Gemcitabine combined with continuous infusion 5-fluorouracil in advanced and symptomatic pancreatic cancer: a clinical benefit-oriented phase II study
Elide MatanoP TagliaferriAnnamaria LibroiaV. DamianoAntonietta FabbrociniSonya De LorenzoAngelo Raffaele Bianco
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Gemcitabine and 5-fluorouracil are the only two compounds with reproducible activity against advanced pancreatic cancer (APC). We have evaluated a novel combination of gemcitabine and 5-fluorouracil on the clinical benefit response (CBR) end point. Eleven consecutive patients with symptomatic APC were entered in a two-stage phase II trial. Gemcitabine was administered by intravenous (i.v.) bolus injection at the dose of 1000 mg m–2 on days 1, 8, 15 and 5-fluorouracil 500 mg m–2 was given by continuous i.v. infusion on days 1–5. Treatment was repeated every 28 days. A CBR was achieved in 7/11 patients. The mean time to loss of CBR was 26.5 weeks (range 14–18, median 22). Toxicity was mild and no APC patient experienced WHO grade 3 toxicity. The gemcitabine/5-fluorouracil combination is well tolerated and produces a symptomatic relief in the majority of APC patients. © 2000 Cancer Research CampaignKeywords:
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Pancreatic Disease
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The experience is reported of the use of the totally implantable "Infusaid" infusion pump in the treatment of 14 patients in our combined clinics for metastatic carcinoma in the liver by means of the antimetabolite 5-FU. At the time of this study the more active antimetabolite 5-FUDR was not available. A comparison is made of overseas reports of the use of 5-FUDR in the Infusaid infusion pump with the experience, in our clinic, of the use of 5-FU.
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Gemcitabine and 5-fluorouracil are the only two compounds with reproducible activity against advanced pancreatic cancer (APC). We have evaluated a novel combination of gemcitabine and 5-fluorouracil on the clinical benefit response (CBR) end point. Eleven consecutive patients with symptomatic APC were entered in a two-stage phase II trial. Gemcitabine was administered by intravenous (i.v.) bolus injection at the dose of 1000 mg m–2 on days 1, 8, 15 and 5-fluorouracil 500 mg m–2 was given by continuous i.v. infusion on days 1–5. Treatment was repeated every 28 days. A CBR was achieved in 7/11 patients. The mean time to loss of CBR was 26.5 weeks (range 14–18, median 22). Toxicity was mild and no APC patient experienced WHO grade 3 toxicity. The gemcitabine/5-fluorouracil combination is well tolerated and produces a symptomatic relief in the majority of APC patients. © 2000 Cancer Research Campaign
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Pancreatic Disease
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The current study was initiated to confirm preliminary reports that 20% or more of patients with colorectal cancer who fail treatment with 5-fluorouracil (FUra) will respond to treatment with either leucovorin plus FUra or with sequential methotrexate, FUra, leucovorin. One hundred two patients with advanced, measureable colorectal cancer who failed treatment with FUra and/or 5-fluorodeoxyuridine (FUdR) were randomized to treatment with either high-dose leucovorin plus FUra (Arm B) or sequential methotrexate, FUra, leucovorin (Arm C). In this interim report, 92 patients were evaluable for toxicity and 89 patients were evaluable for response. Grade 3 or 4 nonhematologic toxicity which was primarily gastrointestinal was experienced by 25% of patients on both treatment arms during at least 1 treatment cycle. Hematologic toxicity was minimal. Among 43 evaluable patients on Arm B, there were 2 complete responses (5%) and 1 minor response (3%). Among 46 evaluable patients on Arm C, there was 1 complete response (2%), 1 partial response (2%), and 6 minor responses (14%). The median time to treatment failure was 2.2 months on Arm B and 3.5 months on Arm C. The median survival was 8.3 months on Arm B and 8.7 months on Arm C. Colorectal cancers that are resistant to FUra are cross-resistant to both experimental combinations.
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Vistonuridine (PN401 or 2',3,'5'-tri-O-acetyluridine) is a newly approved orphan drug that demonstrates promising results as an antidote for 5-fluorouracil (5- FU) overdoses. Fluorouracil is a pyrimidine antimetabolite frequent- ly used as a part of various chemotherapeutic regimens. It is a fluorinated analogue of uracil, a naturally occur - ComPrisi Ng the Lo Ng is LANd, New York Cit Y, r uth L Awre NCe, uP st Ate New York, ANd w ester N New York Poiso N CeNters
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The experience is reported of the use of the totally implantable "Infusaid" infusion pump in the treatment of 14 patients in our combined clinics for metastatic carcinoma in the liver by means of the antimetabolite 5-FU. At the time of this study the more active antimetabolite 5-FUDR was not available. A comparison is made of overseas reports of the use of 5-FUDR in the Infusaid infusion pump with the experience, in our clinic, of the use of 5-FU.
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The antimetabolite 5-fluorouracil is frequently used in the therapy of various malignancies. Cardiotoxicity has frequently been described during treatment, but there is no common agreement on the need to perform cardiovascular monitoring of patients during 5-fluorouracil administration. We report the case of a young patient with an head-neck cancer on whom a continuous electrocardiogram recording was performed, documenting serious ventricular dysrhythmias in the presence of myocardial ischemia during 5-fluorouracil and cis-platin infusion.
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Gemcitabine (2≺,2≺difluoro-2≺deoxycytidine, dFdC) is a synthetic antimetabolite of the cellular pyrimidine nucleotide metabolism. In a first series of in vitro experiments, the drug showed a strong effect on the proliferation and colony formation of the human androgen-sensitive tumor cell line LNCaP and the androgen-insensitive cell lines PC-3 and DU-145. Maximal inhibition occurred at a dFdC concentration as low as 30 nM. In contrast to the cell lines which were derived from metastatic lesions of prostate cancer patients, no inhibitory effects were found in normal primary prostatic epithelial cells at concentrations up to 100 nM. The effect of gemcitabine was reversed by co-administration of 10–100 μM of its natural analogue deoxycytidine. In view of a future clinical application of this anti-tumor drug in advanced prostatic carcinoma, we have compared the effect of gemcitabine on prostatic tumor cells with that on bone marrow granulopoietic-macrophagic progenitor cells, because neutropenia is a common side effect of gemcitabine treatment. The time course of action on the two kinds of cells was markedly different. Colony formation of tumor cells was inhibited by two thirds at a gemcitabine concentration of about 3.5 nM. The same effect on granulopoietic-macrophagic progenitor cells required a concentration of 9 nM. Co-administration of deoxycytidine to gemcitabine-treated tumor cell cultures completely antagonized the effect of gemcitabine whereas addition of deoxycytidine after 48 hr of gemcitabine treatment could not prevent gemcitabine action on the tumor cells. In contrast, more than half of the granulopoietic-macrophagic progenitor cells could still be rescued by deoxycytidine administration after 48 hr. These findings and the marked difference in the susceptibility of neoplastic and normal prostatic cells suggest that gemcitabine is a promising substance which should be further evaluated as to its efficacy in the treatment of advanced prostatic carcinoma. © 1996 Wiley-Liss, Inc.
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A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in the CCRF-CEM human leukemia cell culture assay. Concurrent addition of deoxycytidine to the cell culture system provides about a 1000-fold decrease in biological activity. The inhibition of growth of human leukemia cells in culture led to the in vivo evaluation of this compound as a potential oncolytic agent. Maximal activity in vivo was seen with dFdCyd when administered on an every third day schedule. 1-beta-D-Arabinofuranosylcytosine, administered on a daily for 10-day schedule, was directly compared to dFdCyd in this evaluation. dFdCyd demonstrated good to excellent antitumor activity in eight of the eight murine tumor models evaluated. 1-beta-D-Arabinofuranosylcytosine was substantially less active or had no activity in these same tumor models. This in vivo activity against murine solid tumors supports the conclusion that dFdCyd is an excellent candidate for clinical trials in the treatment of cancer.
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