Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug scheduling alterations can improve the therapeutic index of both 5-fluorouracil and anthracyclines. We investigated a regimen of weekly doxorubicin and continuous infusional 5-fluorouracil (AcF) in loco-regionally recurrent and metastatic breast cancer. The aims of this phase II study were to use low-dose weekly anthracyclines in a patient group where liver metastases are a frequent problem, to optimise scheduling of 5-fluorouracil using continuous infusion and to conserve alkylating agent use for late intensification in responding patients. Fifty-six patients received 5-fluorouracil 200 mg m-2 day-1 and doxorubicin 20-30 mg m-2 week-1 for at least 6 weeks. Sixty-two percent were chemonaive. Patients were evaluated for dose intensity, response, toxicity and survival. Of the assessable patients, 76% achieved UICC response criteria (20% complete response, 56% partial response). WHO grade 3+ toxicities were: alopecia, 98%; mucositis, 62%; neutropenia, 22%; and grade 3 palmar-plantar syndrome, 24%. Median survival was 13 months, with visceral metastasis conferring a significantly worse outcome (P = 0.03). Grade 3+ mucositis was more frequent with planned doxorubicin dose intensity > or = 25 mg m-2 week-1 (P = 0.04). AcF is highly active in breast cancer with acceptable toxicities and can be used before alkylating agent-based high-dose therapy.
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PMID:Weekly doxorubicin and continuous infusional 5-fluorouracil for advanced breast cancer. 898 Apr 5

9-Amino-20(S)-camptothecin (9-AC) is an analog of camptothecin with limited water solubility which has shown significant preclinical activity in a variety of human solid tumor xenografts. A Phase I trial using a soluble formulation of 9-AC, given as a 72-hour continuous infusion, has been completed. Thirty-one patients with resistant cancers received 5-60 micrograms/M2/h at three week intervals. The Maximum Tolerated Dose (MTD) was 45 micrograms/M2/hour. Neutropenia was the dose limiting toxicity, with few significant non-myelosuppressive toxicities. Minor responses were seen in 3/31 patients. Pharmacokinetic studies of 9-AC lactone (closed ring) showed substantial interpatient variability with a predicted half-life of 36 hours. A phase I/II trial of the same formulation of 9-AC is ongoing in refractory leukemia. Stomatitis and diarrhea are the non-myelosuppressive dose limiting toxicities. Evidence of antineoplastic activity has been seen in 3/15 patients. A Phase II trial in previously untreated metastatic breast cancer is also underway. A Phase I trial of a colloidal dispersion formulation, not yet completed, is better tolerated with a MTD > 45 micrograms/M2/h as a 72-hour continuous infusion. Evidence of antineoplastic activity has also been demonstrated.
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PMID:Trials of 9-amino-20(S)-camptothecin in Boston. 899 18

In an attempt to develop new, active, and convenient outpatient combination-chemotherapy regimens for patients with metastatic breast cancer, we performed two phase I studies combining paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus anthracycline for the first-line treatment of metastatic disease, without the use of hematopoietic growth factors. Study I was designed to test the tolerability and antitumor activity of a 3-hour infusion of paclitaxel in combination with an epirubicin intravenous bolus. Study 2 explored a three-drug chemotherapy regimen: a 3-hour paclitaxel infusion with epirubicin and cyclophosphamide. Courses were repeated every 3 weeks. If any dose-limiting events occurred in two or more of six patients in the first course of a given dose level, that dose level was defined as the maximum tolerated dose. Dose-limiting criteria included the following: neutrophils less than 0.25 x 10(9)/L lasting for > or = 5 days, any febrile neutropenia, World Health Organization grade 4 thrombocytopenia, World Health Organization grade > or = 3 nonhematologic toxicity or grade > or = 3 mucositis for more than 5 days, and absence of hematologic recovery at day 35. In both studies, paclitaxel doses were escalated in subsequent groups of three to six patients. For study I, the initial dose level consisted of paclitaxel (110 mg/m2)/epirubicin (50 mg/m2). To date 40 patients have entered the study at eight dose levels. Of the 181 cycles evaluated, grade 3 or 4 neutropenic episodes were observed in 63% of courses, with only five episodes of febrile neutropenia. Grade 2 or 3 neurotoxicity was observed in 43% of patients. Two patients experienced clinical heart failure. The dose-limiting toxicity has not been reached so far. At dose level 7 (paclitaxel [250 mg/m2]/epirubicin [50 mg/m2]), only one patient of six experienced febrile neutropenia. We are currently testing paclitaxel (200 mg/m2)/epirubicin (75 mg/m2). Preliminary evaluation of response documents two complete and 16 partial responses in 37 evaluable patients (48% overall response rate). In study 2, the initial dose level consisted of paclitaxel (150 mg/m2)/epirubicin (50 mg/m2)/cyclophosphamide (500 mg/m2). To date, three dose levels have been investigated in 16 evaluable patients (82 cycles). Grade 3 or 4 neutropenic episodes were observed in 80% of courses, and five episodes were associated with neutropenic fever. Grade 2 neurotoxicity was observed in 28% of patients. The dose-limiting toxicity has not been reached, and we are currently investigating dose level 4 (paclitaxel 225 mg/m2). These trials confirm the tolerability of combined paclitaxel/epirubicin and paclitaxel/epirubicin/cyclophosphamide. The antitumor activity is encouraging.
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PMID:Phase I studies of combined paclitaxel/epirubicin and paclitaxel/epirubicin/cyclophosphamide in patients with metastatic offast cancer: the French experience. 907 33

Preliminary results of this ongoing phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus epirubicin administered as first-line treatment to women with metastatic breast cancer indicate encouraging response rates and no severe toxicity. Among the 57 patients admitted to this study, 52% had received prior adjuvant chemotherapy (85% with cyclophosphamide/methotrexate/5-fluorouracil), 46% had received radiotherapy, and 30% had received both forms of therapy; 63% of patients were postmenopausal, mainly with poorly differentiated tumors, and 80% presented with > or = 2 metastatic sites. Epirubicin 60 mg/m2 was administered intravenously as a 1-hour infusion followed by paclitaxel 175 mg/m2 infused over 3 hours. Standard premedication was given. Granulocyte colony-stimulating factor support was not used. Neutropenia was evident in 72% of cycles but was not severe. Instances of anemia and thrombocytopenia were rare. Alopecia was universal. All nonhematologic toxicity observed was mild or moderate (peripheral neuropathy, myalgia, nausea, vomiting World Health Organization toxicity grade < 2). At this time, 41 patients are currently evaluable for response, complete and partial remission are evident in seven and 21 patients, respectively. The overall response rate so far is 68%. An additional 12 patients show evidence of stable disease, and one has shown disease progression. Paclitaxel is considered a promising new drug in the adjuvant treatment of patients with metastatic breast cancer. Combining it with epirubicin allows safe administration with no evidence of severe cardiotoxicity. The incidence of adverse cardiac events was much lower than that observed with combinations of paclitaxel and doxorubicin.
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PMID:Preliminary results of a phase II study of epirubicin and paclitaxel as first-line treatment in patients with metastatic breast cancer. 907 34

5-Fluorouracil plus folinic acid and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic breast cancer patients. Paclitaxel and 5-fluorouracil have additive cytotoxicity in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic breast cancer. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 neutropenia requiring hospitalization; seven (4%) cycles in two patients required granulocyte colony-stimulating factor due to neutropenia; no patient required platelet transfusions. Grade 3/4 nonhematologic toxicities were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior doxorubicin exposure, 11 (58%) responded compared with nine of 15 (60%) without prior doxorubicin. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic breast cancer.
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PMID:Paclitaxel, 5-fluorouracil, and folinic acid in metastatic breast cancer: BRE-26, a phase II trial. 907 36

Fifty-five consecutive patients with metastatic breast cancer (MBC) (n = 57) were treated with a combination of levofolinic acid (I-FA) 100 mg/m2 plus 5-fluorouracil (5-FU) 340 mg/m2 i.v. on day 1-3, cyclophosphamide (CTX) 600 mg/m2 i.v. on day 1 and mitoxantrone (DHAD) 12 mg/m2 i.v. on day 1. DHAD dose was progressively escalated by 2 mg/m2/cycle up to 18 mg/m2 in the absence of dose-limiting toxicities. Granulocyte colony stimulating factor (G-CSF) was given s.c. in order to prevent neutropenia. DHAD dosage could be increased to 18 mg/m2 in 66 out of 317 cycles of chemotherapy (21%). In most patients the dose-limiting toxicity was represented by myelosuppression. A statistically significant correlation was found between median white blood cell (WBC) or absolute neutrophil count (ANC) nadir and DHAD dose level. Moreover, a statistically significant correlation was observed between the number of chemotherapeutic cycles, nadir ANC and WBC, and the occurrence of anemia and thrombocytopenia of increasing severity. These data suggest the occurrence of progressive cumulative bone marrow toxicity. Although patients who reached different DHAD levels showed differences in mean dose intensity, such differences were not statistically significant. No correlation was found between the increase in dose intensity and type, rate or duration of objective responses. In patients with metastatic breast cancer the overall response rate was 72% (95% CL 57-84%) with a 18% complete response rate. Median duration of response was 12 and 11 months, respectively, for complete and partial responses. Projected median survival of the whole series of patients with MBC was 18 months. These data demonstrate that the combination of 5-FU with I-FA, CTX and DHAD is very active against MBC. G-CSF use allows the increase DHAD dosage up to 18 mg/m2/cycle, but its use may be linked to the occurrence of sometimes severe cumulative hematological toxicity.
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PMID:Dose intensification of mitoxantrone in combination with levofolinic acid, fluorouracil, cyclophosphamide and granulocyte colony stimulating factor support in advanced untreated breast cancer patients. A multicentric phase II study of the Southern Italy Oncology Group. 909 30

Docetaxel is a taxane that disrupts the equilibrium in the polymerization and depolymerization of microtubules, thus inhibiting cell growth. This agent is indicated for the treatment of anthracycline-resistant metastatic breast cancer. The dose-limiting adverse effect is neutropenia, but febrile neutropenia is uncommon. Like paclitaxel, docetaxel is very active in patients with both chemotherapy-resistant and refractory metastatic breast cancer. Although the mechanism of action, spectrum of activity, and side effect profile of this agent are similar to those of paclitaxel, docetaxel may be efficacious in patients with metastatic breast cancer who have become resistant or refractory to paclitaxel therapy. However, more studies are warranted before the role of docetaxel is defined in patients with paclitaxel-resistant breast cancer.
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PMID:Docetaxel in anthracycline-resistant metastatic breast cancer. 911 Jun 51

25 patients older than 65 years with metastatic breast cancer were treated with vinorelbine 30 mg/m2 i.v. days 1 and 8 every 3 weeks; the pharmacokinetics were studied in 10 of them. Vinorelbine showed a large apparent volume of distribution (mean 23.4 l/kg), a long terminal half-life (mean 26.2 h) and a large systemic clearance rate (mean 1.2 l/kg). These results are similar to those reported in younger patients. No correlation has been found between toxicity, age and drug exposure. We observed 6 partial responses out of 20 evaluable patients despite a relatively low mean dose intensity (67%). Severe neutropenia occurred in 37% of the patients; other side-effects were acceptable. This study does not provide a pharmacokinetic rationale for reducing the dosage of vinorelbine in selected elderly patients.
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PMID:Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer. 913 5

When administered as a single agent in pretreated patients with advanced breast cancer, paclitaxel (Taxol) exhibits remarkable antitumor activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line therapy for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and an Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles (6 months) or standard treatment with oral cyclophosphamide (Cytoxan) 100 mg/m2/d days 1 through 14, intravenous methotrexate 40 mg/ m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisolone 40 mg/m2/d (CMFP) days 1 through 14 for six cycles (6 months). Patients whose disease progressed or relapsed were recommended to receive second-line epirubicin. Accrual has been completed with 208 patients randomized, but a preplanned interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by a linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months for paclitaxel-treated patients and 6.4 months for those given CMFP, with median survival durations of 17.3 and 11.3 months, respectively. Grades 3 and 4 neutropenia occurred in 64% of patients treated with paclitaxel and in 63% treated with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% of CMFP courses. Nine percent of the patients had major infections with CMFP, but none were seen with paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel-treated and 27% of CMFP-treated patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results on paclitaxel treatment as compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides comparable control of metastatic cancer to CMFP combination therapy when used as front-line treatment.
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PMID:Paclitaxel as first-line treatment for metastatic breast cancer. The Taxol Investigational Trials Group, Australia and New Zealand. 914 86

Paclitaxel (Taxol), has aroused considerable interest for its high single-agent activity in breast cancer and novel mechanism of action. Epirubicin (Farmorubicin), the 4'epimer of doxorubicin (Adriamycin), also has high activity in breast cancer, with the advantage of a lower rate of toxic side effects-especially cardiac effects-compared with its parent compound. The combination of paclitaxel and doxorubicin has yielded response rates between 63% and 94% in phase I/II studies, but authors reported severe cardiac toxic events. The goal for the current study was to evaluate the combination of paclitaxel and epirubicin, focusing mainly on cardiac toxicity. Of a total of 85 patients entered, 68 patients with metastatic breast cancer were evaluable. Nearly 20% had primary metastatic breast cancer with large tumors. Half had received adjuvant chemotherapy. Study medication in Group A consisted of 60 mg/m2 epirubicin given over 1 hour, followed by paclitaxel 175 mg/m2 as a 3-hour IV infusion. In Group B, 90 mg/m2 epirubicin was combined with 175 mg/m2 paclitaxel, delivered as for Group A. The main toxicity in both groups was neutropenia. In Group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in 7 patients; dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac adverse events were reported in Group A. In Group B, only one patient could be escalated to 200 mg/m2 but three patients required a dose reduction. In this group, one patient had a decrease of left ventricular ejection fraction of more than 10% without any clinical signs. Of 43 patients in Group A and 25 in Group B, the response rate was 67% in Group A and 68% in Group B. The duration of response was 8.2 months in both groups. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 or 90 mg/m2 can be safely administered. The response data were encouraging and further evaluation is warranted.
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PMID:Paclitaxel and epirubicin as first-line therapy for patients with metastatic breast cancer. 914 89


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