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)

We performed a phase I trial of cyclosporin A (CsA) in combination with doxorubicin (dox) to determine the maximally tolerated dose (MTD) of the combination in man, to define the quantitative and qualitative toxicities of the combination, and to determine the pharmacokinetics of the two drugs when used together. CsA was administered as a continuous infusion for 6 days, and dox was administered as a single 10-min infusion 24 h after the initiation of CsA. The starting CsA infusion rate was 5 micrograms/kg/min, and the dox starting dose was 30 mg/m2. Courses were administered every 4 weeks with first CsA and then dox being escalated in consecutive cohorts of patients until the MTD was determined. Twenty-three patients and 40 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 23 patients on the first course for whole blood CsA and plasma dox and doxorubicinol. The MTD of CsA was 6 micrograms/kg/min, and for dox it was 45 mg/m2. Dose-limiting toxicity was neutropenia. Serum creatinine and creatinine clearance did not change over the infusion period. Bilirubin increased from a median of 10 mumol/liter at the initiation of the infusion to a median of 40.4 mumol/liter at the end of the infusion but returned to normal before the next cycle of therapy. Nausea and vomiting were common and marked, whereas thrombocytopenia was mild. Two patients, one with small cell lung cancer and one with breast cancer, had stable disease while receiving treatment for 5 and 6 months, respectively. Mean whole blood steady state concentrations of CsA were 2210 ng/ml during the infusion with total body clearance of 0.177 liter/h/kg. The area under the concentration x time curve (AUC) increased linearly with dose of dox, and total body clearance was independent of dose. The mean total body clearance was 2.46 liters/h/m2, and terminal half-life was 49.6 h. The AUC for dox was greater and clearance was less than has been previously reported at the doses administered in this study. The ratio of AUC for doxorubicinol to AUC for dox was less than expected, suggesting that the metabolism and/or excretion of dox was decreased when administered with CsA. We conclude that dox can be combined with infusioned CsA but at a lower dose than when given alone. This may be due to altered metabolism and/or excretion of dox or increased bone marrow stem cell sensitivity to dox.
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PMID:Phase I pharmacokinetic study of cyclosporin A combined with doxorubicin. 840 70

The efficacy of a 5 day continuous infusion of cisplatin, 25 mg/m2/day, in combination with a bolus infusion of etoposide, 100 mg/m2/day over 2 h for 3 days (PiE therapy), was evaluated in a phase II study of previously untreated patients with small cell lung cancer (SCLC). There were 39 evaluable patients, of whom 17 had limited disease (LD) and 22 extensive disease (ED). The overall response rate was 92% (LD, 100%; ED, 86%). The complete response rate was 21% (LD, 41%; ED, 5%). The median survival time was 45.6 weeks (LD, 123.2 weeks; ED, 28.8 weeks). The major side-effects were grade 3 or 4 leucopenia (55%), neutropenia (88%) and thrombocytopenia (20%). There were no episodes of bleeding, severe infection or treatment-related deaths. PiE therapy was associated with significant myelosuppression, but was effective, with an especially encouraging response rate and survival for LD patients.
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PMID:Phase II study of infusional cisplatin in combination with etoposide in the treatment of small cell lung cancer. 854 Nov

The aim of this Phase II study was to test the feasibility of intensifying standard chemotherapy in the treatment of small cell lung cancer (SCLC) by reducing the interval between cycles from 3 to 2 weeks by adding recombinant human methionyl granulocyte colony-stimulating factor (G-CSF; filgrastim) to shorten the duration of neutropenia following each cycle. Thirty-two patients with SCLC were prescribed six cycles of 2-weekly doxorubicin 50 mg/m2 and cyclophosphamide 1 g/m2 on day 1, and etoposide 120 mg/m2 i.v. on days 1, 2 and 3 (ACE), plus filgrastim in a fixed dose of 300 micrograms s.c. on days 4-14 of each cycle. Three patients died during the treatment period and a further nine had chemotherapy terminated before the sixth cycle, all nine because of toxicity. All 32 patients have been followed up for at least 21 months; 14 (44%) were alive at 12 months and the median survival period was 356 days. Of the 127 intervals between cycles of chemotherapy, 74 (58%) were of the prescribed 14 days, 18 (14%) of 15-20 days, 25 (20%) of 21 days, and 10 (8%) were longer. The results were best during the first four cycles, during which 71% of the 83 intervals were of 14 days and a further 10% were less than 21 days. The main reason for delay was haematological toxicity in 37 of the 53 instances. Symptoms of myelosuppression occurred in 23 patients, but at 14 days after a cycle of chemotherapy, all 127 available neutrophil granulocyte counts were normal. Twenty-one patients received blood transfusion and five platelet transfusion. The only adverse effects attributed to filgastrim were episodes of rash, throat swelling, anorexia and shivering, affecting one patient. We conclude that the policy of adding filgrastim allows the dose intensity of ACE chemotherapy to be increased by reducing the intervals between cycles. The findings reinforce those of a parallel study involving lenograstim.
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PMID:Increasing and planned dose intensity of doxorubicin, cyclophosphamide and etoposide (ACE) by adding recombinant human methionyl granulocyte colony-stimulating factor (G-CSF; filgrastim) in the treatment of small cell lung cancer (SCLC). Medical Research Council Lung Cancer Working Party. 858 54

A study was conducted to examine the feasibility of cisplatin-based chemotherapy in elderly patients (> or = 75 years old) with advanced non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). Thirty-four patients were enrolled between September 1993 and December 1994. Patients with normal organ function and good performance status (PS) received cisplatin-based chemotherapy (cisplatin 80 mg/m2 on day 1 and vindesine 3 mg/m2 on days 2 and 8 for NSCLC, or cisplatin 80 mg/m2 on day 1 and etoposide 100 mg/m2 on days 2 to 4 for SCLC). Ten patients (29%) were eligible for this study, 7 with NSCLC and 3 with SCLC. Reasons for exclusion were ischemic heart disease in 14, poor PS (> or = 2) in 11, reduced creatinine clearance (Cer) in 10, abnormal electrocardiogram without ischemia in 9 and noncompliance with the protocol in 2 patients. Eight patients had two or more reasons. Nine of the 10 eligible patients were able to tolerate two or more courses of chemotherapy. All 3 patients with SCLC responded (1 complete response and 2 partial response), but only 1 of the patients with NSCLC achieved partial response. Toxicity was evaluated according to Japan Clinical Oncology Group criteria. All but one patient experienced grade 4 neutropenia, and 6 patients had infectious episodes requiring antibiotics. Grade 3 anemia and thrombocytopenia were observed in 1 and 2 patients, respectively. Non-hematological toxicities were mild. Only 10 of 34 patients (29%) satisfied our eligibility criteria and they experienced severe myelotoxicity. We conclude that chemotherapy should be given carefully to elderly patients even if they appear to have normal organ function.
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PMID:Prospective evaluation of the feasibility of cisplatin-based chemotherapy for elderly lung cancer patients with normal organ functions. 863 10

Myelosuppression is the major dose-limiting toxicity of chemotherapy in small cell lung cancer (SCLC). The capacity of colony stimulating factors (CSFs) to stimulate granular neutrophil recovery may be of great value to prevent or cure febrile neutropenia and to increase dose-intensity. The aim of this review was to assess the current use of CSFs in SCLC on the basis of experimental and clinical data. Primary CSF administration has been shown to reduce the incidence of febrile neutropenia, hospital admission rate, and antibiotic use subsequent to cyclophosphamidedoxorubicin-high dose etoposide (CDE) chemotherapy, without improvement of survival or disease control. Primary CSF administration may be recommended when the expected incidence of febrile neutropenia is at least 40%. This benefit has not been established with less myelosuppressive regimens, such as cisplatin-etoposide (PE), which remains an alternative combination of SCLC when standard doses are used. A trial comparing high-dose CDE + CSF with PE would be of considerable interest. There is currently little clinical basis for the use of CSFs to increase chemotherapy dose-intensity, outside clinical trials. Peripheral blood progenitor cells mobilized with CSFs offer interesting prospects. Further studies, with later initiation, shorter duration or lower doses of CSFs, are warranted to improve the cost-effectiveness of CSFs. CSF therapy in addition to antibiotics is normally not justified in febrile neutropenia, except perhaps in selected patients with sepsis syndromes, hypotension or pneumonia.
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PMID:Colony-stimulating factors as an adjunct to chemotherapy in small cell lung cancer. 873 24

In attempt to develop a new chemotherapeutic regimen including carboplatin (CBDCA), epirubicin (EPI), and VP-16 in extensive small cell lung cancer, with a higher dose intensity compared with previous experience of our group, we determined the maximum tolerated dose (MTD) of VP-16 when administered in association with CBDCA (300 mg/ m2, i.v., day 1) and EPI (75 mg/m2, i.v., day 1), recycling chemotherapy every 3 weeks, with the support of granulocyte-colony-stimulating factor (G-CSF). A total of 15 patients received three dose levels of VP-16 (mg/m2, i.v., daily on days 1-3): 100 (three patients), 120 (six), and 140 (six). G-CSF was administered subcutaneously at the dose of 5 micrograms/kg/day on days 6-15 of each chemotherapy course. The MTD was established at 140 mg/m2 and myelotoxicity, grade 4 neutropenia with death for sepsis in one case and grade 3 thrombocytopenia in three cases, was dose limiting. The recommended dose of VP-16 for a phase II study is 140 mg/m2.
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PMID:Phase I study of chemotherapy with carboplatin, epirubicin, and escalating dose of VP-16 with G-CSF support in extensive small cell lung cancer. 893 78

Tallimustine binds to the minor groove of DNA where it alkylates the N3 position of adenine and may interfere with gene transcription. We conducted a phase II trial of Tallimustine given at a dose of 750 micrograms/m2 intravenously every 4 weeks in patients with small cell lung cancer progressing or relapsing following cisplatin or carboplatin-based chemotherapy. We treated 14 eligible patients with a performance status 0, 1 or 2, bi-dimensionally measurable disease and adequate end-organ function. The main toxicity was neutropenia with a median granulocyte count of 0.1 x 10(9) per liter (range 0-3.9) and four patients (27%) developing febrile neutropenia. In addition, most patients (93%) experienced lethargy. No objective responses were seen. A mixed response was seen in one patient and three others had stable disease for a median of 3.7 months. We conclude that Tallimustine is an ineffective agent in previously treated small cell lung cancer.
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PMID:Tallimustine is inactive in patients with previously treated small cell lung cancer. A phase II trial of the National Cancer Institute of Canada Clinical Trials Group. 895 81

This phase I study investigated the maximum tolerated dose of cisplatin, etoposide, and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in 18 patients with advanced small cell lung cancer. Cisplatin (80 mg/m2) and etoposide (50 or 80 mg/m2 intravenously and 100 or 160 mg/m2 orally) were infused concomitantly 30 minutes after a 3-hour infusion of paclitaxel (135, 175, or 200 mg/m2). This order of administration was known to cause less toxicity than the reverse order. Granulocyte colony-stimulating factor was given as necessary. Overall, complete responses were observed in 33% of evaluable patients and partial responses were seen in 67%. No patient progressed during therapy. Median survival exceeded 12 months, with 53% of patients alive at 1 year. Untreated patients in similar health survive approximately 6 to 16 weeks. Hematologic toxicities were seen most frequently, and neutropenia was seen most often and was the most severe. Febrile neutropenia occurred in one patient; grade 4 thrombocytopenia did not occur at all. Nonhematologic toxicity was mild. Nausea and vomiting generally were well controlled, and there were no instances of severe allergic reaction. Although the maximum tolerated dose has not yet been defined, one of two patients in the group receiving the highest doses encountered a dose-limiting toxicity. Thus, we expect to recommend the following dosages for further study: cisplatin 80 mg/m2, etoposide 80 mg/m2, and paclitaxel 175 mg/m2. All patients had an objective response and one third had a complete response, compared with 10% of patients in most series. We conclude that paclitaxel can be added safely to full doses of cisplatin and etoposide with encouraging efficacy, and recommend a randomized trial be undertaken to compare the two-drug regimen with the three-drug regimen.
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PMID:Phase I study of cisplatin, etoposide, and paclitaxel in patients with extensive-stage small cell lung cancer: a University of Colorado Cancer Center study. 900 14

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a new cytotoxic chemotherapeutic agent with a novel mechanism of action. Single-agent paclitaxel studies have shown promising activity in both small cell and non-small cell lung cancers. In non-small cell lung cancer, response rates of 22% to 26% and 1-year survival rates of 40% were reported with both 3-hour and 24-hour infusions of paclitaxel. In small cell lung cancer, 24-hour infusions produced response rates of 61%. These data indicate that paclitaxel is one of the most active agents for all lung cancer patients. Combination studies demonstrated that paclitaxel could be combined with either cisplatin or carboplatin at full doses using either a 3-hour or a 24-hour infusion schedule. Response rates with these combinations have been high, usually 40% to 50%, which are higher than with any of the drugs used alone. Neutropenia is the most frequent toxicity and occurs less frequently with the 3-hour infusion. Thrombocytopenia occurred less frequently than expected. One completed randomized study showed that the paclitaxel/cisplatin regimen was superior to the etoposide/cisplatin regimen with respect to response rate and survival. Additional randomized studies are necessary to determine whether the combinations are superior to single-agent paclitaxel, to define the optimal dose with the 3-hour infusion schedule, to define the optimal schedule (3 hours v 24 hours), and to determine whether paclitaxel can be combined with other new agents.
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PMID:The North American experience with paclitaxel combined with cisplatin or carboplatin in lung cancer. 900 16

This study was aimed to evaluate the effect of ifosfamide, cisplatin and etoposide (ICE) combined chemotherapy in small cell lung cancer (SCLC), and to test the feasibility of adding recombinant human granulocyte colony-stimulating factor (rhG-CSF) to aggressive chemotherapy. Thirty consecutive, previously untreated, patients with SCLC (17 with limited disease and 13 with extensive disease) entered this study. The ICE regimen consisted of ifosfamide (I) 4 g/m2 i.v. with same dose mesna i.v. on first day, cisplatin (C) 25 mg/m2 i.v. on days 1 to 3 and etoposide (E) 100 mg/m2 i.v. on days 1 to 3. A total of 30 MU rhG-CSF i.v. were given from day 7 to 14 if WBC were lower than 3000 x 10(6)/L, neutrophils were lower than 1000 x 10(6)/L. Overall response (OR) rate was 93% with a complete response (CR) rate of 23%. Median survival was 12 months [95% confidence interval (CI): 11-14] and median response duration was 10 months [95% CI: 8-10]. Thirty-seven percent of patients had grade 3 neutropenia, 40% had grade 3 anemia, and 1% had grade 2 thrombocytopenia. Nonhematologic toxicity was mild with nausea and vomiting being the most common. RhG-CSF, which reduced leukopenic nadirs and shortened the neutropenic period, was also well tolerated. This chemotherapy protocol seems to be active, well tolerated and is currently being compared with various conventional chemotherapies.
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PMID:Ifosfamide, cisplatin and etoposide (ICE) combined chemotherapy with recombinant human granulocyte colony-stimulating factor support in small cell lung cancer. 910 21


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