusion: The response rates achieved with this schedule seem comparable to those obtained with 5-FU and radiotherapy. These results warrant further evaluation of this combination in patients with unresectable or locally advanced tumors.

Continuous infusion (CI) of 5-fluorouracil (5-FU) and oral leucovorin (LCV) in the treatment of metastatic breast cancer (MBC)

Continuous infusion (CI) of 5-fluorouracil (5-FU) and oral leucovorin (LCV) in the treatment of metastatic breast cancer (MBC)

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

As has been reported previously, leucovorin (LV) modulation increases the response rate of 5-fluorouracil (5-FU) in patients with advanced colorectal carcinoma, but overall survival does not appear to be modified significantly.1, 2 In an attempt to improve results in the treatment of such patients, several trials have been designed to test the efficacy of 5-FU administered as a continuous intravenous infusion. A recent meta-analysis shows a benefit for continuous compared with rapid infusion with regard to response rate with little increase in overall survival.3 According to pharmacokinetic studies,4 several investigators have tried to demonstrate the same effects using 5-FU as a protracted continuous infusion by the maintained oral administration of 5-FU derivatives such as tegafur or tegafur plus uracil (UFT). A majority of these Phase II trials are designed to include LV because they assume it can also be a potential modulator of tegafur or UFT.5-7 However, it remains unproven in prospective randomized trials whether the therapeutic benefit of LV is independent of the schedule of administration of 5-FU (rapid vs. protracted continuous infusion).8, 9 In the same way the results of treatment with maintained continuous infusion of 5-FU are not changed significantly by the concomitant administration of LV in a prospective comparative study; nevertheless, in this trial different doses of 5-FU are included and the schedule of LV is not standard (Table 1). 10 If we accept the validity of these results by assuming a similar effect for the protracted continuous infusion of 5-FU and oral tegafur or UFT, a possible conclusion is that before including LV we should first know the activity of tegafur or UFT alone in patients with advanced colorectal carcinoma. Subsequent studies must be aimed at assessing the effect of the simultaneous administration of LV and 5-FU. Eventually, prospective randomized trials should be designed to compare both tegafur or UFT with or without LV. Meanwhile, before adding other drugs to the regimen, we must select tegafur or UFT alone as the experimental arm for comparison with a rapid infusion 5-FU plus LV (standard therapy) in prospective controlled studies. Alvaro S. Rubiales M.D.*, M. Luisa del Valle M.D.*, * Oncology Department, Hospital Universitario de Valladolid, Valladolid, Spain

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer.

This review describes the early clinical development of uracil-ftorafur (UFT), an oral fluoropyrimidine, designed in 1978 by adding uracil to ftorafur. The review focuses on the treatment of colorectal cancer and summarizes the Japanese experience and the phase I and II trials performed in the United States and Europe. Clinical trials of UFT published in the Western world have included 581 patients with colorectal cancer. UFT has been administered in these trials as a single agent or biomodulated by leucovorin (LV). UFT was administered daily in split doses for periods that ranged from 14 to 28 days. The activity of oral UFT in large-bowel cancer when administered with oral LV (approximately 50 mg/dose) has resulted in objective response rates of approximately 40%. Response rates of approximately 25% (range, 17% to 39%) were reported when UFT was administered as a single agent or with lower doses of LV. The highest dose-intensities of UFT are achieved with 28-day schedules of administration. The maximum-tolerated dose (MTD) of UFT with this schedule, when administered concomitantly with oral LV 150 mg daily, is 300 mg/m2 daily. The dose-limiting toxicity (DLT) of UFT has generally been diarrhea. Other commonly described toxicities include nausea and vomiting, fatigue, and stomatitis. Myelosuppression occurs infrequently. Typically, hand-foot syndrome and neurologic toxicity are lacking. UFT is a fluoropyrimidine active in colorectal cancer. The oral route of administration and improved safety profile represent important advantages over both conventional and infusional fluorouracil (5-FU) regimens.

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced hepatocellular carcinoma

Although UFT 300 mg/m2/day and leucovorin 90 mg/day administered orally in divided doses administered every 8 hours for 28 days repeated every 35 days could be administered safely to patients with advanced hepatomas and good performance status, this combination and schedule has limited activity in treating advanced hepatoma. Biochemical modulation of 5-fluorouracil has yielded higher response rates in hepatoma when compared to treatment with 5-fluorouracil as a single agent, although the impact on survival has been negligible. This study was conducted to determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) plus oral calcium leucovorin in the treatment of patients with advanced hepatocellular carcinoma (hepatoma). Sixteen patients with advanced measurable hepatocellular carcinoma were enrolled onto the trial. All patients had a Karnofski performance status > or = 60%, platelet count > or = 75,000/micro L, total bilirubin < or = 2.0 x institutional upper limit of normal but otherwise normal liver and kidney function profile and bidimensionally measurable disease by CT or ultrasound examination. None of these patients received prior cytotoxic chemotherapy or radiation therapy for advanced disease. Fourteen patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days repeated every 35 days. Two patients registered for the trial but did not receive study medication. Objective tumor response, the primary purpose of this trial, was evaluated after two courses of therapy. Other end-points included toxicity, time to progression, and overall survival. Fourteen patients were evaluable for response and toxicity, respectively. No complete or partial responders were observed in this trial. Three patients had stable disease lasting 17 to 22 weeks. Toxicity was mild with severe (grade 3 or 4) liver pain, diarrhea, anorexia/nausea, fatigue, dyspnea, hyperbilirubinemia, anemia, and edema seen in 3 (21%), 2 (14%), 3 (21%), 2 (14%), 1 (7%), 1 (7%), 1 (7%) and 1 (7%) patients, respectively. The most frequent grade I and 2 toxic effects included fever of unknown origin, dyspnea, nausea, vomiting and diarrhea. UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate antitumor activity against advanced hepatomas. Further treatment using this regimen is not recommended for this disease.

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced pancreatic carcinoma: A University of Chicago phase II consortium study

Uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) has broad anti-tumor activity for cancers arising from the gastrointestinal tract. However, there are no published data regarding the efficacy of leucovorin-modulated UFT in patients with pancreatic cancer. The objective of this trial was to determine the activity and evaluate the toxicity of UFT plus oral calcium leucovorin in patients with advanced pancreatic adenocarcinoma. Fourteen patients with advanced measurable adenocarcinoma of the pancreas were enrolled onto the trial. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided doses every eight hours for 28 days repeated every 35 days. Objective tumor response was evaluated after two courses of therapy. Fourteen patients were evaluable for response and toxicity. No objective responses were seen. The median (range) time to progression and survival were 14 (1.6-37), and 15 (1.9-62) weeks, respectively. Toxicity was mild with severe (grade 3 or 4) hyperbilirubinemia, pain, diarrhea, transaminitis, venous thrombus, weakness, renal failure, confusion, and edema/ascites seen in three (21%), one (7%), two (14%), one (7%), one (7%), one (7%), one (7%), one (7%), and two (14%) patients, respectively. In the 14 patients evaluable, UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate anti-tumor activity against advanced pancreatic adenocarcinoma; however, this oral regimen was well tolerated and devoid of neutropenia, significant oral mucositis or diarrhea.

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma

Protracted oral administration of tegafur (TG) and leucovorin (LV) attempts to simulate the continuous infusion of 5-fluorouracil, with a higher intracellular folate pool. In a prior dose-finding study with a fixed TG dose of 0.75 g/m2/day for a period of 21 days and continuous oral LV, the recommended dose of LV was 45 mg/day in 28-day cycles. Thirty-nine patients with histologic confirmation of adenocarcinoma of the colon or rectum, either advanced or metastatic disease, and who were not candidates for radical treatment were included in a Phase II study using this schedule. One hundred sixty-three cycles of chemotherapy were delivered (median, 4 cycles per patient). Toxicity was observed in the form of diarrhea, which was severe in 12 patients (30.7%). Grade 3 (according to the World Health Organization criteria) oral mucositis was recorded in 7 patients (18%). Asthenia was severe in 10% of the patients. Recuperation from toxicity was rapid and managed primarily on an outpatient basis. Two complete (5.1%) and 13 partial (33.3%) responses were observed, with a global response index of 38.5% (95% confidence interval, 23.2-53.6%). The median overall survival was 11.3 months. The results of this study show that an all-oral regimen of tegafur and leucovorin can obtain biochemical modulation, with a significant response rate, in patients with advanced colorectal carcinoma. Randomized trials are needed to assess the possible advantage of this regimen over intravenous schedules.