Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone marrow and extensive bone involvement have limited the use of chemotherapy with stem cell support for treatment of women with metastatic breast cancer. The toxicity and efficacy of dose-intensive chemotherapy were studied using etoposide and cyclophosphamide without a stem cell support regimen for women with advanced breast cancer. The regimen was well tolerated, with treatment-related mortality similar to dose-intensive therapy with stem cell support. The overall 58% response rate is comparable to the response rate with dose-intensive chemotherapy regimens using stem cell support. The extent of disease, responsiveness to standard therapy, and dose of etoposide affected the response rate. Hematopoietic recovery was fairly prompt and was generally unaffected by the use of hematopoietic growth factors or the presence of breast cancer cells in the marrow. The use of stem cells or recombinant human interleukin-3 (rhIL-3) in combination with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) resulted in some benefit in neutrophil recovery. It was concluded that in many women with advanced breast cancer, a dose-intensive regimen of etoposide and cyclophosphamide results in response or stabilization of disease. Hematopoietic recovery, particularly platelet recovery, may be accelerated by a combination of rhIL-3 and rhGM-CSF.
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PMID:Dose-intensive chemotherapy with etoposide-cyclophosphamide for advanced breast cancer. North American Marrow Transplant Group. 860 May 46

The aim of this phase II study was to determine the feasibility of using two (tandem) courses of high-dose alkylating agents with bone marrow or peripheral blood progenitor cell support in women with stage IV breast cancer. Women with stage IV breast cancer who had achieved a CR or PR during conventional chemotherapy were enrolled in a phase II trial of high-dose cyclophosphamide 7500 mg/m2 and thiotepa 675 mg/m2 (C+T) followed within 180 days by high-dose melphalan (M) 140 mg/m2. Bone marrow and/or GM-CSF mobilized peripheral blood hematopoietic progenitor cells were used to support high-dose C+T and high-dose M. Twenty-seven women were enrolled in this trial. The median age was 45 years (range 32-56). The median PS was 0 and all patients had achieved either a CR (4/27, 15%) or PR (23/27, 85%) to conventional chemotherapy. All 27 women underwent high dose C+T. The predominant toxicities were mucositis (81%), and diarrhea (81%); two patients (7%) died from infectious complications. Following C+T, the median time to hematologic recovery for neutrophils (ANC > 500 cells/mu 1) was 12 days and for platelets (>20 000 cell/mu 1), 23 days. Following C+T, 18 of 22 patients received high dose M; the predominant toxicities were nausea, vomiting (70%), and mucositis (91%). The median time to hematologic recovery for the ANC was 13 days and for platelets, 18 days. The overall response after high dose C+T and high dose M was 67% (CR, 15/27 patients (56%) and PR* (complete resolution of all measurable disease but persistent lytic disease or positive bone scan) 3/27 patients (11%). With median follow-up of 24 months, the actuarial freedom from relapse or treatment failure is 56% at 24 months. At 30 months 56% of patients are alive. For patients who achieve a CR or PR* the actuarial freedom from relapse or treatment failure at 24 months is 88%. In women with stage IV breast cancer who attain a CR or PR to conventional chemotherapy, tandem high-dose chemotherapy with ABMT can lead to prolonged relapse-free survival.
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PMID:Tandem high-dose chemotherapy supported by hematopoietic progenitor cells yields prolonged survival in stage IV breast cancer. 864 Jan 60

Autologous peripheral blood progenitor cells (PBPC) rescue after high-dose chemotherapy has been used progressively as a form of treatment in some solid and hematologic tumors. This increasing use can be explained by both advantages of PBPC rescue over bone marrow rescue (decrease in the duration of marrow aplasia, reduction of platelet transfusions, earlier discharge from hospital, potential use in patients with inadequate bone marrow reserve) and the low number of aphereses (one or two) needed to collect a sufficient number of progenitor cells for autografting. High-dose chemotherapy is likely to be increasingly used after the results of two recently reported studies in which treatment with high-dose compared with standard-dose chemotherapy increases overall survival in metastatic breast cancer patients and relapsed lymphoma patients. After the initial use of unselected mobilizing regimens regardless of the patient characteristics and the tumor type, now it seems more useful to optimize this approach. Mobilization of PBPC can be obtained by several approaches. Moderate or high doses of single agent alone (e.g. cyclophosphamide 4-7 g/m2) or some hematopoietic growth factors alone (e.g. G-CSF, GM-CSF) have been proven to be adequate mobilizing agents. However, the use of hematopoietic growth factors alone may disadvantageously delay the start of an effective chemotherapy. An efficient mobilizing regimen requires the use of both chemotherapy and hematopoietic growth factors: the efficiency of mobilization was greater and with less side effects than chemotherapy alone. It was postulated that PBPC mobilization could be achieved only at hematopoietic recovery following myeloablative chemotherapy. Recently, it has been demonstrated that some standard-dose chemotherapy regimens associated with hematopoietic growth factors are efficient priming agents. We reported that standard-dose CEF chemotherapy plus filgrastim is a disease specific regimen (breast cancer) allowing PBPC mobilization without any relevant toxicity. The maximum release of PBPC has been observed at day 11. The optimal time for PBPC collection is predictable and aphereses can be guided by WBC counts. In conclusion, both standard and high dose chemotherapy are effective priming regimens. So presently a mobilizing regimen should be an effective disease specific chemotherapy program and should contain a hematopoletic growth factor. The choice between standard and high-dose chemotherapy can be based on patients characteristic and disease status.
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PMID:[Mobilization of peripheral blood stem cells with conventional chemotherapy]. 892 33

We studied the effects of escalating doses of recombinant human IL-1 beta in patients receiving high-dose chemotherapy and ABMT for metastatic breast cancer or malignant melanoma. Sixteen patients received IL-1 beta, 4 to 32 ng/kg/day administered subcutaneously for 7 days beginning 3 h after bone marrow infusion. Three patients at the highest dose level also received G-CSF following completion of IL-1 beta. All patients completed the 7 days of therapy. The majority of patients experienced chills and fever following one or more injections, and seven had severe pain at the injection site. There was one episode of hypotension and one episode of transient confusion at the highest dose level; other significant toxicity was not identified. Recovery of neutrophils to > 0.5 x 10(9)l and platelet transfusion independence occurred at a median of 23 and 22 days, respectively, which was comparable to historical controls. The mean number of bone marrow colony-forming unit granulocyte-macrophage (CFU-GM) per 10(5) mononuclear cells on day +21 post-ABMT was more than twice that of control patients or patients receiving G-CSF or GM-CSF. A linear correlation was found between the dose of IL-1 beta and endogenous concentrations of several cytokines. These patients also displayed significantly higher concentrations of endogenous G-CSF compared to historical controls receiving GM-CSF. While IL-1 beta was moderately toxic and had no effect on recovery of peripheral blood counts after ABMT, the increased number of bone marrow CFU-GM suggests that the addition of G- or GM-CSF to a short course of IL-1 beta may accelerate hematologic recovery.
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PMID:A phase I trial of recombinant human interleukin-1 beta (OCT-43) following high-dose chemotherapy and autologous bone marrow transplantation. 905 Dec 40

Interleukin-3 (IL-3) is a multipotent hematopoietic growth factor, which exhibits stimulatory effects on leucocytes, reticulocytes and platelets. Due to its pronounced induction of megakaryopoiesis, IL-3 is thought to be a cytokine with the potential to prevent and to overcome chemotherapy-induced thrombocytopenia. We report on four cases (two of metastatic breast cancer, one of metastatic ovarian cancer and one of Hodgkin's disease) with prolonged chemotherapy-induced thrombocytopenia in whom rhIL-3 in combination with either recombinant human (rh) granulocyte macrophage colony stimulating factor (GM-CSF) or rh granulocyte colony stimulating factor (G-CSF) was administered. In all cases, a steady and clinically significant increase in platelet counts could be observed. No major side effects, neither due to the application of rhIL-3 nor due to rhGM-CSF or rhG-CSF, occurred; only flu-like symptoms were seen, which could effectively be treated with paracetamol. This report highlights the efficacy of combined treatment with rhIL-3 plus rhGM-CSF or rhG-CSF in chemotherapy-induced thrombocytopenia, where megakaryopoiesis could be stimulated efficiently by rhIL-3. Based on this experience, the authors conclude that established thrombocytopenia as a major side effect of myelosuppressive chemotherapy should be considered as an indication for the use of rhIL-3 in interventional treatment. Further investigations in this area are encouraged.
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PMID:Treatment of prolonged chemotherapy induced severe thrombocytopenia with recombinant human interleukin-3--a report on four cases. 909 35

Seventy women with high-risk stage II (n = 10), IIIA (n = 12), IIIB (n = 11), or IV (n = 37) breast cancer received cyclophosphamide 6000 mg/m2, etoposide 2400 mg/m2, and carboplatin 1200 mg/m2 followed by infusion of autologous hematopoietic stem cells (AHSC). Women with high-risk stage II disease had eight or more involved axillary lymph nodes (n = 9) or axillary and breast relapse following lumpectomy, chemotherapy, and radiation therapy (n = 1). Women with measurable stage III or stage IV disease were required to demonstrate complete or partial response to conventional-dose chemotherapy prior to transplant. The overall (complete plus partial) response rate for the 31 patients not in complete remission at the time of transplant was 55%. With a median follow-up of 545 days, the 2-year actuarial progression-free survival rates for patients with stage II, IIIA, IIIB and IV are 86, 75, 42 and 13%, respectively. Factors independently predictive of longer progression-free survival by multivariate analysis included lower stage disease, status of disease at transplant (in CR vs not in CR), and positive estrogen receptor status. Factors predictive of more rapid neutrophil engraftment by multivariate analysis included post-transplant administration of hematopoietic growth factors, greater number of infused CFU-GM, mobilization with G-CSF or cyclophosphamide/G-CSF (vs mobilization with GM-CSF or no mobilization), and lower stage disease. Only one patient (1.4%) died prior to day 100 from any cause. High-dose cyclophosphamide, etoposide, and carboplatin followed by infusion of AHSC constitutes an active and well-tolerated regimen in the treatment of women with high-risk non-metastatic or metastatic breast cancer.
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PMID:Phase II study of high-dose cyclophosphamide, etoposide, and carboplatin (CEC) followed by autologous hematopoietic stem cell rescue in women with metastatic or high-risk non-metastatic breast cancer: multivariate analysis of factors affecting survival and engraftment. 928 41

Previous studies have suggested that in vivo granulocyte colony-stimulating factor (G-CSF) pharmacokinetics may change over time. We studied three patients treated with high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) for metastatic breast cancer after intravenous administration of recombinant human (rh) G-CSF (5 or 16 microg/kg/day). We investigated plasma G-CSF concentrations and absolute neutrophil counts (ANCs/pL) in these patients on three separate days. G-CSF plasma clearance increased with time post-ABMT with no change in the apparent volume of distribution (Vd) of G-CSF. Regression analysis of G-CSF plasma clearance and ANCs revealed a linear relationship, with r2 = 0.85 (p = 0.00025). We further investigated this phenomenon in vitro by estimating pharmacokinetic parameters for rhG-CSF using a model in which polymorphonuclear neutrophils (PMNs) were incubated with rhG-CSF. We found that, at low G-CSF concentrations in vitro, there was an increase in G-CSF clearance with increasing ANCs, but at higher G-CSF concentrations this relationship did not hold. We suggest that this finding resulted from aggregation and polymerization of G-CSF at high concentrations when kept at 37 degrees C for 24-48 hours in vitro. Using fluorescence staining techniques, our data suggest there are changes over time in the amount of G-CSF bound to PMNs. These changes may reflect reexpression or recycling of the G-CSF receptor, and could explain the continuing clearance of G-CSF by PMNs in vitro. The strong positive correlation between G-CSF plasma clearance and ANCs in vivo is compatible with the hypothesis that neutrophils mediate one of the major pathways for rhG-CSF clearance.
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PMID:The role of polymorphonuclear neutrophils (PMNs) in clearance of granulocyte colony-stimulating factor (G-CSF) in vivo and in vitro. 940 90

A phase I study of escalating doses of humanized bispecific antibody (bsAb) MDX-H210 with granulocyte-colony-stimulating factor (G-CSF) was conducted in patients with metastatic breast cancer that overexpressed HER2/neu. The main objectives of the study were to define the maximal tolerated dose (MTD) of MDX-H210 when combined with G-CSF, to measure the pharmacokinetics of MDX-H210 when administered with G-CSF, and to determine the toxicity, biological effects and possible therapeutic effect of MDX-H210 with G-CSF. MDX-H210 is a F(ab)' x F(ab)' humanized bispecific murine antibody that binds to both HER2/neu and the FcgammaR1 receptor (CD64), and was administered intravenously weekly for three doses followed by a 2-week break and then three more weekly doses. A total of 23 patients were treated, and doses were escalated from 1 mg/m2 to 40 mg/m2 with no MTD reached. The toxicity of the bsAb + G-CSF combination was modest, with no dose-limiting toxicity noted: 19 patients had fevers, 7 patients had diarrhea, and 3 patients had allergic reactions that did not limit therapy. The beta-elimination half-life varied from 4 h to 8 h at doses up to 20 mg/m2. Significant release of cytokines interleukin-6, G-CSF, and tumor necrosis factor alpha was observed after administration of bsAb. Circulating monocytes disappeared within 1 h of bsAb infusion, which correlated with binding of bsAb, noted by flow-cytometric analysis. Significant levels of human anti-(bispecific antibody) were measured in the plasma of most patients by the third infusion. No objective clinical responses were seen in this group of heavily pre-treated patients.
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PMID:A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu. 1023 84

In a prospective randomized trial, 40 stage IV breast cancer patients undergoing intermediate high-dose chemotherapy (cyclophosphamide, 5-fluorouracil plus epirubicin or methotrexate), received either recombinant human G-CSF (rhG-CSF, group I) or ciprofloxacin and amphotericin B (CAB, group II) for prevention of febrile leucopenia (FL). In group I, seven of 18 patients developed FL (after 10/108 courses); in group II, seven of 22 patients (7/98 courses) (P = NS). Median hospitalization duration and costs were not different. RhG-CSF was 6.6 times more expensive per course than CAB. In conclusion, prophylactic CAB has similar efficacy to rhG-CSF in this setting, and is more cost-effective.
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PMID:Prevention of febrile leucopenia after chemotherapy in high-risk breast cancer patients: no significant difference between granulocyte-colony stimulating growth factor or ciprofloxacin plus amphotericin B. 1038 2

To increase the dose-intensity of two drugs in metastatic breast cancer, we tested the feasibility, in phase I studies, of two schedules of epirubicin (E) and cyclophosphamide (C) - sequential (E--> C) and alternating (E/C) - with respect to the standard combination (EC). Drugs were given at three planned-dose levels, plus either G-CSF or GM-CSF. Patients with metastatic (30), inoperable stage IIIb (2) or inflammatory (7) breast cancer were treated. The doses of EC, given every 21 days (4 cycles), were 75/1500, 82.5/2250, 90/3000 mg/m2. In the E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at cycles 2, 4 and 6. In the E--> C schedule, three cycles of epirubicin then three cycles of cyclophosphamide were administered. In both experimental schedules, drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m2 (E) and 2000, 3000, 4000 mg/m2 (C). The average relative dose-intensity was 1.2-fold and 2-fold greater with E/C and E--> C, respectively, than with EC. The third level dose was feasible with all schedules. Grade 4 leucopenia occurred in 77% of patients. Thrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8%). Eighty-one percent of patients on experimental schedules required red blood cell support versus 44.4% of patients on EC. At the third level, platelet transfusions were more frequent among patients treated with EC (27. 8%). Non-haematological toxicity was mild: about 20% of patients experienced grade 3 vomiting, irrespective of schedule. Only 2 patients had grade 3 mucositis; no patient developed heart failure. Fever (61% of patients) and bone pain (55.5% of patients) were relevant in the GM-CSF treated groups and 12 patients shifted to G-CSF. The overall response rate was 84.6%: 5/39 (12.8%) complete response and 28/39 (71.8%) partial response. At 30/9/98, median survival was 29.5 months, with no difference between patients with metastatic and stage IIIb/inflammatory breast cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5-year estimated survival was 19% (95% confidence intervals = 7-31%). Rapidly alternating or sequential cycles of epirubicin and cyclophosphamide with CSF support is a feasible strategy that allows a higher increase of dose-intensity of the single drugs. Hospitalization and anemia were more frequent with the experimental schedules, and thrombocytopenia with the standard schedule. Overall, this intensified therapy was very active.
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PMID:The impact of schedule on acute toxicity and dose-intensity of high-dose chemotherapy with epirubicin and cyclophosphamide plus colony stimulating factors in advanced breast cancer. 1040 45


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