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PubMed1986

A randomized trial of two regimens of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone in advanced breast cancer.

One-hundred evaluable patients with progressive advanced breast carcinoma untreated by cytotoxic chemotherapy but resistant to hormone therapy and irradiation were randomly allocated to receive either a combination of cyclophosphamide (600 mg/m2), methotrexate (40 mg/m2), 5-fluorouracil (600 mg/m2) IV every 3 weeks and prednisone 20 mg/m2 PO daily, with diminishing doses (intermittent group), or a combination of cyclophosphamide (100 mg/m2 PO on days 1-15, alternating with a 15-day rest period), methotrexate 20 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV weekly for 20 weeks and prednisone 20 mg/m2 PO daily, with diminishing doses in the remission induction period, followed by a maintenance regimen of cyclophosphamide 100 mg/m2 PO on days 1-15, methotrexate 20 mg/m2 IV on days 1, 8 and 15, 5-fluorouracil 500 mg/m2 IV on days 1, 8, and 15, and prednisone 20 mg/m2 PO on days 1-15, with a 3-week rest period between the courses (intensive group). Entry was from 1 December 1982 to 30 November 1983. Objective responses were seen in 20/49 (41%) patients in the intermittent group and 34/51 (67%) in the intensive group (chi 2 = 6.72; P less than 0.01). The estimated median duration of response was 11 months in the intermittent group and 14 months in the intensive group. The estimated median survival was greater in the intensive group, but the difference was not statistically significant, although this parameter can be influenced with alternative additional chemotherapy. Toxicity was similar in both groups. These data suggest there are no therapeutic and survival advantages to the 3-weekly IV protocol compared with our previous regimen CMFP.

Adult↗
PubMed1996

Histopathological response to preoperative chemotherapy including 5-fluorouracil additionally assessed by immunocytochemical and pharmacologic parameters in patients with advanced gastric cancer.

To investigate quantitative methods for assessing the response to preoperative downstaging chemotherapy (PDC), the immunocytochemical expression of proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) as well as a pharmacologic study of the rate of thymidylate synthetase inhibition (TSIR) were studied in resected specimens obtained from patients with advanced gastric cancer. Fifty-one patients with advanced gastric cancer who received PDC (30 with 5-fluorouracil peroral administration and the other 21 with intravenous administration of 5-fluorouracil and cisplatin) were studied. The labeling index of PCNA (PCNA-LI) and BrdU were measured. The PCNA suppression (PCNA-S), which was measured by both the values of prechemotherapeutic PCNA-LI in endoscopically biopsied specimens and postchemotherapeutic PCNA-LI in resected specimens, was also examined. TSIR was measured by a protein-bound radiochemical method. We compared the above-mentioned parameters with the histopathological response to PDC according to the General Rules for Gastric Cancer Study. In the patients with peroral 5-flurorouracil, a stepwise regression analysis showed that TSIR is a significantly effective for determining the histopathological response to PDC. In the patients with 5-fluorouracil and cisplatin, PCNA-S was the most effective indicator of the histopathological response to PDC, as shown by a stepwise regression analysis. The present study thus showed that both TSIR and PCNA-S were effective additional indicators of the histopathological response to PDC.

Administration, Oral↗
PubMed1989

Inhibited methionine incorporation in human squamous carcinomas of the oral cavity as a measure for response to 5-fluorouracil.

Human epithelial cells and fibroblasts from malignant tumors and healthy tissues of the oral cavity were exposed in vitro to increasing concentrations of 5-fluorouracil. In order to determine whether the two cell types showed a difference in uptake, accumulation was measured over time using tritiated fluorouracil. Maximal drug uptake occurred in highly proliferative epithelial cells from cancerous tissue at 3 h, whereas fibroblasts from the same tissue and other cell types from healthy tissue exhibited a steadily increasing uptake over a long period of time. By use of [3H]methionine, a direct correlation could be demonstrated between the amount of incorporated drug and the fall in the rate of de novo protein synthesis. Furthermore, suppression of protein synthesis was closely related to the inhibition of cell division. These results indicate that the level of de novo protein synthesis can be a direct measure of the anticancer effect of fluorouracil.

Carcinoma, Squamous Cell↗
PubMed1980

Mechanism of cytotoxicity of 5-fluorouracil: distinction between the irreversible cytotoxic effect of 5-fluorouridine and the reversible cytotoxic effect of 5-fluoro-2'-deoxyuridine on murine lymphoma L5178Y cells in culture.

To determine the relative importance of the DNA and RNA effects in the cytotoxicity of 5-fluorouracil, we determined the effects of brief exposure to 5-fluorouridine and 5-fluoro-2'-deoxyuridine, compared with 5-fluorouracil, on the subsequent growth of murine lymphoma L 5178 Y cells during prolonged incubations following the removal of the drug from the culture medium. 5-Fluoro-2'-deoxyuridine markedly inhibited cell proliferation by continuous exposure. However, its inhibitory effect by exposure even at 1,000 muM for 1 h easily disappeared within 1 week after removal of the drug from the culture medium. This result indicates that the cytotoxic effect of 5-fluoro-2'-deoxyuridine is reversible on cell proliferation. On the other hand, the exposure to 5-fluorouridine, even at the low concentration of 1.5 muM for 1 h, caused a substantial and irreversible inhibition on cell proliferation. The cytotoxic effect of 5-fluorouracil was also an irreversible action similar to that of 5-fluorouridine.

Animals↗
PubMed1976

Effect of 5-fluorouracil and cycloheximide on the early development of Phycomyces blakesleeanus spores and the activity of N-acetylglucosamine synthesizing enzymes.

The development of germinating Phycomyces spores was not inhibited by 5-fluorouracil (1mM) until the emergence of the germination tube. Fluorouracil was incorporated into RNA as efficiently as uracil; it did not inhibit the synthesis of proteins and the increase in respiratory activity during early development. Cycloheximide inhibited development as well as the increase in respiration and protein synthesis. This suggested that protein synthesis or some other cycloheximide dependent process, but no mRNA synthesis, was needed for the first developmental stages. The activity of two enzymes involved in the synthesis of N-acetylglucosamine increased markedly during germination. THis increase was inhibited by both 5-fluorouracil and cycloheximide; this suggested that those enzymes were synthesized on mRNA formed during germination.

Acetylglucosamine↗
PubMed1990

Treatment of metastatic breast cancer with the combination of ifosfamide, epirubicin and 5-fluorouracil.

An ongoing trial of combination chemotherapy using ifosfamide (Holoxan), epirubicin and 5-fluorouracil was started in 1987. A total of 30 patients with metastatic cancer of the breast received 1.5 g/m2 i.v. ifosfamide over 60 min on days 1-3, 50 mg/m2 i.v. epirubicin on day 1 and 500 mg/m2 i.v. 5-fluorouracil on day 1, followed by mesna (Uromitexan) given at 20% of the ifosfamide dose at 0, 4 and 8 h. The courses were repeated every 4 weeks. In all, 198 courses were given, ranging from 3 to 13 (median, 7) cycles/patient. The mean age of the 30 patients was 48 years (range, 35-66 years); 5 had not previously received chemotherapy and the others had failed prior cytotoxic and endocrine therapy. Overall, 28 patients were evaluable, 7 (25%) showed a complete response and 15 (54%) had a partial response, for an overall response rate of 22/28 (79%). Three patients showed stable disease with improved symptoms, and in three cases disease progression occurred. The median duration of response was 9 months (range, 3-20 months). Median survival was 11 months for all patients, 15 months for CRs, 10 months for PRs, 6 months for stable disease and 12 months for progressive disease (PD). Survival for the 22 responding patients was 12 months. Toxicity was acceptable and included alopecia, mucositis, nausea, vomiting, diarrhoea, mild cystitis and myelosuppression. Epirubicin did not appear to produce cardiac toxicity, and ifosfamide with mesna did not seem to result in severe urotoxicity. Chemotherapy with ifosfamide, epirubicin and 5-fluorouracil proved to be effective for treatment of advanced breast cancer and should be further studied in large, controlled trials.

Adult↗
PubMed1994

The cardioprotector ADR-529 and high-dose epirubicin given in combination with cyclophosphamide, 5-fluorouracil, and tamoxifen: a phase I study in metastatic breast cancer.

The purpose of this study was to determine the maximal tolerable dose (MTD) of epirubicin and ADR-529 given in combination with cyclophosphamide, 5-fluorouracil, and tamoxifen. A total of 64 breast cancer patients with locally advanced disease or a first metastatic event were included. Using fixed doses of cyclophosphamide, 5-fluorouracil, and tamoxifen, cohorts of ten patients were treated with escalating doses of epirubicin and ADR-529. With the use of protocol criteria specifying evaluation after the first course, the MTD was not reached. Dose reductions carried out due to hematologic toxicity during the first four courses made it impossible to escalate doses of epirubicin beyond 80 mg/m2 given together with ADR-529 600 mg/m2. The vascular toxicity of ADR-529 necessitated central venous access in a number of patients. For phase III evaluation of ADR-529 given together with cyclophosphamide, epirubicin, 5-fluorouracil, and tamoxifen (CEF/TAM) we recommend using epirubicin/ADR-529 at 60/600 mg/m2. Together with evaluation of the cardioprotective properties of ADR-529, we recommend evaluating the impact of ADR-529 on the efficacy of cytotoxic therapy and investigating further the toxicity of ADR-529.

Adult↗
PubMed1994

Variability in the pharmacokinetics of cyclophosphamide, methotrexate and 5-fluorouracil in women receiving adjuvant treatment for breast cancer.

A total of 23 women with stage II breast cancer receiving adjuvant cyclophosphamide, methotrexate and 5-fluorouracil had detailed pharmacokinetic monitoring performed on the first and third courses of therapy. The area under the concentration time curve (AUC) of each of these three drugs varied by a factor of 3-4 among patients. No systematic change in pharmacokinetics between the first and third courses was seen for cyclophosphamide, methotrexate or 5-fluorouracil, and the mean AUC for each of the three drugs did not change. However, significant intrapatient variability in drug pharmacokinetics was observed for all three drugs such that the AUC, clearance and half-life in an individual on the third course could not be reliably predicted from data generated on the first course. On the basis of these results, cyclophosphamide, methotrexate, and 5-fluorouracil pharmacokinetic data from one treatment would not be useful information from which the doses of subsequent courses could be determined.

Adult↗
PubMed1994

Phase I/II study of cisplatin, 5-fluorouracil and alpha-interferon for recurrent carcinoma of the head and neck.

Current chemotherapy regimens have failed to demonstrate a significant impact on the overall survival of patients with recurrent head and neck cancer; therefore, new agents or combinations of agents are necessary to improve outcome. Alpha-interferon potentiates the activity in vitro of both agents of one of the most active regimens currently available, cisplatin and 5-fluorouracil. The purpose of the current study was to evaluate the feasibility and efficacy in patients with recurrent head and neck cancer of adding alpha-interferon to cisplatin 14 mg/m2 daily and 5-fluorouracil 700 mg/m2 daily for 5 days. No significant toxicity occurred with alpha-interferon at dose level 0, 1 x 10(6) units/m2 daily for five days. Of four patients treated at dose level +1, alpha-interferon 3 x 10(6) units/m2, two developed prolonged grade III neutropenic following the fourth course. One of three patients developed grade IV thrombocytopenia and 6 of 13 courses at this dose level resulted in grade III neutropenia. A phase II study was performed in 19 patients with cisplatin 17 mg/m2/day, 5-fluoruracil 700 mg/m2/day and alpha-interferon 3 x 10(6) units/m2/day. During the phase II study grade III neutropenia occurred in 6 patients and grade IV neutropenia in another patient during at least one course. Grade III and IV thrombocytopenia occurred in one patient each during the phase II study. Overall, major responses occurred in 7 or 23 patients (30%): 5 in phase I and 2 in phase II. In conclusion, the addition of alpha-interferon to cisplatin and 5-fluorouracil is feasible, but does not appear to increase response rates in recurrent head and neck cancer.

Adult↗
PubMed1995

Punctal and canalicular stenosis associated with systemic fluorouracil therapy. Report of five cases and review of the literature.

Ocular side effects of systemic fluorouracil include excessive lacrimation, due to punctal and canalicular stenosis and fibrosis. Obstruction of the tear ducts after systemic therapy with fluorouracil is more frequent than is assumed. Five patients with breast cancer and punctal or canalicular stenosis are presented. Although complaints of epiphora usually resolve two weeks after cessation of systemic therapy, local antibiotics and steroids may be indicated. In patients with persisting complaints, and patients treated with fluorouracil for a prolonged period of time, prophylactic intubation of the tear ducts with silastic tubes has been advocated. (Conjunctivo)dacryocystorhinostomy may be unavoidable.

Aged↗
PubMedDate not supplied

Flucytosine conversion to fluorouracil in humans: does a correlation with gut flora status exist? A report of two cases using fluorine-19 magnetic resonance spectroscopy.

A relationship between the gut flora level, particularly gram-negative enterobacilli, and the in vivo flucytosine conversion to fluorouracil has been observed in humans from the fluorine-19 magnetic resonance spectroscopy analysis of urine from two patients treated with the flucytosine- (6 to 9 g/day) amphotericin B (1 mg/kg/day) combination. Indeed the percentage of fluorouracil metabolites was extremely low (less than 0.6% of total fluorinated compounds excreted) when the number of enterobacillary colonies was low (less than 10(3] and higher (3.5 to 8.8%) when enterobacillary colonies were under reconstitution or in the normal range (10(5) to 10(8]. The intestinal microflora assessment may therefore be of high interest to predict the risk of an additive flucytosine-induced myelotoxicity suspected to be due to fluorouracil during flucytosine chronic therapy.

Adolescent↗
PubMed1990

A simple high pressure liquid chromatographic method for the determination of fluorouracil to monitor patients on regional infusion for hepatic metastases.

A rapid and sensitive high pressure liquid chromatographic method has been developed for the routine monitoring in serum of the antineoplastic agent fluorouracil, during continuous intraportal administration. Serum spiked with internal standard, bromouracil, was gently shaken for 10 min with ethylacetate at an acidic pH. The evaporated extract was dissolved in the mobile phase containing potassium phosphate buffer. Assays were performed at ambient temperature on a Chrompack LiChrosorb RP 18 column (2 X 100 X 3.0 mm) equipped with a guard column. The retention time of fluorouracil was 2-6 min. The calibration curve was linear from 25 to 2,000 ng/ml. The coefficient of variation was less than or equal to 1.6% for within-run precision and less than or equal to 2.9% for day-to-day precision. The mean recovery of fluorouracil was 57%.

Chromatography, High Pressure Liquid↗
PubMed1994

Local excision of rectal carcinoma. Early results with combined chemoradiation therapy using 5-fluorouracil and leucovorin.

PURPOSE: This study was undertaken to evaluate the treatment morbidity, functional outcome, and recurrence risk of patients undergoing local excision and combined chemoradiation therapy for rectal carcinoma. METHODS: Eighteen patients underwent local excision of their rectal carcinoma. Four patients underwent local excision alone (T1-2, N0-X, low risk), 10 patients underwent local excision with postoperative chemoradiation therapy using 5-fluorouracil and leucovorin (T1-2, N0-X, high risk), and 4 patients underwent local excision, chemoradiation therapy, and six months of additional 5-fluorouracil and leucovorin (T3 or N1). RESULTS: Of the four patients undergoing local excision alone, there was no treatment morbidity or alteration in functional outcome. Of the 14 patients receiving chemoradiation therapy, three reported early Grade 3-4 toxicity manifested by cystitis, proctitis, or perineal skin desquamation. At six months, two patients reported persistent rectal urgency and occasional fecal incontinence, and 11 patients reported increasing stool frequency (average, 3: range, 2-8). The six months of additional 5-fluorouracil and leucovorin were well tolerated and did not appear to further affect functional outcome. There were no local recurrences, although one patient developed distant metastatic disease. CONCLUSION: This treatment regimen, while generally well tolerated, is associated with significant acute toxicity in certain patients. We have identified specific causative factors which can be modified to decrease acute morbidity, including the elimination of leucovorin during the combined chemoradiation therapy.

Adenocarcinoma↗
PubMed1995

Whole abdominal radiotherapy and concomitant 5-fluorouracil as adjuvant therapy in advanced colon cancer.

PURPOSE: This analysis was undertaken to assess whole abdomen radiation therapy and concurrent 5-fluorouracil for toxicity and patterns of failure in high-risk colon cancer patients after curative surgical resection. METHODS: Eighteen patients were treated adjuvantly after curative resection. Four patients (22 percent) had Stage B and 14 (78 percent) had Stage C disease. Histology was poorly differentiated in 4 (22 percent) and moderately differentiated in 14 (78 percent) patients. Four patients received whole abdominal radiation only, 30 Gy at 1 Gy/day. Fourteen patients had an additional locoregional boost of 9.6 to 16 Gy at 1.6 Gy/day. The liver received 19.8 Gy at 0.67 Gy/day. 5-Fluorouracil was given as a continuous infusion during therapy. RESULTS: With a median follow-up of three years, 6 of 18 (33 percent) patients have relapsed. Failure occurred locally in 3 of 18 (17 percent) and distantly in 4 of 18 patients (22 percent). Four of six (67 percent) failures occurred in the liver. The five-year actuarial survival and disease-free survival were 78 percent and 66 percent, respectively. Median elapsed time on radiotherapy was 73 days, with 5 of 18 patients (28 percent) requiring two or more weeks of unplanned treatment breaks. Acute Grade 3 to 4 toxicity (diarrhea, leukopenia) occurred in 3 of 18 patients (17 percent), with late complications (bowel obstruction) occurring in 2 of 18 patients (11 percent). CONCLUSIONS: Whole abdominal radiotherapy with concomitant 5-fluorouracil appears to improve local control but not to prevent liver metastases. Significant toxicity resulted in frequent interruption of therapy and protracted its course. Whether this adjuvant regimen impacts on survival or offers an advantage over locoregional irradiation remains to be studied.

Abdomen↗
PubMed2002

The clinical efficacy of neoadjuvant chemotherapy in squamous esophageal cancer: a prospective nonrandomized study of pulse and continuous-infusion regimens with Cisplatin and 5-Fluorouracil.

BACKGROUND: We evaluated cisplatin and 5-fluorouracil as preoperative adjuvant chemotherapy for patients with locally advanced squamous esophageal cancer and compared two different infusion regimens. The outcomes were also compared with those of our historical control patients treated by surgery alone. METHODS: From 1991 to 1997, 83 consecutive esophageal cancer patients underwent surgical exploration after completion of two cycles of cisplatin and 5-fluorouracil chemotherapy regimens, either in pulse or in continuous infusion cycles. Outcomes were compared with those of 76 historical control patients. Both groups were comparable in demographic characteristics and tumor stages. The resection rates, operative morbidity, mortality, and survival rates were compared. RESULTS: Partial response was achieved in 50% of patients who received chemotherapy. There was no chemotherapy-related mortality. The resection, morbidity, and mortality rates and median survival between the surgery-alone group and the chemotherapy group were 71.1% vs. 82%, 51% vs. 55%, and 4% vs. 10.8%, 12.0 vs. 13.5 months, respectively (P >.05). There was also no statistically significant difference between the two regimens. CONCLUSIONS: Preoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil infusion, in pulse or continuous regimens, followed by surgery for squamous esophageal cancer patients had no added benefit in the overall survival.

Adult↗
PubMed1996

Cost-effectiveness of adjuvant chemotherapy with cyclophosphamide+methotrexate+fluorouracil in patients with node-positive breast cancer.

BACKGROUND: The analysis of published survival curves can be used as the basis for incremental cost-effectiveness analyses in which two treatments are compared with each other in terms of cost per life year saved. In patients with node-positive breast cancer adjuvant chemotherapy with cyclophosphamide+ methotrexate+fluorouracil has been reported to improve survival in comparison with patients who are not given this treatment. METHODS: To assess the pharmacoeconomic profile of this adjuvant chemotherapeutic regimen in terms of cost per life-year gained, we conducted an incremental cost-effectiveness analysis in which the Gompertz model was used to calculate the lifetime estimate of the patient-years gained by treated subjects compared to controls. RESULTS: Using data from a published, controlled long-term trial involving 207 patients treated with cyclophosphamide+methotrexate+fluorouracil and 179 controls, we estimated that this adjuvant chemotherapy improved life expectancy by 357 patient-years per 100 subjects. Direct costs, which were almost exclusively related to the administration of chemotherapy, were estimated to be US $159,516 per 100 patients. On the basis of these data, adjuvant chemotherapy was found to imply an incremental cost of US $447 per life-year saved. CONCLUSIONS: The cost-effectiveness ratio of adjuvant chemotherapy with cyclophosphamide+methotrexate+fluorouracil in patients with node-positive breast cancer seems to be particularly favourable in comparison with estimates of cost per life-year saved previously calculated for other types of pharmacological intervention.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Thymidine phosphorylase activity in renal cell carcinoma: relationship between histological parameters and chemosensitivity to fluorouracil-related drugs.

Thymidine phosphorylase (TdR-Pase) is an essential enzyme in the metabolism of fluorouracil-related drugs and is also a potent angiogenic factor. We measured the TdR-Pase activity in human renal cell carcinomas (RCCs) to assess the relationship between TdR-Pase activity and the degree of tumor malignancy. We also investigated the relationship between TdR-Pase activity and chemosensitivity to fluorouracil-related drugs. A total of 61 RCC tissue specimens and 39 normal kidney tissue specimens were obtained. TdR-Pase activity was measured by enzyme-linked immunosorbent assay. The in vitro histoculture drug response assay was also performed to examine tumor sensitivity to 5-fluorouracil (5-FU) and doxifluridine (5'-DFUR). The TdR-Pase activity of RCCs was 13-fold that of the normal tissues. Activity increased with histological grade, and,was significantly higher in high-stage tumors (T3 or higher). TdR-Pase activity exhibited a significant positive correlation with sensitivity to 5-FU and 5'-DFUR. High TdR-Pase activity in human RCC was confirmed to predict high tumor grade and stage. RCCs with high TdR-Pase activity were also sensitive to FU-related drugs.

Antimetabolites, Antineoplastic↗
PubMed1996

Phase II study of the combination of carboplatin and 5-fluorouracil in metastatic nasopharyngeal carcinoma.

A carboplatin and 5-fluorouracil (CF) chemotherapy protocol was designed to evaluate tumor response and toxicity in patients with metastatic nasopharyngeal carcinoma (NPC). Patients with metastatic NPC were treated with a maximum of eight courses of CF. Carboplatin was given at 300 mg/m2 by intravenous bolus on day 1 and 5-fluorouracil at 1 g/m2 per day by continuous infusion on days 1-3; cycles were repeated once every 3 weeks. A total of 42 patients were evaluable for response and toxicity. They received a median of 6 courses (range 2-8) of chemotherapy. The overall response rate was 38% (16/42), comprising 7 complete responses (CR, 17%) and 9 partial responses (PR, 21%). The median survival was 12.1 months (range 6-54.2 months). The treatment was well tolerated. Toxicity was mainly bone marrow suppression. There were four episodes of neutropenic fever, but no renal toxicity or treatment-related death was documented. The combination of carboplatin given at a fixed dose of 300 mg/m2 for 1 day and 5-fluorouracil given at 1 g/m2 per day for 3 days produced an objective response rate of 38% and tolerable side effects.

Adult↗