Prolonged infusion of gemcitabine in stage IV breast cancer

Akrivakis, K.; Schmid, Peter; Flath, Bernd; Schweigert, M.; Sezer, Orhan; Mergenthaler, H.-G.; Possinger, K.

doi:10.1097/00001813-199907000-00003

Cited by 43 publications

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“…A phase I study of the continuous infusion of gemcitabine for up to 6 h has been reported in patients with metastatic breast cancer [9], and a follow-up phase II study of that approach showed an overall response rate of 25% and stable disease rate of 30% [6]. …”

Section: Discussionmentioning

confidence: 99%

“…This enzyme is saturated at plasma concentrations achieved after infusion for 30 min; therefore, accumulation of higher concentrations of intracellular dFdCTP cannot be achieved by higher dosage but only by prolonged infusion time. A phase I trial of continuous infusion of gemcitabine for up to 6 h has been reported in metastatic breast cancer patients [9], and a follow-up phase II trial showed an overall response rate of 25% and stable disease rate of 30% with that approach [10]. Continuous infusion of gemcitabine at the rate of 10 mg/m 2 /min was also used in a phase II trial in metastatic lung cancer [11].…”

Section: Introductionmentioning

confidence: 99%

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Phase I Study of Prolonged-Infusion Gemcitabine Combined with Cyclophosphamide in Patients with Metastatic Carcinoma of the Breast: Tolerability of an Optimal Dose Schedule

et al. 2009

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Background: A phase I study was initiated to determine the maximum tolerated dose (MTD) of prolonged-infusion gemcitabine combined with cyclophosphamide in patients with metastatic breast carcinoma (MBC). Methods: Patients with MBC were treated with gemcitabine infusion at 10 mg/m²/min and cyclophosphamide by intravenous piggyback injection, 4 h after initiation of the infusion. We treated 3–6 patients at a particular dose level until the MTD was determined. Results: Overall, 44 patients received a total of 197 courses of therapy. Both drugs were given on days 1, 8 and 15 to 14 patients (68 courses). Delayed white blood cell recovery necessitated first protocol amendment to drop cyclophosphamide on days 8 and 15 in 9 patients (43 cycles). A second amendment was needed to drop gemcitabine on day 15 because of thrombocytopenia in 21 patients (86 courses). The dose-limiting toxicity was thrombocytopenia. The MTD of an optimal dose schedule was 800 mg/m² gemcitabine infused at a rate of 10 mg/m²/min on days 1 and 8, and 400 mg/m² cyclophosphamide, by intravenous piggyback injection, on day 1, 4 h after initiation of the gemcitabine infusion. Conclusions: The MTD can be given safely every 4 weeks to patients with MBC. Phase II studies are warranted to evaluate the clinical activity of this therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase I Study of Prolonged-Infusion Gemcitabine Combined with Cyclophosphamide in Patients with Metastatic Carcinoma of the Breast: Tolerability of an Optimal Dose Schedule

et al. 2009

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“…The AUC of dFdU, the main deaminated metabolite of gemcitabine, and OS time significantly correlated with the expression and activity of cytidine deaminase (p Ͻ .05). Studies on the prolonged infusion of gemcitabine during 3, 4, 6, and 24 hours at low dose levels in patients with advanced solid tumors found low MTD values between 180 and 450 mg/m 2 [72][73][74][75]. Besides treatment with single-agent gemcitabine, FDR infusion of gemcitabine has been investigated in combination with other chemotherapeutic agents, such as carboplatin and cisplatin.…”

Section: Phase I/ii Dose-finding Studies Investigating Prolonged (Fdrmentioning

confidence: 99%

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

2008

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After completing this course, the reader will be able to:1. Describe the molecular pharmacology of nucleoside analogues.2. Explain transport, metabolism, and elimination in relation to the activity of gemcitabine.3. Describe the clinical pharmacology of gemcitabine in relation to its rate of administration.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTGemcitabine is frequently used in the treatment of patients with solid tumors. Gemcitabine is taken up into the cell via human nucleoside transporters (hNTs) and is intracellularly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active triphosphate metabolite 2,2-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into DNA and inhibits DNA synthesis. In addition, gemcitabine is extensively deaminated to 2,2-difluorodeoxyuridine, which is largely excreted into the urine. High expression levels of human equilibrative nucleoside transporter type 1 were associated with a significantly longer overall survival duration after gemcitabine treatment in patients with pancreatic cancer.Clinical studies in blood mononuclear and leukemic cells demonstrated that a lower infusion rate of gemcitabine was associated with higher intracellular dFdCTP levels. Prolonged infusion of gemcitabine at a fixed dose rate (FDR) of 10 mg/m 2 per minute was associated with a higher intracellular accumulation of dFdCTP, greater toxicity, and a higher response rate than with the standard 30-minute infusion of gemcitabine in patients with pancreatic cancer.In the current review, we discuss the molecular pharmacology of nucleoside analogues and the influence of hNTs and dCK on the activity and toxicity of gemcitabine, which is the basis for clinical studies on

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“…Common side effects of taxanes are neutropenia, anemia, neurological symptoms, stomatitis and dermal afflictions [11,12]. Gemcitabine is a pyrimidine analogue antimetabolite drug that has been used as an alternative in the treatment of metastatic breast cancer [13][14][15]. It is known as an option for combination therapy because of its mechanism of action, toxicity profile, additive or synergistic activity in vitro and a lack of cardiotoxicity.…”

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confidence: 99%

Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial

Schröder

Rack

Sommer

et al. 2016

Geburtshilfe Frauenheilkd

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!Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients. Methods: Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3-4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support. Results: No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5 %, p < 0.001), as was leukopenia (64.1 vs. 58.5 %, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8 %, FEC-D: 36.3 %, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3 %, SGOT: 2%), whereas neuropathy (1.2 %), arthralgia (1.6 %) and bone pain (2.6 %) were more common using FEC-D. Dose reductions > 20 % (4 vs. 2.4 %) and postponement of treatment cycles (0.9 vs. 0.4 %) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm. Conclusion: The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles.

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Prolonged infusion of gemcitabine in stage IV breast cancer

Cited by 43 publications

References 0 publications

Phase I Study of Prolonged-Infusion Gemcitabine Combined with Cyclophosphamide in Patients with Metastatic Carcinoma of the Breast: Tolerability of an Optimal Dose Schedule

Phase I Study of Prolonged-Infusion Gemcitabine Combined with Cyclophosphamide in Patients with Metastatic Carcinoma of the Breast: Tolerability of an Optimal Dose Schedule

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial

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