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PubMed2002

Capecitabine and tegafur + uracil: new preparations. Metastatic colorectal cancer: two oral fluorouracil precursors, few advantages.

(1) The standard chemotherapy for metastatic colorectal cancer is intravenous fluorouracil combined with calcium folinate. This treatment improves the median survival time by approximately 4-6 months compared with optimal palliative care. (2) Two metabolic precursors of fluorouracil are now available in the European Union for first-line oral treatment of metastatic colorectal cancer, namely capecitabine and tegafur + uracil. According to the licensing terms, only the tegafur-uracil combination must be given with calcium folinate. (3) The evaluation files on each of these two cytotoxic agents contain data from two comparative unblinded trials versus intravenous fluorouracil + calcium folinate (Mayo Clinic protocol). None of these trials showed a difference in survival. (4) Both drugs caused severe diarrhoea in 12% of patients. Severe palmoplantar erythrodysesthesia was more frequent on capecitabine. Longer postmarketing follow-up is available for the tegafur + uracil combination, which has been used in Japan for many years. (5) Patients receiving capecitabine or tegafur + uracil + calcium folinate have to take large numbers of tablets or capsules. (6) In practice, the standard treatment for metastatic colorectal cancer remains the fluorouracil + calcium folinate combination. The tegafur + uracil + calcium folinate combination is only useful for patients who prefer oral administration. Capecitabine has no documented advantage over this latter combination.

Administration, Oral↗
PubMed1963

Effects of uracil and thymidine on the development of resistance to 5-fluorouracil in Pediococcus cerevisiae.

White, P. J. (Roswell Park Memorial Institute, Buffalo, N.Y.) and C. A. Nichol. Effects of uracil and thymidine on the development of resistance to 5-fluorouracil in Pediococcus cerevisiae. J. Bacteriol. 85:97-105. 1963.-Growth of Pediococcus cerevisiae ATCC 8081 in a basal semidefined medium was inhibited by 5-fluorouracil (FU) and 5-fluoro-2'-deoxyuridine (FUDR). Addition of uracil slightly decreased sensitivity to FU, but did not affect inhibition by FUDR. Addition of thymidine alone increased sensitivity to FUDR 500-fold, but did not appreciably affect sensitivity to FU. This organism was able to grow in the presence of high concentrations of either drug when both uracil and thymidine were added to the medium. Substrains resistant to FU were developed in the basal medium, or in basal medium with added uracil, or with thymidine. The substrains developed in the presence of uracil or thymidine were not resistant when these compounds were omitted from the medium. Cross resistance to FUDR was shown only when thymidine was present. The ability to use thymidine as a growth factor in the absence of leucovorin was lost in the substrains developed in the presence of uracil, though not in the other substrains. Washed suspensions of organisms of all strains hydrolyzed FUDR to FU, the parent strain being most active in this respect. The cellular uptake of fluorouracil-2-C(14) was less in all of the resistant substrains than in the parent strain, whether or not uracil or thymidine was present during the incubation. This uptake of FU-C(14) was decreased most markedly in the substrains which became resistant to FU in the absence of uracil.

Deoxyuridine↗
PubMed1998

An intravitreal sustained-release triamcinolone and 5-fluorouracil codrug in the treatment of experimental proliferative vitreoretinopathy.

OBJECTIVE: To determine the efficacy and pharmacokinetics of an intravitreal sustained-release triamcinolone acetonide and 5-fluorouracil (TA/5-FU) codrug in the treatment of experimental proliferative vitreoretinopathy (PVR). METHODS: The therapeutic efficacy of the TA/5-FU codrug was determined in a rabbit model that simulates human PVR. Intravitreal levels of triamcinolone and 5-fluorouracil were measured at different time points and drug release in vitro was tested. Toxic effects were evaluatedby electroretinograpy, clinical examination, and light microscopy. RESULTS: Both the severity of PVR grade and the percentage of eyes with moderate or worse tractional detachment were significantly less in eyes treated with the codrug. The therapeutic effect of the intravitreal codrug was paralleled by sustained intravitreal levels of triamcinolone and 5-fluorouracil. There were no drug-related toxic effects evident on clinical or histopathologic examination of eyes containing the TA/5-FU codrug. CONCLUSIONS: The intravitreal sustained-release TA/5-FU codrug effectively inhibits the progression of PVR in a rabbit model that closely resembles PVR in humans. The TA/5-FU codrug may simultaneously target different components of the wound-healing response.

Animals↗
PubMed1981

Punctal-canalicular stenosis related to systemic fluorouracil therapy.

This is, to our knowledge, the first report in the ophthalmic literature of punctal-canalicular stenosis and concomitant epiphora associated with the prolonged administration of fluorouracil; to our knowledge, fluorouracil is the first systemically administered agent to cause obstruction in the lacrimal system. Each of three patients receiving this antimetabolite alone and one patient receiving it in combination with methotrexate and cyclophosphamide were studied for complaints of epiphora. All four patients exhibited stenosis or occlusion of one or more puncta, while three also had one or four of their canaliculi stenosed. Two patients exhibited recurrent epiphora, beginning one to two days after each administration of fluorouracil and resolving in two to three days. One patient experienced amelioration of her symptoms after Silastic tube intubation of her canalicular system.

Adenocarcinoma↗
PubMed1986

Aqueous concentrations of fluorouracil after intravitreal injection. Normal, vitrectomized, and silicone-filled eyes.

Treatment of postoperative vitreoretinopathy with combined intravitreal fluorouracil and liquid silicone may result in increased corneal and retinal toxicity. We therefore investigated the movement of carbon 14-labeled fluorouracil from the vitreous into the anterior chamber in normal rabbit eyes and in eyes filled with either balanced salt solution or silicone after vitrectomy and lensectomy, with or without preservation of the anterior capsule. Only 0.56% of intravitreally injected fluorouracil was recovered from the anterior chamber over a four-hour period in normal eyes. This impermeability was partly maintained if the anterior capsule was retained (9.98%), particularly if the eye contained silicone (2.52%). The greatest amount was recovered when both lens capsules were removed (43.7%). Corneal toxicity is most likely to occur in this situation.

Animals↗
PubMed1988

Fluorouracil therapy of intraocular Greene melanoma in the rabbit.

We evaluated the efficacy of intraocular and periocular fluorouracil treatment in an experimental iris tumor of the rabbit (Greene amelanotic melanoma). Four consecutive intravitreal injections of 1 mg of fluorouracil given twice weekly completely suppressed tumor growth in all treated eyes for six weeks if treatment was initiated 24 hours after tumor implantation. In contrast, all control eyes implanted with an equal number of Greene melanoma cells but treated with intravitreal saline developed massive tumor invasion of the iris within two weeks. Additional subconjunctival therapy following intravitreal therapy for two weeks was only slightly more effective than intravitreal therapy alone. If therapy was delayed for one week, the iris tumors became macroscopically visible and subsequent treatment with intravitreal and subconjunctival fluorouracil was of limited value in suppressing growth.

Animals↗
PubMed1995

Effect of mitomycin C and fluorouracil-supplemented trabeculectomies on the anterior segment.

OBJECTIVES: To determine whether there is increased risk to the corneal endothelium when mitomycin C is used in trabeculectomy surgery instead of fluorouracil, and whether these agents play a role in accelerating cataract formation. DESIGN, SETTINGS, AND PARTICIPANTS: We analyzed the corneal endothelium and the lens preoperatively and postoperatively in 30 eyes of 21 patients who underwent either a fluorouracil- or mitomycin C-supplemented trabeculectomy. RESULTS: No significant differences were found between these two groups in the rate of cataract progression, magnitude of endothelial cell loss, or appearance of endothelial cell morphologic characteristics. Endothelial cell loss accounted for approximately 7% to 8% of the preoperative counts in both groups. In addition, four (27%) of 15 eyes in each group showed evidence of cataract progression as graded by the Lens Opacities Classification System II. CONCLUSION: Fluorouracil- and mitomycin C-supplemented trabeculectomies cause similar changes in the lens and corneal endothelium.

Aged↗
PubMed1983

Effects of protein-calorie malnutrition and refeeding on fluorouracil toxicity.

Mice were used to study the effects of protein-calorie malnutrition and its reversal on granulocyte-macrophage production and fluorouracil's toxic effect on bone marrow. An in vitro quantitative clonal culture technique for bone marrow granulocyte-macrophage progenitor cells (GM-CFC) was used. Animals on a protein-free but otherwise complete diet for ten days had a significant contraction in total marrow cellularity and GM-CFC numbers paralleling the animal's weight loss. The acute toxic effect of fluorouracil on bone marrow was not increased in protein-deprived animals. On refeeding, there was a biphasic response in the degree of toxic effect on marrow. Animals refed for one day had significantly increased fluorouracil-related marrow abnormalities. However, animals refed for four days, when marrows were repleted, were partially protected from the drug's cytotoxic effects. The increased sensitivity in mice refed for one day was related to more GM-CFC in active DNA synthesis.

Animals↗
PubMed1975

Erythroplasia of Queyrat. Treatment with topically applied fluorouracil.

Three patients with biopsy-confirmed erythroplasia of Queyrat were treated with topically applied fluorouracil. The lesions cleared completely, and recurrence-free follow-up periods ranged from 20 to 60 months. There were normal histological findings in posttreatment biopsy specimens in two of the patients. A literature review yielded five additional cases successfully treated with fluorouracil applied topically. Patients with histologically confirmed erythroplasia of Queyrat should be afforded treatment with topically applied fluorouracil, as results appear to be superior to those of surgical or radiological treatment, with less morbidity.

Administration, Topical↗
PubMed1975

Topical chemotherapy of lentigo maligna with 5-fluorouracil.

Three patients with biopsy-proven lentigo maligna were treated with topical 5-fluorouracil. Treatment consisted of twice daily application of 5% 5-fluorouracil cream for 13, 6, and 9 weeks, respectively. Two patients demonstrated presence of invasive melanoma; in one the melanoma was evident before chemotherapy, and in the other the lesion became evident after chemotherapy. In both the lentigo was treated topically and the melanoma excised locally. Posttreatment followup times through April 1, 1974 have been 42, 24, and 22 months, respectively. There has been no evidence of metastases in any patient. Topical chemotherapy with 5-fluorouracil cream appears to offer an encouraging alternative method of therapy for lentigo maligna of the face.

Aged↗
PubMed1977

Treatment of advanced adenocarcinoma of the pancreas with combinations of streptozotocin plus 5-fluorouracil and streptozotocin plus cyclophosphamide.

One hundred and sixteen patients with advanced and metastatic adenocarcinoma of the pancreas were randomized to treatment with combined Streptozotocin and 5-fluorouracil or combined Streptozotocin and cyclophosphamide. Toxic reactions to each regimen were qualitatively similar and consisted of nausea and vomiting during the time of treatment and subsequent leukopenia and thrombocytopenia. Renal toxicity was less frequent and only rarely severe. Among 51 eligible and evaluable patients treated with the Streptozotocin-cyclophosphamide combination, 12% showed objective response and among 42 patients treated with Streptozotocin + 5-fluorouracil, 12% showed objective response. The Streptozotocin + 5-fluorouracil-treated patients showed a slight advantage in survival. Neither regimen can be considered of substantive value to the patient with advanced pancreatic carcinoma.

Adenocarcinoma↗
PubMed1984

Chemotherapy of diffuse malignant mesothelioma. Phase II trials of single-agent 5-fluorouracil and adriamycin.

Twenty consecutive patients with a confirmed diagnosis of diffuse malignant mesothelioma of the pleura or peritoneum, previously untreated with chemotherapy, were studied in a Phase II trial of single-agent 5-fluorouracil. One partial response of 24 months was seen. Eleven patients were treated with single-agent Adriamycin (doxorubicin) after progression on 5-fluorouracil, and one partial response of 34 months was seen. It is concluded that 5-fluorouracil has only minimal activity in diffuse malignant mesothelioma. Preliminary data suggest that Adriamycin has little activity as a second-line agent.

Adult↗
PubMed1989

Concomitant 5-fluorouracil infusion and high-dose radiation for stage III non-small cell lung cancer.

Thirty patients with Stage III non-small cell lung cancer were entered on a trial to evaluate the feasibility of combined radiation and concomitant 5-fluorouracil infusion. Patients had received prior debulking surgery (nine), induction chemotherapy (16), or no therapy (five). Radiation employed standard fractionation (180-200 rad/day) administered to a median cumulative dose of 5500 rad (range, 4500-6200 rad). 5-Fluorouracil was infused 24 hours per day throughout the period of radiation at a dose of 300 mg/m2/day for a median of 42 days (range, 28-56 days). Radiation complications included pneumonitis three of 30 (10%) and esophagitis (27%). Chemotherapy complications included stomatitis, two of 27 (7%), and hand-foot syndrome, three of 30 (10%). Treatment interruptions were necessary in six of 30 (20%) and four of 30 required parenteral nutrition. At a median follow-up of 12 months 26/30 (87%) maintained local control and eight had distant metastases (three of whom presented with Stage IV disease). 5-Fluorouracil delivered continuously throughout standard fractionation radiation to high cumulative doses is feasible and practical. Comparative clinical trials of the various combined radiation and chemotherapy schedules employed are in order. One additional clinical observation was the identification of six of 30 (20%) with brain metastases at presentation or after 12 months, all of whom had adenocarcinoma histologic subtype.

Aged↗
PubMed1992

Continuous-infusion cisplatin, 5-fluorouracil, and bolus methotrexate in the treatment of advanced non-small cell lung cancer.

BACKGROUND: Cisplatin and 5-fluorouracil have noted synergy in preclinical systems. The authors combined methotrexate with infusional cisplatin and 5-fluorouracil in an attempt to produce a regimen with improved activity in advanced NSCLC: METHODS: Twenty-six ambulatory patients with previously untreated non-small cell lung cancer were treated with continuous-infusion cisplatin (25 mg/m2/day for 5 days), 5-fluorouracil (800 mg/m2/day for 5 days), and intermediate-dose methotrexate (200 mg/m2 on days 15, 22), followed by leucovorin rescue (PFM regimen). RESULTS: Patients received a median of four cycles of therapy. Two patients had a complete response, and 10 had a partial response (overall response rate, 46.2% or 12 of 26). The median time to treatment failure was 22.5 weeks; the median survival was 55 weeks from the start of chemotherapy. There were no toxic deaths attributed to chemotherapy. Thrombocytopenia was the only Grade 4 toxicity (27%). Grade 1/4 and 2/4 peripheral neuropathy occurred in 17 of 26 patients (66%) and was associated with a cumulative cisplatin dose of more than 300 mg/m2. CONCLUSIONS: PFM (using continuous-infusion cisplatin) produced a high response rate but resulted in an high incidence of low-grade peripheral neuropathy.

Adult↗
PubMed1993

Feasibility of dose-intensive continuous 5-fluorouracil, doxorubicin, and cyclophosphamide as adjuvant therapy for breast cancer.

BACKGROUND: Several studies support the belief that the efficacy of adjuvant chemotherapy in breast cancer is related to the dose intensity of the chemotherapy used (expressed in milligrams per square meter per week). Retrospective analyses indicate that the actual delivered dose intensity may correlate more strongly with efficacy than the intended dose delivery. METHODS: A doxorubicin-based adjuvant regimen was studied for breast cancer. It was modeled on the Southwest Oncology Group's regimen of cyclophosphamide, methotrexate, and 5-fluorouracil in that daily oral cyclophosphamide and weekly intravenous 5-fluorouracil were used, but weekly doxorubicin was substituted for methotrexate and administered in both the adjuvant and neoadjuvant setting to 29 patients. RESULTS: The actual dose delivery was 1.21-1.24-fold that calculated for the delivered dose in the two other adjuvant regimens using the same three drugs (5-fluorouracil, doxorubicin, and cyclophosphamide) for which this could be determined. This regimen was tolerated well. Toxicity was minimal and consisted largely of expected neutropenia. CONCLUSIONS: Whether improved dose intensity can be increased further with the use of growth factors or actually confers improved outcomes awaits the results of larger future trials.

Adult↗
PubMed1993

Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer.

BACKGROUND: Cardiotoxicity related to the widely used cytotoxic compound 5-fluorouracil (5-FU) is rare compared with the frequency observed with the use of anthracyclines. More effective protocols incorporating active biomodulatory compounds like folinic acid (FA) or combination chemotherapy change type and severity of toxicity as well. The objective of the current study was to assess cardiotoxicity of the combination 5-FU and folinic acid. METHODS: The authors' multicenter experience with 390 patients treated for advanced gastrointestinal cancer with intermediate-dose folinic acid and 5-FU was reviewed. RESULTS: The overall risk of cardiotoxicity was 3%, which is not significantly higher than that reported with 5-FU alone. Eight of 53 patients with a history of cardiac disease reported cardiac symptoms (15.1%), compared with 5 of 337 patients (1.5%) with a no history of cardiac disease. Median time to symptoms was 3 days (range, 2-6). Nine patients had symptoms resembling myocardial ischemia, one patient died due to assumed myocardial infarction related closely to fluorouracil treatment, four patients had supraventricular arrhythmia, and one patient had congestive heart failure. A history of cardiac disease was the only risk factor associated with cardiotoxicity. Relapses were frequent on reinstitution of therapy despite cardiac symptoms in the preceding cycle. Therapeutically or prophylactically administered nitrates had no significant effect. CONCLUSION: Physicians should be aware of the cardiotoxic properties of active fluorouracil treatment. The combination of 5-FU and leucovorin does not differ from single-agent therapy in frequency or type of cardiotoxicity. Close monitoring of patients is mandatory, especially for those patients at high risk for cardiac side effects. Treatment should be discontinued if coronary symptoms develop, because neither effective treatment nor prophylaxis exists for such symptoms.

Adult↗
PubMed1994

Continuous-infusion cisplatin, 5-fluorouracil, and leucovorin for advanced non-small cell lung cancer.

BACKGROUND: Cisplatin, 5-fluorouracil, and leucovorin (PFL) have demonstrated synergistic activity in preclinical models. Continuous infusion of these agents maximizes the potential for synergistic interaction and forms the basis of the PFL regimen. METHODS: Sixty-one patients with advanced (Stages IIIB and IV) non-small cell lung cancer were entered into the study. Thirty-one were treated with cisplatin 25 mg/m2/day on days 1-5, 5-fluorouracil 800 mg/m2/day on days 2-6, and calcium leucovorin 500 mg/m2/day on days 1-6. Because of severe mucositis, the final 30 patients were treated with the same dosage of cisplatin but with the deletion on day 6 of leucovorin and 5-fluorouracil. Cycles were repeated every 28 days. Response was assessed after two cycles. Responding patients received an additional two cycles. Patients with Stage IIIB disease received radiation therapy to the mediastinum and sites of involved disease. RESULTS: PFL had an overall response rate of 41%. Median survival was 8.1 months, and median time to treatment failure was 4.2 months. Importantly, 68% (17 of 25) of responses were maximal after just two cycles of chemotherapy. Notable toxicities included mucositis (43% > or = Grade 3) and myelosuppression. Response, time to failure, or survival did not differ between the two schedules. Mucositis was less severe with 4-day PFL. CONCLUSIONS: PFL as given in this manner is an active regimen for the treatment of patients with advanced non-small cell lung cancer. The rapidity of response makes it a regimen for incorporation into protocols for Stage IIIA disease. A neoadjuvant study using PFL is underway.

Adult↗
PubMed1994

A phase I trial of immediate postoperative intraperitoneal floxuridine and leucovorin plus systemic 5-fluorouracil and levamisole after resection of high risk colon cancer.

BACKGROUND: The purpose of this study was to evaluate the toxicity of immediate postoperative intraperitoneal (IP) floxuridine (FUdR) and leucovorin (LV) after resection of high risk colon cancer, and to determine the appropriate dose of intravenous fluorouracil (FU) plus levamisole during concurrent intraperitoneal therapy. METHODS: The authors conducted a tertiary referral Comprehensive Cancer Center Phase I Trial in patients with resected colon cancer at high risk for recurrence. After resection of all gross disease, intraperitoneal treatment was administered twice daily for 3 days every 2 weeks for three cycles (Days 1-3, 15-17, 29-31). Intravenous FU daily for 5 days was administered on days 29-33 concurrently with the third cycle of intraperitoneal therapy. Fluorouracil doses during the last cycle of intraperitoneal therapy were escalated; intraperitoneal FUdR and LV doses and weekly intravenous FU doses (starting on Day 58) were fixed. RESULTS: Twenty-six patients with resected high risk colon cancer were treated. Three had Dukes' B2, 16 Dukes' C, and 7 Dukes' D (M1) resected tumors. Intraperitoneal therapy was well tolerated with no increase in operative morbidity and no operative mortality. Two patients had > or = Grade 3+ toxicity during IP therapy alone. There were no treatment related deaths. During concurrent intraperitoneal and intravenous chemotherapy, the maximum tolerated dose of FU was 300 mg/m2/day for 5 days. The recommended dose for Phase II or III trials is 200 mg/m2/day for 5 consecutive days. Pharmacokinetic analysis indicated that using the doses used in this trial, measurable systemic concentrations of FUdR and LV were obtained during IP therapy. This may have contributed to observed toxicity with intravenous FU doses of 300-400 mg/m2. With a median duration of follow-up of 18 months, four patients had recurrence of disease. No peritoneal recurrences have been noted to date. CONCLUSIONS: Immediate postoperative IP FUdR and LV are well tolerated after resection of high risk colon cancer. The recommended dose of intravenous FU beginning on Day 29 (concurrent with the last dose of IP therapy) is 5FU 200 mg/m2 for 5 consecutive days. The remaining year of adjuvant fluorouracil and levamisole can be administered with standard dose attenuation. Although follow-up is short, the lack of recurrent peritoneal metastases is encouraging. Additional trials with this approach are warranted in patients with high risk colorectal cancer.

Adult↗