5-fluorouracil In Patients Research Articles

Compliance to chemotherapy with oxaliplatin and 5 fluorouracil in patients with advanced rectal cancer who have received prior high-dose pelvic radiotherapy

3747 Background: Pelvic radiotherapy (RT) may compromise the compliance and effectiveness of future chemotherapy (CT). Patients and Methods: 20 patients (15 male, 5 female), mean age 69 yrs (range 51–75) were studied in a prospective, multicenter, phase II study. All patients had recurrent or metastatic diease. All had received previous pelvic RT: 45Gy 25 fx (15), 45 Gy 30 fx (3), 45 Gy 20 fx (2) and 25 Gy 5 fx (1) at a 16 months prior to this study. Most patients had received concurrent chemoradiation (CRT). Patients were treated with a schedule consisting of oxaliplatin 85 mg/m2 on day 1 and 5FU 400 mg/m2 iv bolus and 600 mg/m2 iv 22hour infusion with folinic acid on day 1 and 2. A maximum of eight cycles of CT were administered every two weeks. Results: A median number of 7 cycles of CT was given (range 3–8), with 132 cycles being given in total. There were 8 episodes of grade III neutropaenia (1 with sepsis). There were 4 episodes of grade III/IV diarrhoea, two of which required hospitalisation, but all resolved. In 18 evaluable patients patients the overall response rate was 33% (3 CR; 3 PR), with 2 patients having SD. Conclusion: This study shows that the combination of oxaliplatin, 5FU and folinic acid after high-dose pelvic RT is well tolerated and has comparable efficacy to that seen in other metastatic studies and a dose intensity equal to that achieved in adjuvant studies. Based on the results of this study, adjuvant oxaliplatin is being delivered in a randomised phase III study (CHRONICLE) following CRT. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Sanofi

Compliance to chemotherapy with oxaliplatin and 5 fluorouracil in patients with advanced rectal cancer who have received prior high-dose pelvic radiotherapy

3747 Background: Pelvic radiotherapy (RT) may compromise the compliance and effectiveness of future chemotherapy (CT). Patients and Methods: 20 patients (15 male, 5 female), mean age 69 yrs (range ...

1211 Evidence based symptom management for patients with breast cancer: clinical pathways teach process, implementation and evaluation

Objective: To measure the gene expression of the metabolic enzymes of 5 fluorouracil (thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase) to assess the efficacy of 5 fluorouracil inpatients with head and neck cancerPatients and Methods: Tissue specimens of 64 patients with head and neck cancer (41 men and 23 women with a mean age of 62.6 years) who had been surgically treated from April 1997 to March 2004 were included in this study. The mRNA expressions of thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase genes were examined from the surgically resected tissues using the Danenberg tumour profile method. The mRNA levels of the 4 enzymes were compared between tumour tissues and adjacent healthy tissues.Results: All specimens showed that thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase levels were significantly higher in the primary tumours than in the adjacent healthy tissues, while the levels of dihydropyrimidine dehydrogenase were significantly lower in the primary tumours than in the adjacent healthy tissues.Conclusion: Prediction of the efficacy of 5 fluorouracil therapy in the treatment of head and neck cancer from the measurement of mRNA levels of its metabolic enzymes appears to be feasible and possibly beneficial. Key words: Head and neck neoplasms, Orotate phosphoribosyltransferase, Thymidine phosphorylase, Thymidylate synthase

DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study

Present clinical algorithms assign adjuvant chemotherapy according to prognosis, but clinical decision-making would be greatly improved if reliable predictive markers were available to identify which subsets of patients benefit most from treatment. We examined molecular markers in preserved tissue from patients with Dukes' B or C colon cancer randomised to receive, or not, adjuvant fluorouracil, and assessed each marker's prognostic and predictive value. Formalin-fixed paraffin-embedded paired normal and tumour samples were obtained from 393 patients with colon cancer from the UK AXIS trial of postoperative portal vein infusion fluorouracil versus control. We measured loss of heterozygosity (LOH) and microsatellite instability at four loci: P53 (17p13), D18S61 (18q22.3), D18S851 (18q21.1), and DP1 (5q21). The prognostic value of each marker was assessed with the log-rank test, and the predictive value by comparison of treatment hazard ratios with the chi(2) test for heterogeneity (CSH). In 228 (58%) patients informative for LOH at D18S61, this marker was significantly predictive: benefit from fluorouracil was significantly greater in patients retaining heterozygosity than in those with LOH (CSH p=0.02). Conversely, LOH at D18S61 was a significant prognostic marker of improved outcome in untreated patients. 314 (80%) patients were informative for LOH at at least one of the three 17p and 18q sites, of whom half retained heterozygosity at one or more site. The effect of chemotherapy in these patients was striking (hazard ratio 0.45, 95% CI 0.28-0.73), whereas chemotherapy had no effect in patients with no retained heterozygosity (0.91; 0.56-1.48), CSH p=0.039. Retention of heterozygosity at one or more 17p or 18q sites was associated with the ability to benefit from adjuvant fluorouracil. These results support the principle of developing molecular markers as predictive factors in treatment decisions.

A phase II trial of weekly intravenous gemcitabine and cisplatin with continuous infusion fluorouracil in patients with metastatic renal cell carcinoma

BackgroundWe reported previously that the combination of gemcitabine and continuous infusion fluorouracil (5-FU) has activity in renal cell carcinoma [1]. Based upon in vitro synergy of gemcitabine/cisplatin and 5-FU/cisplatin, we hypothesized that the addition of cisplatin could improve the objective response rate of gemcitabine and 5-FU with manageable toxicity. Patients and methodsTwenty-one patients with metastatic renal cell carcinoma (RCC) and a Cancer and Leukemia Group B performance status of 0 to 2 were enrolled. Ten had received prior systemic therapy. Treatment consisted of gemcitabine 600 mg/m2 and cisplatin 20 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Continuous infusion 5-FU was given from day 1 to day 21. ResultsNo complete responses and one partial response were observed for an objective response rate of 5% (95% confidence interval 0% to 24%). Two minor responses (25% to 50% regression) were also observed. The median overall survival was 10 months with 35% of patients surviving at 1 year. Grade 3–4 myelosuppression (mostly thrombocytopenia) occurred in nine (43%) patients. Nausea/vomiting and neuropathy were dose-limiting in an additional five patients. Only 51% of treatment cycles were delivered on time and without dose reduction. ConclusionsThe addition of cisplatin to gemcitabine and 5-FU did not improve the objective response rate of gemcitabine and 5-FU alone and added to the toxicity. Due to the cumulative toxicity, further trials with this cisplatin-containing regimen in RCC are not indicated.

Biochemical modulation of fluorouracil in patients with metastatic colorectal cancer

Eniluracil with 5-FU administered orally with or without leucovorin on a 5-day schedule appears to be active and well-tolerated when given as primary therapy to patients with untreated metastatic colorectal carcinoma.

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

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

Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer.

A randomized trial was designed to compare cisplatin (CDDP) and fluorouracil (FU) versus carboplatin (CBDCA) and FU as neoadjuvant treatment in stage IV-M0 head and neck cancer to assess whether CBDCA-FU is better than CDDP-FU with regard to response and toxicity. Patients were randomized to receive CDDP 100 mg/m2 intravenously on day 1 and FU 5,000 mg/m2 over a 120-hour continuous infusion, or CBDCA 400 mg/m2 over a 24-hour continuous infusion on day 1 and FU with the same schedule. Both regimens were repeated every 21 days. The patients received three courses of chemotherapy, excluding those who failed to achieve a partial response (PR) after the second course. Complete responders were treated with radiotherapy. The remaining patients underwent surgery if the tumor was resectable. Interim analysis was performed when 95 patients were included. The trial was stopped due to significantly better results in the control arm. Differences in response (P = .04) were favorable to CDDP-FU. Hematologic toxicity predominated in the CBDCA-FU arm (P < .001). Mucositis and vomiting predominated in the CDDP-FU arm (P = .03, P < .001, respectively). Favorable outcomes (complete response [CR] plus any grade of toxicity and PR plus grade 0 to 3 toxicity) predominated in the CDDP-FU arm (P = .02). Only the treatment assigned was associated with response (P = .02) and favorable outcomes (P = .009) in the logistic regression analysis. In the CDDP-FU arm, disease-free and overall survival were significantly better. Cox regression analysis showed that only treatment association with disease-free survival remains significant. Our results indicate that CDDP-FU is more effective than CBDCA-FU as neoadjuvant treatment in stage IV-M0 head and neck cancer.

A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer

A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1–3, N1–2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and flourouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased accoring to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionucleide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m 2, epirubicin = 50 mg/m 2, fluorouracil = 375 mg/m 2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 50 mg/m 2 and fluorouracil = 500 mg/m 2 (level 2), 69 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 60 mg/m 2, and fluorouracil = 500 mg/m 2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 70 mg/m 2, and fluorouracil = 500 mg/m 2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide,methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.

Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma.

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.

Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial.

Between 1976 and 1985, 391 patients (202 premenopausal, 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years, both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS, P less than .001; S, P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age, with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years, development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS, P = .9; S, P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.

Phase I clinical and pharmacologic study of intraperitoneal cisplatin and fluorouracil in patients with advanced intraabdominal cancer.

Fluorouracil (5-FU) and cisplatin display marked therapeutic synergy in preclinical models and are effective in the treatment of a number of solid tumors when combined and administered intravenously (IV). Each drug has also been administered intraperitoneally (IP) and displays a favorable pharmacologic profile and acceptable clinical toxicity. We therefore undertook a phase I study to determine the feasibility and toxicity of combination IP chemotherapy with these agents. Thirty-one patients with histologically documented malignancy confined to the peritoneal space were treated with cisplatin 90 mg/m2 mixed with 5-FU in 2 L of lactated Ringer's solution and given IP for 4 hours every 28 days. Cohorts of at least three patients received starting 5-FU concentrations ranging from 5 mmol/L (1,300 mg in 2 L) to 20 mmol/L. The dose-limiting toxicity was neutropenia with a median granulocyte nadir of 156 cells per microliter occurring at a 5-FU dose of 20 mmol/L. Intrapatient escalation of the 5-FU dose was permitted and 15 cycles of chemotherapy were delivered at 5-FU concentrations greater than 20 mmol/L, the highest concentration being 30.7 mmol/L (8 g of 5-FU in 2L). Other toxicities included mild to moderate nausea during all cycles of therapy, vomiting in 54% of cycles, and diarrhea in 15% of cycles. Abdominal pain, renal dysfunction, peripheral neuropathy, and oral mucositis occurred infrequently and were not related to the 5-FU dose. Peritoneal fluid and plasma 5-FU concentrations were measured by high-performance liquid chromatography (HPLC) in selected patients. Mean peak plasma 5-FU concentrations ranged from 6.19 mumol/L to greater than 60 mumol/L, and peritoneal fluid to plasma 5-FU area under the curve (AUC) ratios ranged from 85 to 1,150. Nine of 15 patients with nonbulky disease had resolution of malignant ascites or at least a 50% reduction of peritoneal studding by tumor at repeat laparotomy. We conclude that combination IP chemotherapy with cisplatin and 5-FU is technically feasible and has acceptable clinical toxicity and a favorable pharmacologic profile. The recommended starting 5-FU dose for phase II trials is 3,900 mg mixed with 90 mg/m2 of cisplatin in 2 L of isotonic fluid.

Adverse effects of intraperitoneal fluorouracil in patients with optimal residual ovarian cancer after second-look laparotomy: a Gynecologic Oncology Group Study.

Twenty-seven patients with ovarian cancer who had failed combination chemotherapy were offered intraperitoneal (IP) fluorouracil (5-FU) as salvage therapy in an attempt to ascertain the efficacy of such a therapeutic method. All patients had minimal residual epithelial cancer. The median number of treatment cycles was six. Major problems with dialysate inflow and egress occurred in ten patients and required discontinuation of therapy. An additional ten patients experienced hematologic toxicity with a median nadir WBC of 2,300/microL. Therapy was altered but not discontinued because of this complication. Other adverse sequelae, such as abdominal pain, were manageable with medication. IP 5-FU is technically feasible on a multiinstitutional basis in residual ovarian cancer, but its therapeutic role remains to be defined.

Plasma and tumor tissue pharmacology of high-dose intravenous leucovorin calcium in combination with fluorouracil in patients with advanced colorectal carcinoma.

Plasma pharmacokinetics of high-dose (500 mg/m2) leucovorin calcium (dl-5-formyltetrahydrofolic acid [dl-CF]) and fluorouracil (FUra) have been evaluated in patients with advanced colorectal cancer treated with the combination of FUra and dl-CF by two different intravenous (IV) schedules: (A) In patients with no prior chemotherapy, dl-CF was administered by a two-hour IV infusion and FUra by rapid IV injection one hour after the start of the dl-CF infusion and (B) in previously treated patients, dl-CF and FUra were administered by five-day continuous IV infusion (CI). Following the two-hour infusion of dl-CF, mean peak plasma concentration and elimination half-life of I-5-formyltetrahydrofolic acid (I-CF) were 24 +/- 6 mumol/L and 0.8 +/- 0.1 hour, respectively. CI of dl-CF over five days yielded a mean steady-state plasma level of I-CF of only 1.2 +/- 0.5 mumol/L. Peak and steady-state plasma concentrations of the metabolite 5-methyl tetrahydrofolic acid were comparable in the two schedules (17 +/- 8 mumol/L for the two-hour infusion and 12 +/- 5 mumol/L for the CI). Areas under the concentration v time curve (AUC) of total reduced folates were significantly greater under conditions of CI: 89.0 v 16.7 mmol/L/min for the two-hour infusion. In tumor tissue, 5,10-methylenetetrahydrofolate increased eight-fold two to four hours following the two-hour infusion and two-fold during the CI of dl-CF and FUra. Inhibition of thymidylate synthase (dTMP-S) by the two-hour and CI infusion schedules were 66% v 39%, respectively. The observed differences in the intracellular dTMP-S folate cofactor pools and the degree of inhibition of dTMP-S achieved in patients treated by two different schedules may be due to differences in the biochemical properties and/or to differences in the modulation of FUra metabolism by folate of tumor tissues obtained from newly diagnosed and previously treated patients.

Fluorouracil as an Adjuvant to Colorectal Cancer Surgery; The Breakthrough That Never Was

To the Editor.— In an article published inThe Journal(235:2825, 1976) that was endorsed by an editorial, and Ross claimed significant improvement of five-year cure rate for patients with type B and C Dukes colorectal cancer through the use of fluorouracil as a surgical adjuvant.The Journaleditorial would appear to offer enthusiastic concurrence: Li and Ross show clearly the benefit from two postoperative courses of fluorouracil in patients with colorectal carcinoma, and One of the striking features... is the exceptionally short duration of treatment with fluorouracil necessary to achieve the impressive results. It is scarcely surprising that such outspoken claims made breakthrough headlines in the news media. These claims have no foundation in fact. and Ross have attempted to demonstrate the effectiveness of fluorouracil as a surgical adjuvant by comparing survivorship in patients so treated from 1965 to 1970 with survivorship in patients treated with