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PubMed1993

Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer.

PURPOSE: This study was designed to determine if hepatic arterial therapy with floxuridine (F), mitomycin, and carmustine (BCNU) (FMB) is superior to hepatic arterial therapy with F alone in previously treated patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Ninety-five patients were randomized to intrahepatic FMB versus intrahepatic F. All patients had tumor progression after systemic chemotherapy (either therapeutic or adjuvant). RESULTS: There was no significant difference in response rate (47% FMB v 33% F; P = .17). Median survival was similar in the two groups, 19.1 months for the FMB group compared with 14.0 months for the F group (P = .23). The overall median survival was 16.8 months. In patients who received prior adjuvant therapy, there was no difference between the two groups, but response rate was high in both (50% FMB v 62% F). The response rate for all patients who had received only prior adjuvant therapy versus all those who had received prior therapy for metastatic disease was 57% and 35%, respectively (P = .066). In the subset of patients whose disease had progressed with prior systemic chemotherapy, the response rate to FMB was greater than that to F (47% v 23%; P = .035). CONCLUSION: The overall partial response rate of 39% and the overall survival of 16.8 months from initiation of intrahepatitis therapy show that hepatic arterial therapy is a reasonable treatment option for patients whose tumor does not respond to systemic therapy or whose disease progresses after adjuvant therapy for colorectal cancer.

Adult↗

PubMed1994

A phase I/II study of alternating constant rate infusion floxuridine with constant rate infusion vinblastine for the treatment of metastatic renal cell carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is largely chemoresistant. The efficacy of cell cycle specific chemotherapeutic agents, particularly those with short half-lives, may be enhanced by the use of constant rate infusion schedules. Infusional floxuridine has been demonstrated to have a response rate of approximately 20%. Infusional vinblastine has not been tested extensively in patients with metastatic RCC. The sequential use of these agents was designed to increase efficacy and limit toxicity. METHODS: Fifteen patients with metastatic RCC were treated with constant rate infusion floxuridine, 0.075 mg/kg/day for 14 days, followed by a constant rate infusion of vinblastine, 0.7 mg/m2/day for 14 days. The cycle repeated every 28 days and floxuridine and vinblastine doses were incrementally increased until the maximum tolerated dose (MTD) for each patient was reached. RESULTS: Four patients had partial responses (27%), which were maintained for 3, 9, 16 and 19+ months, whereas five patients had stable disease for 3-15 months. Median survival from initiation of therapy was 379 days. Three of four responses occurred in nonpulmonary locations, and all responses occurred in patients who had a prior nephrectomy. MTD for floxuridine was 0.1 mg/kg/day and for vinblastine, 0.7 mg/m2/day. Toxic reaction to floxuridine was limited to diarrhea, whereas the principle dose-limiting toxic reaction for vinblastine was neutropenia. Catheter-related complications were also observed. CONCLUSIONS: Alternating constant rate infusion floxuridine and constant rate infusion vinblastine is active in the treatment of metastatic RCC. Whether this regimen is superior to infusional floxuridine is undetermined. Although the toxicity associated with this regimen is manageable, it appears to be more severe than that reported with infusional floxuridine alone.

Adult↗

PubMed1993

Alpha-2B-interferon plus floxuridine in metastatic renal cell carcinoma. A phase I-II study.

BACKGROUND: Both alpha-interferon and floxuridine are active in metastatic renal cell carcinoma (MRCC); the two agents have demonstrated antitumor synergism and different clinical toxicities. The purpose of this study was to determine the maximum tolerable dose (MTD) of floxuridine (FUDR), administered as a constant continuous infusion for 14 days every 28 days, in combination with fixed doses of alpha-2B-interferon and to preliminarily evaluate the antitumor activity of this combination. METHODS: Sixteen patients entered the study; six had previously received alpha-interferon. Alpha-2B-interferon was administered at the dose of 10 x 10(6) IU intramuscularly 3 times/week and floxuridine at the starting daily dose of 0.075 mg/kg. This dose was escalated at each subsequent cycle up to dose-limiting toxicity. RESULTS: Most common toxicities included fever and flue-like symptoms, fatigue, anorexia, diarrhea, mucositis, and nausea, and 55% of patients experienced greater than or equal to Grade 2 toxicity, mostly diarrhea, for floxuridine doses greater than 0.125 mg/kg/d. Among 15 evaluable patients, 1 achieved a complete response and 4 achieved a partial one (33%; 95% confidence interval, 12-62%). Three partial responses were obtained in patients pretreated with alpha-interferon plus vinblastine. CONCLUSIONS: The combination of alpha-2B-interferon and floxuridine is feasible, and in our regimen the recommended daily dose of floxuridine for Phase II studies was 0.125 mg/kg. This combination is active in metastatic renal carcinoma, but further studies are needed to determine whether alpha-2B-interferon has added anything to the FUDR infusion or vice versa.

Adult↗

PubMed1989

Stability of floxuridine and leucovorin calcium admixtures for intraperitoneal administration.

The stability of floxuridine and leucovorin calcium in admixtures of 0.9% sodium chloride injection at various concentrations, temperature conditions, and time points was determined. Admixtures of floxuridine and leucovorin calcium were prepared in 1-L plastic bags containing 0.9% sodium chloride injection. Admixtures containing the following three concentrations were prepared: floxuridine 1 g and leucovorin calcium 30 mg, floxuridine 2 g and leucovorin calcium 240 mg, and floxuridine 4 g and leucovorin calcium 960 mg. The admixtures were stored at refrigerated temperature (4-8 degrees C), ambient room temperature (20 degrees C), and near-physiologic body temperature (40 degrees C). Drug concentrations were measured with a stability-indicating high-performance liquid chromatographic (HPLC) method at 0, 4, 8, 24, and 48 hours (4-8 degrees C) and at 0, 1, 3, 6, 24, and 48 hours (20 degrees C and 40 degrees C). A second set of samples at the same concentrations was prepared and sequentially stored at refrigerated, room, and near-physiologic temperatures to simulate actual-use conditions; these samples were assayed by HPLC at 0, 4, 8, 24, and 48 hours (4-8 degrees C); 49, 51, 54, and 60 hours (20 degrees C); and 61, 63, 66, and 72 hours (40 degrees C). All solutions were protected from light. Floxuridine and leucovorin calcium were stable at each concentration and temperature condition tested for a minimum of 48 hours. However, leucovorin calcium was more subject to decomposition at near-physiologic temperature than at other temperatures, with the most degradation at the lowest concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, High Pressure Liquid↗

PubMed1993

A phase II study of constant-infusion floxuridine for the treatment of metastatic renal cell carcinoma.

BACKGROUND: Twenty-nine patients with metastatic renal cell carcinoma (RCC) were treated with constant-infusion floxuridine (FUdR, Roche Laboratories, Nutley, NJ). METHODS: The initial dosage was 0.075 mg/kg/day for 14 days every 28 days and was increased or decreased by 0.025-mg/kg/day increments at each subsequent cycle until the maximum tolerated dose (MTD) was achieved. RESULTS: All patients were fully assessable. One (4%) patient had a complete response, 5 (17%) had a partial response, 13 (50%) had stabilized disease, and 10 (34%) had progressive disease. The treatment-limiting toxic effect was diarrhea, and the median tolerated dosage was 0.1 mg/kg/day for 14 days every 28 days (range, 0.05-0.275 mg/kg/day). Five of the six responses occurred at a dosage of 0.1 mg/kg/day or less, which was achievable in most patients. Patients who reached their MTD without achieving a complete or partial response were switched to circadian-infusion floxuridine to determine whether an increased dose intensity could be administered and whether this would translate into additional responses. A higher median tolerated dosage of 0.15 mg/kg/day was achieved with circadian administration; however, no additional responses were observed. The median survival time was 891 days after the diagnosis of metastatic RCC and 445 days after the institution of floxuridine therapy. CONCLUSIONS: Constant-infusion floxuridine is active against metastatic RCC and produces a response rate that appears to be comparable to that of circadian administration of floxuridine.

Adult↗

PubMed1994

Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases.

Very few patients with liver metastases from colorectal cancer can be cured. We have investigated whether a treatment to slow the growth of liver metastases, hepatic-artery infusion of floxuridine, improves palliation in this setting. In a randomised study of 100 patients, we compared quality of life and survival in patients who received hepatic-artery infusion of floxuridine and in those who received conventional symptom palliation. 95% of control patient survival time was spent with normal quality-of-life scores, which suggests that the aim of treatment should be to prolong normal-quality survival rather than merely to sustain quality of life. There was a significant prolongation (p = 0.03) in overall survival in floxuridine-treated patients compared with controls (median 405 vs 226 days). There were similar significant prolongations in normal-quality (ie, normal symptom scores) survival for physical symptoms (p = 0.04), anxiety (p = 0.04), and depression (p = 0.04). This survival benefit was associated with significant reductions in metastasis size on computed tomography (p = 0.001) and in serum carcinoembryonic antigen concentration (p = 0.006) in floxuridine-treated patients. There was no evidence of treatment-related hepatotoxicity as assessed by serum aspartate aminotransferase and bilirubin measurements. This is the first demonstration that survival can be prolonged with normal quality of life in patients with colorectal liver metastases. We conclude that hepatic-artery floxuridine infusion can be recommended for suitable patients.

Anxiety↗

PubMed1990

Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial.

Seventy-four patients with liver metastasis from proved colorectal primary adenocarcinoma were entered into a prospective, randomized clinical trial to evaluate treatment with intra-arterial floxuridine compared with standard outpatient therapy with fluorouracil delivered by intravenous bolus injection. Eligible patients were randomized to hepatic arterial chemotherapy with an implanted infusion pump or systemic chemotherapy. No crossover between treatment arms was permitted, and patients were followed up to progression and death. Objective tumor response was observed in 48% of patients receiving intra-arterial floxuridine and in 21% of patients receiving intravenous fluorouracil. Time to hepatic progression was significantly longer in the group given intra-arterial therapy: 15.7 vs 6.0 months. However, time to overall progression (6.0 vs 5.0 months) and survival (12.6 vs 10.5 months) were not statistically different. Based on these data, we cannot recommend treatment with intra-arterial floxuridine as given in this study for metastatic colorectal cancer to the liver.

Adenocarcinoma↗

PubMed1994

Gastric mucosal injury after hepatic arterial infusion chemotherapy with floxuridine. A clinical and pathologic study.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) of liver metastases of colon cancer with an implantable pump is associated with liver and gastrointestinal complications. METHODS: The authors retrospectively studied the clinical features and gastric histopathology of nine patients who received HAIC and had gastritis develop and in whom biopsy specimens were available. RESULTS: Gastritis was heralded in these patients by epigastric pain and tenderness, nausea, vomiting, weakness, and anorexia. In seven patients, 18 gastric ulcers were endoscopically detected. Mucosal damage developed despite prophylactic antiulcer therapy and healed only upon cessation of HAIC. These observations suggest that the predominant drug given, floxuridine, was the responsible toxic agent. Seventeen biopsy specimens were reviewed, and all exhibited varied histologic evidence of inflammation, reactive glandular changes, and cell necrosis. These mucosal changes were present even in tissues obtained from patients without ulcers. In addition, floxuridine-induced glandular atypia was noted in eight biopsy samples from six patients. The crowded glands were distorted and lined by large cells that included bizarre forms with pleomorphic nuclei. CONCLUSIONS: Gastric injury in HAIC appeared analogous to the general features encountered in reactive gastritis resulting from chemical irritants. The glandular atypia is peculiar to HAIC, and although the changes were morphologically alarming, in this clinical situation care should be exercised not to interpret floxuridine-induced atypia as carcinoma.

Adult↗

PubMed1989

Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?

A 43-year-old man underwent abdominoperineal resection of a rectal adenocarcinoma, and left hepatic lobectomy for a single metastasis. He then received hepatic artery infusions of floxuridine. The tumor did not recur, but sclerosing cholangitis and liver failure developed which necessitated orthotopic liver transplantation. In the hilus of the native liver, obstructive arteriopathy and portal venopathy were found. These lesions probably had been caused by drug-induced intravascular thrombosis. Thus, the sclerosing cholangitis that develops in many patients after floxuridine infusion may be ischemic rather than toxic. The patient described here is well, 14 months after orthotopic liver transplantation. Therefore, in some cases of floxuridine-induced cholangitis, liver transplantation appears to be indicated despite a history of metastasizing carcinoma.

Adult↗

PubMed1975

Effect of deoxyuridine coadministration on toxicity and antitumor activity of fluorouracil and floxuridine.

The addition of deoxyuridine (UDR) to fluorouracil (FU) or floxuridine (5-fluoro-2' deoxyuridine) (FUDR) produced a substantial increase in their toxicity in BDF1 mice. Antitumor assays using sarcoma 180 tumor-bearing mice showed a concomitant increase in tumor growth inhibition for the nucleoside-drug combination over identical doses of the single drug. However, no significant increase in antitumor activity with the combination treatment was demonstrated when equitoxic doses were given. Additional support for the therapeutic equality of the single and combination drug regimens was the similarity of the therapeutic indexes for each treatment regimen involving either fluorouracil or floxuridine. The results suggested that any therapeutic benefit achieved with the combination therapy could be duplicated with either fluorouracil or floxuridine at a higher dose.

Animals↗

PubMed1991

High-performance liquid chromatographic method for the simultaneous measurement of floxuridine and fluorouracil in human body fluids.

A method for the simultaneous measurement of floxuridine (5-fluorodeoxyuridine) and fluorouracil in human plasma and peritoneal fluid has been developed. This method utilizes high-performance liquid chromatographic analysis with a Zorbax RX column (25 cm x 4.6 mm I.D.) plus a guard cartridge of the same material. The sensitivity limits for this assay are 0.25 mumol/l in a 20-microliters sample. The detection limit at a signal-to-noise ratio of 3 is 2.5 nmol/l. This procedure has been used to quantitatively measure concentration versus time profiles of floxuridine and fluorouracil in plasma and peritoneal fluid of human patients after receiving intraperitoneal administration of floxuridine.

Ascitic Fluid↗

PubMed1985

Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine.

High response rates have been reported with hepatic intra-arterial infusions of floxuridine in patients having colorectal carcinoma metastatic to the liver. The major toxicity of this therapy has been described as "chemical hepatitis." In a randomized trial of intravenous v intra-arterial floxuridine, we observed that all 35 patients receiving intra-arterial therapy developed significant increases in alkaline phosphatase and, in some cases, serum glutamic oxaloacetic transminase and/or bilirubin. Seven patients receiving intra-arterial therapy were studied with cholangiography which, in all cases, demonstrated sclerosis of the intrahepatic and/or extrahepatic bile ducts. In addition, liver biopsies showed cholestasis and pericholangitis with minimal hepatocyte damage. These findings suggest that "biliary sclerosis" rather than "chemical hepatitis" is the predominant toxicity associated with hepatic intra-arterial infusions of floxuridine.

Aged↗

PubMed1992

Five-minute treatments with fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenon's capsule fibroblasts.

Proliferating human Tenon's capsule fibroblasts were exposed for 5 minutes to a wide range of concentrations of fluorouracil, floxuridine, and mitomycin. High concentrations of all three agents had prolonged effects on cell proliferation and morphologic characteristics compared with untreated control cells up to 36 days. The highest concentrations of both floxuridine (15,000 micrograms/mL) and mitomycin (1000 micrograms/mL) had an apparent cidal effect, reducing cell numbers below initial cell density. In contrast, although the highest concentration of fluorouracil (25,000 micrograms/mL) inhibited cell proliferation by more than 50% relative to the untreated control cells at 36 days, the cell numbers still increased fourfold compared with the initial cell density. These results demonstrate that 5-minute treatments with high concentrations of these drugs have prolonged effects on the proliferation of human Tenon's capsule fibroblasts in vitro. Single-dose regimens using high concentrations of these drugs at the time of operation may achieve results similar to those of protocols that involve repeated applications.

Cell Division↗

PubMed1986

Fibrosis of extrahepatic biliary system after continuous hepatic artery infusion of floxuridine through an implantable pump (Infusaid pump).

A case of severe fibrosis of the extrahepatic biliary system after hepatic artery infusion of floxuridine is described. The clinical and pathologic features are presented, and its pathogenesis discussed. The authors suggest investigation of an alternate drug schedule and/or dosage of floxuridine to eliminate or minimize this serious complication.

Biliary Tract↗

PubMed1977

Liposomal entrapment of floxuridine.

Floxuridine was found to have an apparent initial entrapment within negatively charged sphingomyelin liposomes about three times higher than its parent, fluorouracil. The drug also diffused out of the liposomes at a much lower rate than fluorouracil. Substitution of lecithin for sphingomyelin destroyed the effect. Liposomal entrapment may provide enhanced stability and decreased toxicity of floxuridine, permitting wider therapeutic utilization of pyrimidine nucleosides.

Chemistry, Pharmaceutical↗

PubMed1996

Intraperitoneal mitoxantrone or floxuridine: effects on time-to-failure and survival in patients with minimal residual ovarian cancer after second-look laparotomy--a randomized phase II study by theSouthwest Oncology Group.

A randomized phase II study of intraperitoneal (ip) mitoxantrone or floxuridine (FUDR) was performed for the treatment of minimal residual epithelial ovarian cancer found at second-look laparotomy after initial platinum-based chemotherapy. Entry was to take place within 30 days of reassessment laparotomies, with documentation of peritoneal metastases either microscopic or gross with cytoreduction to less than or equal to 1 cm in largest diameter. Patients were stratified by the site of the largest disease present (microscopic to 0.5 cm maximum diameter versus greater than 0.5 to 1 cm maximum diameter), by time of registration (< 14 days versus up to 30), and by serum CA-125 (< or = 35 versus >35 units/ml) prior to randomization to either ip mitoxantrone 10 mg/m2 every 2 weeks X 9 or ip floxuridine (FUDR) 3 g (total dose)/ day X 3 days every 3 weeks X 6 cycles. Implantable ip systems and 1.5-2 liters of normal saline were used to deliver the drugs of 83 patients registered between December 1988 and January 1994; there were 6 pathology exclusions and 9 surgical exclusions, and 1 nonevaluable patient for a total of 39 evaluable on mitoxantrone and 28 on FUDR being evaluable. FUDR is the choice for further study because of a progression-free survival exceeding 15% at 1 year over mitoxantrone and a median overall survival of 38 months. It should be emphasized again that the goal of a randomized phase II selection design is to select a winner for phase III testing should there be a substantial difference between the treatments with respect to the primary endpoint. Comparative conclusions between the treatment arms should not be attempted due to the inherently much smaller sample sizes. This should reemphasize the limitations in a comparison of efficacy; however, the toxicologic differences still emerge quite clearly.

Adult↗

PubMed1996

Alternating floxuridine and 5-fluorouracil hepatic arterial chemotherapy for colorectal liver metastases minimizes biliary toxicity.

BACKGROUND: The goals of this study of a hepatic arterial infusion (HAI) regimen of alternating floxuridine and 5-fluorouracil were to evaluate the treatment-related toxic effects, the antitumor response rate, and patient survival. METHODS: Fifty-seven consecutive patients were treated with implanted HAI pumps and received a regimen of alternating floxuridine (0.1 mg/kg/day continuous HAI for 7 days) followed by a weekly HAI pump bolus of 5-fluorouracil (15 mg/kg for 3 weeks). Any changes in treatment plan because of toxicity, antitumor response, and survival were recorded. RESULTS: Thirty-one (54.4%) patients responded to this HAI regimen; 14 (24.5% )patients had stable disease, and 12 (21.1%) progressed during treatment. Responders or patients with stable disease had a significantly (P < 0.05) improved survival rate (19 months median) compared with patients in whom disease progressed (12 months median). Two (3.5%) patients developed biliary sclerosis and 12 (21.1%) had mild transient liver function abnormalities. The liver alone or in combination with another area was the site of first progression of disease in 40 (70.2%) patients. CONCLUSIONS: This regimen had reversible or no hepatobiliary toxicity in more than 95% of patients. Tumor reduction or stabilization of disease was observed in 79% of the patients, who had a median survival of 19 months. Reduced toxicity and more effective chemotherapeutic regimens may increase the likelihood of survival after HAI chemotherapy for unresectable colorectal liver metastases.

Adult↗

PubMed1991

Circadian infusion of floxuridine in patients with metastatic renal cell carcinoma.

A total of 42 patients with metastatic renal cell carcinoma received floxuridine infusion for 14 days at monthly intervals. The drug was delivered via an external programmable pump on a time-modified or circadian schedule; the highest dose of 68% was given between 3 and 9 p.m. Of the 42 patients 25 (60%) had undergone prior nephrectomy. Of the 40 evaluable patients 4 (10%, 95% confidential interval 3 to 24%) achieved a partial response: 3 of the 4 had undergone prior nephrectomy, while 1 had undergone renal angioinfarction. Another 4 patients (10%) had responses at metastatic sites but no response in the primary kidney tumor. The median duration of response for these 2 groups of patients was 65 and 27 weeks, respectively, and the most responsive site was the lungs. The treatment was generally well tolerated and could be administered on an outpatient basis. Our study confirms the limited but definite activity of floxuridine infused on a circadian schedule in patients with metastatic renal cell carcinoma. We observed responses in metastasis equally in patients with or without prior nephrectomy.

Adult↗