Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study.

BACKGROUND: Eniluracil is a potent, irreversible inactivator of dihydropyrimidine dehydrogenase, the major catabolic enzyme for 5-fluorouracil (5-FU). Pretreatment with eniluracil significantly increases plasma half-life, plasma concentration and oral bioavailability of 5-FU. This multicenter phase II trial was designed to estimate the 6-month survival rate in patients with metastatic adenocarcinoma of the pancreas treated with 5-FU and eniluracil. PATIENTS AND METHODS: One hundred and sixteen patients (61 with no prior chemotherapy and 55 with prior chemotherapy) were registered for treatment with eniluracil 50 mg (total dose) p.o. on days 1-7 and 5-FU 20 mg/m(2)/day p.o. on days 2-6 of a 28-day treatment cycle. RESULTS: In 106 patients evaluable for survival, the 6-month survival rate was 34% [95% confidence interval (CI) 22% to 47%, median survival 3.6 months] for patients who had not been treated previously with chemotherapy and 29% (95% CI 16% to 42%, median survival 3.4 months) for those who had received prior chemotherapy. For those patients with measurable disease, the confirmed response rates were 8% and 2%, respectively. The most common grade 3-4 toxicities were neutropenia (29% of patients) and diarrhea (12% of patients). Overall, 69% of patients experienced a grade 3 or worse adverse event during treatment. CONCLUSIONS: These results suggest that the combination of a 7-day course of eniluracil and a 5-day course of oral 5-FU has limited activity in patients with advanced pancreatic cancer, and is associated with a high frequency of clinically significant adverse events.     

Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition.

PURPOSE: This study determined the effect of different weekly dosing schedules of 5-fluorouracil (5-FU)/leucovorin (LV)/eniluracil on dihydropyrimidine dehydrogenase (DPD) activity and plasma uracil levels. METHODS: Plasma and mononuclear cells were isolated from peripheral blood samples obtained before, during, and at various times after 5-FU/LV/eniluracil therapy. Two schedules were studied: 20 mg of eniluracil p.o. plus 30 mg of LV p.o. on days 1-3 with a single dose of 5-FU given day 2, or 30 mg of LV p.o. on days 1-2 with a single dose of eniluracil and 5-FU on day 2. DPD activity was determined with a radioisotopic enzyme assay; the reaction products were separated by high-performance liquid chromatography. Plasma uracil levels were determined by gas chromatography-mass spectroscopy. RESULTS: During oral therapy, DPD activity was profoundly depressed, and uracil levels were strikingly elevated with both schedules. With the daily-for-3-days schedule, DPD activity was similar to baseline values by 3 weeks after the earlier eniluracil dose, whereas it appeared to recover earlier in patients receiving the single-dose schedule, reaching baseline values by 2 weeks. Although baseline uracil values did not predict DPD activity accurately, plasma uracil levels >0.95 microM were associated with significantly lower DPD activity (median, 18.4 versus 287.6 pmol/min/mg). CONCLUSIONS: When eniluracil is given with 5-FU/LV, DPD inhibition appears to be influenced by schedule, and the time to recovery is much longer than has been observed with eniluracil given alone.     

Randomised study of tegafur and oral leucovorin versus intravenous 5-fluorouracil and leucovorin in patients with advanced colorectal cancer

This randomised, open-label trial compared oral tegafur (FT)/leucovorin (LV) with the intravenous bolus 5-fluorouracil (5-FU)/LV as first-line chemotherapy for advanced colorectal cancer (CRC). Patients were randomised to receive oral FT 750 mg/m2/day for 21 days and LV 15 mg/m2 every 8 h in cycles repeated every 28 days (n=114), or intravenous LV 20 mg/m2 followed by 5-FU 425 mg/m2 daily for 5 days every 4 weeks for 2 cycles, and later every 5 weeks (n=123). Response rate was significantly higher in the FT/LV arm (27%, 95% CI 19-35) than in the 5-FU/LV arm (13%, 95% CI 7-19) (p<0.004). The median time to progression was 5.9 months (95% CI, 5.3-6.5; FT/LV arm) and 6.2 months (95% CI, 5.4-6.9; 5-FU/LV arm). Median overall survival was 12.4 months (95% CI, 10.3-14.5 months; FT/LV arm) and 12.2 months (95% CI, 8.9-15.7 months; 5-FU/LV arm) (p=n.s.; hazard ratio FT/LV:5-FU/LV=1.02). 5-FU/LV showed a higher incidence of grade 3/4 neutropenia (4.1 vs. 0%). Non-hematological toxicities showed similar incidences in the two treatment arms. Oral FT/LV was more active than IV 5-FU/LV in terms of objective response rate with similar overall survival, and with a favorable toxicity profile. This makes FT/LV a valid alternative to the IV 5-FU schedule in CRC patients.     

Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors.

PURPOSE: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule. PATIENTS AND METHODS: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m(2) on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m(2) PO bid on day 2). RESULTS: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m(2) PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m(2) PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. CONCLUSION: The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.     

Paclitaxel, 5-fluorouracil, and cisplatin combination chemotherapy for the treatment of advanced gastric carcinoma

BACKGROUND: Although the clinical efficacy of paclitaxel in the treatment of gastric carcinoma has not been clearly defined, recent reports have suggested a possible role in the treatment of upper gastrointestinal carcinomas in vitro and in vivo. In this study, the authors evaluated the efficacy and toxicity of a combination chemotherapy that included paclitaxel, 5-fluorouracil (5-FU), and cisplatin in the treatment of patients with advanced gastric carcinoma. METHODS: Forty-one gastric carcinoma patients with metastatic disease, unresectable advanced disease, or relapsed disease were treated with the following regimen, administered every 28 days: paclitaxel 175 mg/m2 by 3-hour intravenous (i.v.) infusion on Day 1, 5-FU 750 mg/m2 by 24-hour continuous i.v. infusion on Days 1-5, and cisplatin 20 mg/m2 by 2-hour i.v. infusion on Days 1-5. Twenty-six patients had measurable disease, and 15 had evaluable disease. All patients were assessable for toxicity. RESULTS: Twenty-one of the 41 patients (51%; 95% confidence interval [CI], 36.5-65.7%) demonstrated an objective response, including 4 complete responses (10%; 95% CI, 3.9-22.5%). Sixty-five percent of the patients with measurable disease (17 of 26; 95% CI, 58-92.5%) and 27% of the patients with evaluable disease (4 of 15: 95% CI, 11.1-52.3%) achieved a complete response or a partial response. The median response duration was 17 weeks (range, 4-90 weeks), and the median survival duration for all patients was 26 weeks (range, 8 to 118+ weeks). The major toxicity of this treatment was myelosuppression with neutropenia of World Health Organization Grade 3 and 4 in 24% and 10% of the patients, respectively. Nonhematologic toxicity included mucositis, nausea/vomiting, diarrhea, neurotoxicity, and alopecia. Fluid retention occurred in two patients, and one patient had an anaphylatic reaction. Dose reduction was necessary for one patient, because Grade 4 neutropenia and mucositis occurred. CONCLUSIONS: Paclitaxel, 5-FU, and cisplatin was an active combination regimen in the treatment of advanced gastric carcinoma. The toxicity of this regimen was tolerable. Based on these findings, this combination regimen could be an attractive treatment in the preoperative setting.     

Phase I study of eniluracil, a dihydropyrimidine dehydrogenase inactivator, and oral 5-fluorouracil with radiation therapy in patients with recurrent or advanced head and neck cancer.

5-Fluorouracil (5-FU) is an effective enhancer of radiation therapy (RT) in head and neck cancers. Due to rapid, predominantly hepatic metabolism by dihydropyrimidine dehydrogenase (DPD) and suggested clinical benefit from prolonged drug exposure, 5-FU is commonly given by continuous infusion. Eniluracil is a novel DPD-inactivator designed to prolong the half-life of 5-FU and provide sustained plasma concentrations of 5-FU with oral dosing. We conducted a Phase I study of the safety and efficacy of eniluracil given with oral 5-FU in patients receiving concurrent RT for recurrent or advanced squamous cell carcinomas of the head and neck. Thirteen patients with recurrent, metastatic, or high-risk (defined as an expected 2-year survival rate of <10%) head and neck cancer were enrolled and treated with concomitant chemoradiotherapy on an every-other-week schedule. Eniluracil at a fixed dose [20 mg twice a day (BID)] was given for 7 consecutive days (days 1-7). 5-FU and RT were given on 5 consecutive days (days 2-6). One patient was treated with once-daily RT (2.0 Gy fractions). The remaining patients received hyperfractionated RT (1.5-Gy fractions BID). The initial dose of 5-FU was 2.5 mg/m2 given BID. Dose escalation in patient cohorts was scheduled at 2.5-mg/m2 increments, with intrapatient dose escalation permitted. Lymphocyte DPD activity and serum 5-FU and uracil concentrations were monitored during two cycles. DPD activity was completely or nearly completely inactivated in all patients. Sustained, presumed therapeutic concentrations of 5-FU were observed at a dose of 5.0 mg/m2 given BID. Cumulative dose-limiting myelosuppression (both neutropenia and thrombocytopenia) was observed during the fourth and fifth cycles following administration of 5.0 mg/m2 5-FU BID. One patient died of neutropenic sepsis during cycle 4. Other late cycle toxicities included diarrhea, fatigue, and mucositis. Grade 3 mucositis was observed in 4 patients, but no grade 4 mucositis or grade 3 or 4 dermatitis was observed. A second patient death occurred during cycle 1 of treatment. No specific cause of death was identified. The study was subsequently discontinued. Cumulative myelosupression was the significant dose-limiting toxicity of oral 5-FU given with the DPD-inactivator eniluracil on an every-other-week schedule. Clinical radiation sensitization was not observed, based on the absence of dose-limiting mucositis and dermatitis. Alternative dosing schedules need to be examined to determine the most appropriate use of eniluracil and 5-FU as radiation enhancers.     

Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer.

PURPOSE: To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m(2)/1.15 mg/m(2) twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m(2)/20 mg/m(2) once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point. RESULTS: A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P =.01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P =.354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients. CONCLUSION: Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.     

Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors.

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m(2) BID for 7 days) during the first study period, followed by 5-FU (300 mg/m(2) CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary alpha-fluoro-beta-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for > or = 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean +/- SD steady-state plasma concentration (C(P)) and area under the curve (AUC)(144-168h) for CVI 5-FU (104 +/- 45 ng/mL and 2,350 +/- 826 ng x h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 +/- 7.7 ng/mL and 722 +/- 182 ng x h/mL, respectively [P <.00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C(P) and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.     

Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial

BACKGROUND: Gemcitabine has broad activity in a variety of solid tumors including biliary tract carcinomas. The authors evaluated 6-month survival, response, and toxicity associated with a combination of gemcitabine, 5-fluorouracil (5-FU), and leucovorin (LV) in patients with unresectable or metastatic biliary tract or gallbladder adenocarcinoma (ACA). METHODS: A 4-week course included 1000 mg/m2 gemcitabine by intravenous infusion over 30 minutes on Days 1, 8, and 15, 25 mg/m2 LV by intravenous push, and 600 mg/m2 5-FU by intravenous push after LV. RESULTS: Forty-two patients were enrolled in 6 months, 35 of whom had metastatic disease. Patients with biliary tract ACA included 24 with hepatic disease (19 patients had intrahepatic disease and 5 patients had extrahepatic disease) and 4 with disease in the ampulla of Vater. All patients were evaluable and received a median of 4 courses of treatment (range, 1-21 courses). Commonly occurring severe toxicity (NCI CTC Grade 3 or worse) included: dyspnea (four patients), nausea (four patients), fatigue (seven patients), thrombocytopenia (six patients), emesis (four patients), and diarrhea (four patients). Five partial responses (9.5%) occurred, 3 of which were sustained for > or = 8 weeks. No treatment-related deaths occurred. Thirty-two patients had disease progression and 38 died after a median follow-up of 20 months (range, 1.4-24 months). The median time to disease progression was 4.6 months (95% confidence interval [95% CI], 2.4-6.6%). The median survival period was 9.7 months (95% CI, 7-12%). CONCLUSIONS: This combination regimen was manageable in patients with advanced biliary tract and gallbladder ACA. Of 42 patients, 24 (57%) survived > or = 6 months, satisfying the primary end point of the trial. The length of survival suggested that gemcitabine, 5-FU, and LV had benefit equivalent to gemcitabine alone.     

Phase I study to evaluate multiple regimens of intravenous 5-fluorouracil administered in combination with weekly gemcitabine in patients with advanced solid tumors: a potential broadly active regimen for advanced solid tumor malignancies.

BACKGROUND: The purpose of this study was to determine the maximum tolerated dose and toxicity profile of gemcitabine given on a weekly schedule with continuous infusion 5-fluorouracil. PATIENTS AND METHODS: Eligible patients with advanced solid tumors received escalating doses of gemcitabine 200 and 300 mg/m(2) weekly as a 30-minute infusion on Days 1, 8, and 15 every 4 weeks (schedule 1) or 450, 600, 800, 1000, 1250, 1500, 1800, and 2200 mg/m(2) on Days 1 and 8 (schedule 2) every 3 weeks, respectively. At the completion of gemcitabine infusion (Day 1), patients received fixed dose continuous infusion of 5-fluorouracil at either 300 mg/m(2) (Days 1-21) or 200 mg/m(2) (Days 1-21; schedule 1) every 4 weeks or 200 mg/m(2) (Days 1-14; schedule 2] every 3 weeks, respectively. Toxicity assessments were performed weekly on study, and efficacy measurements were performed every 6-8 weeks. RESULTS: Seventy patients with advanced solid malignancies received a total of 220 cycles of combination chemotherapy. Eleven (14.3%) patients received no more than 1 treatment cycle of combination therapy. Schedule 1 maximum tolerated dose of gemcitabine was 600 mg/m(2)/week when combined with 5-fluorouracil (5-FU) at 200 mg/m(2)/day (Days 1-21) repeated every 4 weeks. The schedule 2 maximum tolerated dose of gemcitabine was 2200 mg/m(2)/week when combined with 5-FU dosed at 200 mg/m(2)/day (Days 1-14) repeated every 3 weeks. In schedule 1, the limiting factor for gemcitabine delivery was the Day 15 dose that often was omitted because of myelosuppression and/or mucositis. In schedule 1 cycle 1, nonhematologic toxicity was common and included Grade 3-4 toxicities: mucositis (8 patients), fatigue (2 patients), and anorexia (1 patient). One patient had Grade 3-4 neutropenia at dose level 5 (maximum tolerated dose). In schedule 2 cycle 1, hematologic toxicities were more common than nonhematologic toxicity and included Grade 3 anemia (3 patients), Grade 3 neutropenia (4 patients), and Grade 3 thrombocytopenia (2 patients). The nonhematologic toxicities included Grade 3 mucositis (3 patients), Grade 3 fatigue (2 patients), and Grade 3 dehydration (1 patient). Overall, antitumor activity was observed in seven patients. Three of 30 patients with cytokine refractory renal cell carcinoma (RCC; relative risk [RR] 10 %; 95% confidence interval [CI], 0.82-22%) had a partial response. Of the remaining 27 patients with RCC, 4 patients had a minor response, and 10 patients had stable disease lasting a median of 6.4 (range, 4-12) months. The remaining 5 responses occurred in 40 patients (RR, 12.5%; 95% CI, 4.2-26.8%): 2 patients with 5-FU refractory colon carcinoma, 1 patient with hepatoma, 1 patient with paclitaxel-cisplatin-resistant ovarian carcinoma, and 1 patient with cisplatin-resistant head and neck squamous cell carcinoma had a partial response. CONCLUSIONS: For Phase II development, gemcitabine 450-600 mg/m(2) on Days 1, 8, and 15 can be safely combined with 5-FU 200 mg/m(2) given as a continuous infusion (Days 1-21) of a 28-day cycle or gemcitabine 1800 mg/m(2) Days 1 and 8 given with 5-FU 200 mg/m(2) as a continuous infusion (Days 1-14) of a 21-day cycle. The observed antitumor activity in several solid tumors, especially in renal cell carcinoma, warrants broad Phase II evaluation.     

Capecitabine plus oxaliplatin for the first-line treatment of elderly patients with metastatic colorectal carcinoma: final results of the Southern Italy Cooperative Oncology Group Trial 0108

BACKGROUND: In patients with metastatic colorectal carcinoma (MCC), capecitabine has demonstrated a superior response rate (RR), equivalent disease progression-free (PFS) and overall survival (OS), and an improved overall tolerability profile compared with bolus 5-fluorouracil/leucovorin (5-FU/LV). The FOLFOX4 regimen, combining oxaliplatin with LV and bolus plus infusional 5-FU (LV5FU2), has been shown to improve RR and PFS versus LV5FU2, and it was more effective and less toxic than irinotecan plus bolus 5-FU/LV. Capecitabine (an oral fluoropyrimidine) may be an effective, well tolerated, and more convenient alternative to 5-FU/LV in combination with oxaliplatin, especially in older patients. METHODS: Elderly (> or = 70 years) patients with MCC were treated with a 3-weekly regimen of oxaliplatin at an initial dose of 85 mg/m(2) intravenously on Day 1 plus capecitabine 1000 mg/m(2) orally twice daily from Days 2 to 15 (XELOX regimen). In the absence of Grade > or = 2 hematologic toxicity, oxaliplatin was increased to 100 mg/m(2) in the second cycle, and in the absence of Grade > or = 2 nonhematologic adverse events during Cycle 2, capecitabine was increased to 1250 mg/m(2) twice daily in the third and subsequent cycles. After the first 35 patients (first series), the treatment protocol was amended so that only an oxaliplatin increase to 110 mg/m(2) and 130 mg/m(2) during Cycles 2 and 3, respectively, was planned in the remaining 41 patients (second series). RESULTS: Seventy-six patients with a median age of 75 years (range, 70-82 years) entered the current study. In the first series, the oxaliplatin dose was increased in 18 (51%) patients, and the capecitabine dose was increased in 4 (11%) patients. In the second series, the oxaliplatin dose was increased to 110 mg/m(2) in 26 (63%) patients, and to 130 mg/m(2) in 19 (46%) patients. In all, 2 complete and 29 partial responses were observed, for an overall RR of 41% (95% confidence interval [CI], 30-53%). The median PFS was 8.5 months (95% CI, 6.7-10.3 months), and the median OS was 14.4 months (95% CI, 11.9-16.9 months). In a multivariate analysis, the presence of disease symptoms affected both PFS and OS, whereas OS also was independently affected by male gender and disease spread. Age had no independent effect on PFS or OS. Five percent of patients developed Grade > or = 3 hematologic toxicity during treatment, Grade 3 peripheral neuropathy occurred in 8% of patients, and severe hand-foot syndrome in 13% of patients. CONCLUSIONS: Fit elderly patients with MCC showed a good RR to XELOX with only mild toxicity observed in most patients. XELOX, should, therefore be considered as an important therapeutic option for elderly patients with MCC.     

A phase II trial of oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma

Only a minority of patients with hepatocellular carcinoma (HCC) may benefit from curative treatments, whereas there is no standard therapy for the remaining patients. The objective of this multicentre, open label phase II study was to estimate the objective tumour response rate of a 28-day regimen of oral eniluracil/5-fluorouracil (5-FU) in patients with chemotherapy-naı̈ve, or anthracycline-refractory, inoperable HCC. 45 patients received courses of twice daily oral 5-FU (1.0 mg/m²) and eniluracil (10 mg/m²) for the first 28 days of each 5-week course. Patients were assessed at regular intervals to determine the tumour response and to evaluate toxicity. Patients were followed-up for a minimum of 6 months. No patient showed a partial or complete tumour response, and 18 patients (40%) had a best response of stable disease (95% confidence interval (CI) 25%, 55%). The median duration of progression-free survival (PFS) was 13.7 weeks (95% CI 10.0–20.0 weeks), and the median duration of overall survival (OS) was 50.3 weeks (range 1.1–64.1+ weeks). The combination of eniluracil/5-FU was well tolerated and had an acceptable safety profile. Only 7 patients (16%) reported at least one adverse event (AE) of grade 3 or 4 intensity considered reasonably attributable to the study medication. In conclusion, oral eniluracil/5-FU had minimal, if any, activity in patients with inoperable HCC, but the safety profile was acceptable.     

A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer.

BACKGROUND: We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of protracted venous infusion (PVI) 5-fluorouracil (5-FU) against the standard bolus monthly regimen of 5-FU/leucovorin (LV) given for 6 months as adjuvant treatment in colorectal cancer (CRC). PATIENTS AND METHODS: Patients with curatively resected stage II and III CRC were randomly assigned to 5-FU/LV [5-FU 425 mg/m(2) intravenously (i.v.) and LV 20 mg/m(2) i.v. bolus days 1-5 every 28 days for 6 months] or to PVI 5-FU (300 mg/m(2)/day for 12 weeks). RESULTS: Between 1993 and 2003, 801 eligible patients were randomised to 5-FU/LV (n=404) or PVI 5-FU (n=397). With a median follow-up of 5.3 years, 231 relapses and 220 deaths have been observed. Five-year relapse-free survival (RFS) was 66.7% [95% confidence interval (CI) 61.6% to 71.3%] and 73.3% (95% CI 68.4% to 77.6%) with bolus 5-FU/LV and PVI 5-FU, respectively [hazard ratio (HR) 0.8; 95% CI 0.62-1.04; P=0.10]. Five-year overall survival (OS) was 71.5% (95% CI 66.4% to 75.9%) and 75.7% (95% CI 70.8% to 79.9%) with bolus 5-FU/LV and PVI 5-FU, respectively (HR 0.79; 95% CI 0.61-1.03; P=0.083). There was a significant survival advantage for patients starting adjuvant chemotherapy within 8 weeks (P=0.044). Significantly less diarrhoea, stomatitis, nausea and vomiting, alopecia, lethargy, and neutropenia (all with P <0.0001) were seen with PVI 5-FU. CONCLUSIONS: There was no OS difference between the two arms, although PVI 5-FU was associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, as well as significantly less toxicity. Based on our results, the probability of 12 weeks of PVI 5-FU being inferior to 6 months of bolus 5-FU/LV is extremely low (P <0.005), and therefore shorter duration of adjuvant treatment should be explored further.     

Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies

Background:This study was performed to evaluate thepharmacokinetics, bioequivalence, and feasibility of a combined oralformulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc.,Research Triangle Park, North Carolina), an inactivator of dihydropyrimidinedehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FUformulation oral dosing form is to simplify treatment with these agents, whichhas been performed using separate dosing forms, and decrease the probabilityof severe toxicity and/or suboptimal therapeutic results caused byinadvertently high or conversely insufficient 5-FU dosing. Patients and methods:The trial was a randomized, three-waycrossover bioequivalence study of three oral dosing forms of eniluracil/5-FUtablets in adults with solid malignancies. Each period consisted of two daysof treatment and a five- to seven-day washout phase. Eniluracil at a dose of20 mg, which results in maximal DPD inactivation, was administered twice dailyon the first day and in the evening on the second day of each of the threetreatments. On the morning of the second day, all patients received a totaleniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as eitherseparate tablets (treatment A) or combined eniluracil/5-FU tablets in twodifferent strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). Thepharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinaryexcretion of eniluracil, 5-FU, uracil, and -fluoro--alanine (FBAL),were studied. To determine the bioequivalence of the combined eniluracil/5-FUdosing forms compared to the separate tablets, an analysis of variance onpharmacokinetic parameters reflecting eniluracil and 5-FU exposure wasperformed. Results:Thirty-nine patients with advanced solid malignancies hadcomplete pharmacokinetic studies performed during treatments A, B, and C. Thepharmacokinetics of eniluracil and 5-FU were similar among the three types oftreatment. Both strengths of the combined eniluracil/5-FU dosing form and theseparate dosing forms were bioequivalent. Mean values for terminal half-life,systemic clearance, and apparent volume of distribution for oral 5-FU duringtreatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and50.7/51.5/50.0 liters, respectively. The intersubject coefficient of variationfor pharmacokinetic variables reflecting 5-FU exposure and clearance intreatments ranged from 23% to 33%. The urinary excretion ofunchanged 5-FU over 24 hours following treatments A, B, and C averaged52.2%, 56.1%, and 50.8% of the administered dose of 5-FU,respectively. Parameters reflecting DPD inhibition, including plasma uraciland urinary FBAL excretion following treatments A, B, and C were similar.Toxicity was generally mild and similar following all three types oftreatments. Conclusions:The pharmacokinetics of 5-FU and eniluracil weresimilar and met bioequivalence criteria following treatment with the separateoral formulations of 5-FU and eniluracil and two strengths of the combinedformulation. The availability of a combined eniluracil/5-FU oral dosing formwill likely simplify dosing and decrease the probability of severe toxicityor suboptimal therapeutic results caused by an inadvertent 5-FU overdose orinsufficient 5-FU dosing in the case of separate oral formulations, therebyenhancing the overall feasibility and therapeutic index of oral 5-FU therapy.     

The prognostic significance of thymidylate synthase and dihydropyrimidine dehydrogenase in colorectal cancer of 303 patients adjuvantly treated with 5-fluorouracil

Cytotoxic effect of 5-fluorouracil 5-FU is mediated through inhibition of thymidylate synthase (TS), and 5-FU is catabolised by dihydropyrimidine dehydrogenase (DPD). Efficacy of 5-FU may therefore depend on the TS and DPD activity of colorectal cancer. Archival tumour specimens from 303 consecutive patients were analysed for the expression of TS and DPD using immunohistochemistry. All patients were completely resected for colorectal cancer stages II-III and have subsequently received adjuvant treatment with 5-FU. In a multivariate analysis adjusting for the impact of bowel obstruction and vascular tumour invasion, diffuse TS pattern was significantly associated with increased risk of recurrence (hazard ratio (HR) = 1.9; 95% confidence interval (CI): 1.1-3.2; p = 0.02), but without significant association to death (HR = 1.6; 95% CI: 0.9-2.8; p = 0.08). High TS intensity was not significantly associated with lower risk of recurrence (HR = 0.6; 95% CI: 0.3-1.1; p = 0.07) or death (HR = 0.6; 95% CI: 0.3-1.2; p = 0.2). High DPD intensity was significantly associated with increased risk of recurrence (HR = 1.5; 95% CI: 1.1-2.3; p = 0.03) and death (HR = 1.6; 95% CI: 1.1-2.5; p = 0.02). Patients with a combination of low TS and high DPD intensity were at significantly increased risk of both recurrence (HR = 2.1; 95% CI: 1.0-4.2; p = 0.04) and death (HR = 2.0; 95% CI: 1.0-4.0; p = 0.05). No relationship between tolerability and toxicity of 5-FU and TS and DPD expression was found. It is concluded that characterizing colorectal carcinomas by TS and DPD expression may disclose subsets of patients with significantly greater risk of disease recurrence and early death. This may be utilized in the selection of patients for treatment approaches and for decision on follow-up programs.     

Oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma.

BACKGROUND: Conventional systemic chemotherapy currently available for patients with inoperable hepatocellular carcinoma is ineffective. The purpose of this study was to evaluate the safety and efficacy of eniluracil/5-fluorouracil (5-FU) in the treatment of patients with this highly refractory disease. PATIENTS AND METHODS: This multicenter, open-label study evaluated a 28-day oral regimen of 5-FU (1 mg/m2 twice daily) plus the dihydropyrimidine dehydrogenase inhibitor, eniluracil (10 mg/m2 twice daily), in patients with chemotherapy-naive or anthracycline-refractory inoperable hepatocellular carcinoma. RESULTS: A total of 36 patients enrolled into the study. No patient showed a confirmed partial or complete tumor response, although nine patients (25%) had a best response of stable disease. The median duration of progression-free survival was 9.6 weeks [95% confidence interval (CI) 9.1-10.6 weeks], and the median duration of overall survival was 32.7 weeks (95% CI 17.4-71.6 weeks). Eniluracil/5-FU was well tolerated. Diarrhea, the most frequent treatment-related non-hematological toxicity, occurred in 11 patients (31%). Hematological toxicities were infrequent and usually mild. CONCLUSIONS: Eniluracil/5-FU as a 28-day oral outpatient regimen is well tolerated by patients with inoperable hepatocellular carcinoma, although minimal activity was observed when given as monotherapy at the dose used in this study.     

Phase II trial of a biweekly regimen of fluorouracil and leucovorin plus irinotecan in patients with previously untreated advanced gastric cancer

To investigate the therapeutic value and safety of the biweekly regimen of 5-fluorouracil (5-FU) and leucovorin (LV) plus irinotecan (CPT-11) in patients with previously untreated advanced gastric cancer (AGC). A total of 50 patients (M/F 35/15; median age = 65) with AGC, none of whom had received chemotherapy for advanced disease, were accrued in this trial. Fifteen patients (30%) were 70 years old or older. At the time of their accrual, cytotoxic chemotherapy, consisting of LV 100 mg/m(2) (2-hour i.v. infusion) followed by 5-FU 400 mg/m(2) (bolus) and 5-FU 600 mg/m(2) (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m(2) (1-hour infusion) on day 1, was initiated. Treatment courses were repeated every 2 weeks until evidence of progressive disease, unacceptable toxicity or withdrawal of consent. All patients were assessable for toxicity and 48 of 50 for response evaluation, having completed at least four courses of chemotherapy. Complete response was achieved in 2 patients (4%, intent to treat) and partial response in 16 (32%) (overall response rate, 36%; 95% confidence interval [CI]: 22%-50%). Twenty-four patients (48%) had stable disease and 6 patients (16%) progressed. The median time to progression was 8 months (95% CI: 6-10 months) and median overall survival 14 months (95% CI: 6-22 months). Between the subgroups of patients <70 years old and 70 or older, there were no significant differences in efficacy. One toxic death occurred. Treatment tolerance was generally mild to moderate and easy to treat. The main grade 3/4 toxicities were neutropenia (32%), diarrhea (16%), and anemia (8%). Grade 3-4 neutropenia was the only treatment-related serious adverse event significantly more common in patients older than those aged <70 (53.3% vs 22.8%, respectively; P = 0.03). Our data suggest that the biweekly regimen of LV and 5-FU plus CPT-11 in untreated patients with AGC is active and has an acceptable safety profile. Further evaluation of this regimen seems to be warranted in a phase III trial.     

Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: a randomised, multicentre phase II study.

BACKGROUND: We have investigated the efficacy, safety and quality of life profiles of three therapeutic combinations [irinotecan + leucovorin (LV)/5-fluorouracil (5-FU), oxaliplatin + LV/5-FU and irinotecan +oxaliplatin] in patients with metastatic colorectal cancer after failure of a 5-FU-based regimen, or whose disease had progressed within 6 months of the end of treatment. PATIENTS AND METHODS: One hundred and one patients were randomised to receive either: (i) irinotecan 180 mg/m(2) on day 1 followed by an LV 200 mg/m(2) infusion, before a 5-FU 400 mg/m(2) bolus followed by a 5-FU 600 mg/m(2) infusion (LV5FU2 regimen), on days 1 and 2 every 2 weeks; (ii) oxaliplatin 85 mg/m(2) on day 1 followed by the LV5FU2 regimen on days 1 and 2 every 2 weeks; or (iii) oxaliplatin 85 mg/m(2) followed by irinotecan 200 mg/m(2), both on day 1 every 3 weeks. The primary end point was overall response rate (ORR). RESULTS: The intention-to-treat ORRs were 11.4% [95% confidence interval (CI) 3.2-26.7), 21.2% (95% CI 9.0-38.9) and 15.2% (95% CI 5.1-31.9), respectively, in the three arms. Tumour growth control was >or=60% for all three combinations and overall survivals were 12.2 months (95% CI 9.2-16.0), 11.5 months (95% CI 9.0-14.1) and 11.0 months (95% CI 8.1-12.2), respectively. All patients were evaluable for safety. Main grade 3-4 toxicity was neutropenia (33 to 39% of patients). CONCLUSIONS: Thus, second-line treatment with irinotecan/LV5FU2, oxaliplatin/LV5FU2 or irinotecan/oxaliplatin, provides good tumour growth control and survival coupled with an acceptable safety profile.     

Phase II study of tailored chemotherapy for advanced colorectal cancer with either 5-fluouracil and leucovorin or oxaliplatin and irinotecan based on the expression of thymidylate synthase and dihydropyrimidine dehydrogenase.

BACKGROUND: Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are essential enzymes for 5-fluorouracil (5-FU) metabolism. In patients with advanced colorectal cancer (ACRC), retrospective studies have shown that low expression levels of TS and DPD correlated with response to 5-FU. We performed a prospective study in which the choice of first-line chemotherapy with either 5-FU or a non-5-FU containing regimen was based on TS and DPD expression. PATIENTS AND METHODS: Fresh-frozen samples of metastases were obtained from 58 previously untreated patients with ACRC. mRNA expression of TS and DPD was quantified using an RT-PCR assay. Patients with low tumor expression of both TS and DPD received weekly bolus 5-FU/leucovorin (LV) 500 mg/m2 (group A); patients with high TS and/or DPD received 3-weekly oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 (group B). After progression, cross-over to the alternative regimen was attempted. RESULTS: Of 53 eligible patients, 31 had tumors with both low TS and low DPD, and were treated in group A. A response was observed in 11 patients [35%; 95% confidence interval (CI) 19% to 54%]. Cross-over to second-line oxaliplatin/irinotecan resulted in a partial response in two out of 16 patients (13%; 95% CI 1% to 38%). In group B, four out of 22 patients responded (18%; 95% CI 5% to 40%), while no responses were observed in 12 patients after cross-over to 5-FU/LV (0%; 95% CI 0% to 28%). CONCLUSIONS: Prospective selection of 5-FU/LV chemotherapy based on low TS and DPD expression in patients with ACRC did not confirm the high response rates reported in retrospective studies. The procedure of obtaining metastatic tissue and quantitation of enzymes appeared feasible but cumbersome. Before assessing the clinical utility of a predictive marker in a randomized trial, future studies should focus on prospective validation of the assay in a large and well defined population.     

Diagnosis and Treatment of Chronic Prostatitis Caused by Chlamydia trachomatis

Abstract

To investigate the therapeutic value and safety of the biweekly regimen of 5-fluorouracil (5-FU) and leucovorin (LV) plus irinotecan (CPT-11) in patients with previously untreated advanced gastric cancer (AGC). A total of 50 patients (M/F 35/15; median age = 65) with AGC, none of whom had received chemotherapy for advanced disease, were accrued in this trial. Fifteen patients (30%) were 70 years old or older. At the time of their accrual, cytotoxic chemotherapy, consisting of LV 100 mg/m² (2-hour i.v. infusion) followed by 5-FU 400 mg/m² (bolus) and 5-FU 600 mg/m² (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m² (1-hour infusion) on day 1, was initiated. Treatment courses were repeated every 2 weeks until evidence of progressive disease, unacceptable toxicity or withdrawal of consent. All patients were assessable for toxicity and 48 of 50 for response evaluation, having completed at least four courses of chemotherapy. Complete response was achieved in 2 patients (4%, intent to treat) and partial response in 16 (32%) (overall response rate, 36%; 95% confidence interval [CI]: 22%-50%). Twenty-four patients (48%) had stable disease and 6 patients (16%) progressed. The median time to progression was 8 months (95% CI: 6-10 months) and median overall survival 14 months (95% CI: 6-22 months). Between the subgroups of patients <70 years old and 70 or older, there were no significant differences in efficacy. One toxic death occurred. Treatment tolerance was generally mild to moderate and easy to treat. The main grade 3/4 toxicities were neutropenia (32%), diarrhea (16%), and anemia (8%). Grade 3-4 neutropenia was the only treatment-related serious adverse event significantly more common in patients older than those aged ≤70 (53.3% vs 22.8%, respectively; P = 0.03). Our data suggest that the biweekly regimen of LV and 5-FU plus CPT-11 in untreated patients with AGC is active and has an acceptable safety profile. Further evaluation of this regimen seems to be warranted in a phase III trial.