levoleucovorin and Hypotension

To determine the plasma pharmacokinetics and the maximum-tolerated dose (MTD) of intravenous (IV) azidothymidine (AZT) administered 90 to 120 minutes after fluorouracil (5-FU) and leucovorin and to preliminarily evaluate the antitumor activity of this combination in metastatic colorectal cancer.. 5-FU 500 mg/m2 IV bolus was administered once a week in the middle of a 2-hour infusion of leucovorin; AZT was given as a 90 to 120-minute IV infusion 60 minutes after 5-FU. Initial AZT dose was 0.5 g/m2, and it was escalated in successive cohorts of three patients by 0.5 to 2 g/m2.. Thirty-five chemotherapy-naive metastatic colorectal cancer patients were entered onto the study, and AZT doses ranged from 0.5 to 10 g/m2. The peak AZT plasma concentration increased from 21.9 to 995.6 micromol/L. The area under the concentration/time curve (AUC) also showed a progressive, but not linear increase from 40.34 to 3,108 h x micromol/L. The most relevant toxicity was diarrhea, which was severe in six patients (17%). Toxicities were not AZT-dose-related, except fpr hypotension, which occurred in patients treated at AZT doses > or = 7 g/m2 and became dose-limiting for AZT 10 g/m2. Among 34 assessable patients, 15 objective responses were observed (44%; 95% confidence interval 27 to 62), lasting a median of 44 weeks; five (15%) were complete.. AZT doses > or = 6 g/m2 administered IV over 90 to 120 minutes produce maximum plasma concentration and AUC similar to those previously reached in murine tumor models. Dose-limiting toxicity is hypotension, which occurs at AZT 10 g/m2. The recommended AZT dose for further studies is 8 g/m2. The combination of 5-FU plus leucovorin plus AZT is feasible with acceptable toxicities, and has promising activity in metastatic colorectal cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Confidence Intervals; Drug Administration Schedule; Female; Fluorouracil; Humans; Hypotension; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Zidovudine

It has been demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) can ameliorate chemotherapy-induced neutropenia. The extent to which GM-CSF can increase the actual delivered dose intensity of combination chemotherapy over multiple cycles of therapy to patients with advanced breast cancer has not been well defined. We conducted a phase I/II study of dose-intensive FLAC chemotherapy (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) in combination with GM-CSF in patients with locally advanced and metastatic breast cancer to study the acute and cumulative toxicities, anti-tumor activity and dose-intensity achievable with this regimen.. Eighty-one patients with newly diagnosed stages IIB, III and IV breast cancer who were previously untreated with chemotherapy and who had measurable disease received multiple cycles of FLAC chemotherapy plus E. coli-derived GM-CSF administered every three weeks.. FLAC plus GM-CSF as associated with significant cumulative hematologic toxicity. Ninety-eight percent of patients developed grade 4 neutropenia; 29% of all cycles administered required hospitalization for fever and neutropenia; 41% and 22% of cycles required red blood cell and platelet transfusions, respectively. Other significant toxicities with E. coli-derived GM-CSF included mild to moderate first dose effects (hypotension, dyspnea, abdominal cramping) in 30% of patients; late occurring anaphylactoid reactions in 11% of patients; and vascular thromboses. The average delivered dose intensities over all cycles were cyclophosphamide, 210 mg/m2/week; doxorubicin, 14.8 mg/m2/week and 5-fluorouracil, 342 mg/m2/week. The overall clinical response rates were 100% and 83% for LABC and metastatic patients, respectively. There were 23% (6/26) pathologic CR's in the LABC patients given neoadjuvant FLAC and 22% (12/54) clinical CR's in the stage IV patients. The median survival of the LABC patients has not been reached (> 26 months) and is 30 months for the stage IV patients.. The administration of multiple cycles of FLAC plus E. coli-derived GM-CSF therapy is associated with cumulative, dose-limiting myelosuppression, especially thrombocytopenia, as well as significant clinical toxicity. A modest increase in FLAC dose intensity over the starting doses was achievable with the addition of GM-CSF. FLAC chemotherapy has substantial antitumor activity in the treatment of advanced breast cancer. The potential usefulness of FLAC plus GM-CSF must be balanced by its considerable cost and alteration in patients' quality of life due to toxicity. Combination hematopoietic growth factor strategies may be able to reduce the toxicity of FLAC and to allow further increase dose intensity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Dyspnea; Escherichia coli; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypotension; Leucovorin; Middle Aged; Neoplasm Staging; Neutropenia; Recombinant Proteins; Regression Analysis; Remission Induction; Survival Rate

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Female; Fluorouracil; Humans; Hypotension; Leucovorin; Liver Neoplasms; Middle Aged; Rectal Neoplasms

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chills; Fever; Fluorouracil; Humans; Hypotension; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Nausea; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Vomiting

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Histamine H1 Antagonists; Humans; Hypotension; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms

Topics: Adenocarcinoma; Angina Pectoris; Electrocardiography; Female; Fluorouracil; Heart; Heart Diseases; Humans; Hypotension; Intestinal Neoplasms; Intestine, Small; Leucovorin; Middle Aged; Syndrome; Tachycardia; Ventricular Function, Left