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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan is a semi-synthetic, water soluble topoisomerase I inhibitor which has recently been approved for the treatment of ovarian cancers after failure of first-line therapy. A number of different dosing schedules are being investigated in clinical trials including oral administration, a daily infusion on 5- or 3-consecutive days and a continuous infusion for 21 days. A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks, as standard schedule, produced response rates of 13.8 to 20.5% in the 3 largest phase II/III studies in women with advanced ovarian cancers who had either failed to respond or had relapsed after an initial response to platinum-based chemotherapy (N = 92 to 139), continuous 21-day infusion of topotecan 0.3 to 0.5 mg/m2 has shown efficacy in 2 small phase II studies. There were no statistically significant difference in efficacy between topotecan (1.5 mg/m2/day for 5 consecutive days every 21 days) and paclitaxel (175 mg/m2/day given over 3-h every 21 days) in the randomized phase III study. In 3 large clinical trials, response to topotecan was higher in patients who were platinum sensitive (19.2 to 29%) than in those whose disease was platinum resistant or refractory (11.3 to 13.3%) not statistically significant in 1 study, statistical analysis not reported in the other 2 trials. Myelosuppression, particularly neutropenia, is the dose-limiting toxicity of topotecan. It is reversible, dose-related and non-cumulative. In 2 large studies, topotecan produced grade 4 neutropenia in 78 and 79% of patients and in 40 and 37% of all treatment courses (febrile neutropenia occurred during 3% of 552 courses in 1 study). Grade 4 thrombocytopenia was seen in 18 and 25% of patients and in 6 and 10% of all courses, respectively. Grade 4 neutropenia was significantly more common in patients receiving topotecan than in those receiving paclitaxel (79 vs 23%), as was grade 4 thrombocytopenia (25 vs 2%), in a single randomized clinical trial. Non-hematological adverse events during topotecan therapy were mostly mild. A step beyond is the combination treatment including topotecan as a 3- or 5 days schedule plus a platinum compounds or topoisomerase II inhibitor. These associations of drugs are based on the preclinical data of the in vitro studies showing a synergy of the anti-tumor activity. A novel schedule of topotecan is also the "alternating" chemotherapy consisting of different doublet of drugs given as a sequential way or as a really sequential topotecan therapy. Both methods of combining topotecan as second/salvage treatment or front line therapy are being investigated by numerous authors. Preliminary data suggest interesting results in terms of efficacy, manageable toxicity and new schedules of treatment for topotecan. Low dosages of drug in combination with other agent do not seem to influence the well-known data of efficacy or safety of topotecan literature. Probably the 3-day schedule allows a combination treatment, otherwise not feasible with the standard 5-day administration.
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PMID:[Topotecan: prospects for using it in combination therapy for ovarian carcinoma]. 1078 95

Topotecan, a soluble semisynthetic derivative of camptothecin, is a specific inhibitor of topoisomerase I and is endowed of potent antiproliferative effect in vitro and in vivo on tumoral cell lines as well as on endothelial cells. Moreover, topotecan is able to interfere with the development of blood vessels in many in vivo experimental models. During the last years, several phase I clinical studies have demonstrated that the five-daily schedule is the most effective for the treatment of neoplastic diseases of children and adults. In particular, the best clinical results have been obtained in patients affected by metastatic ovarian cancer, small cell (SCLC) and non-small cell lung carcinoma (NSCLC), as well as mammary and gastrointestinal neoplasms. High response rates have been observed in myelodysplastic syndromes and myeloma. The clinical effectiveness of topotecan has been also demonstrated in ovarian carcinoma, even after failure of first or second line chemotherapy and in SCLC, where the response rate is 39%, while the percentage decreases up to 7% in case of drug resistance, with a median survival of 5.4 months. Toxicologic profile of topotecan is foreseeable and manageable, and the most frequent and severe toxicity is represented by myelosuppression. Leukopenia and neutropenia, which follow the administration of topotecan, are non-cumulative and self-limiting and unfrequently complicated by infections, whereas non-hematologic toxicities are uncommon and generally of mild-to-moderate degree. Topotecan is under continuous clinical evaluation for the treatment of neoplasms other than those reported above, alone or in combination with antineoplastic drugs in poly-chemotherapeutic protocols.
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PMID:[Preclinical pharmacology and clinical uses of topotecan]. 1078 94

The effect of topotecan on CA-125 serum levels was evaluated in 30 patients with advanced epithelial ovarian cancer. All patients had progressive disease and were relapsing during (11 patients) or after (19 patients) chemotherapy containing paclitaxel and platinum. Topotecan (1.0 mg/m(2)/day) was administered intravenously on Days 1-5 every 3 weeks. The patients had received a median of 2 (1-5) prior regimens. Four patients had increased CA-125 only, and 26 had both measurable disease and increased CA-125. Two patients (7%) achieved a clinical partial response with durations of 5 and 10+ months, respectively. Eighteen other patients (60%) exhibited no clinical change with a median duration of 5+ months (range: 2-11+ months). Among these patients 9 (30%) had a biochemical response. The rate of change in CA-125 (s, slope of the exponential regression curve) during treatment with topotecan was compared with s over a period before treatment. A decrease in s was observed in 20 patients (74%). Comparing the mean values of s before and during topotecan, a significant (P = 0.005) decrease was seen in the CA-125 serum levels. The mean doubling times before and during treatment were 59 and 1421 days, respectively. Toxicity was mainly hematologic. Neutropenia grades III and IV were seen in 16 and 10 patients, respectively. No patients died due to side effects. Generally the side effects were mild to moderate. In conclusion, at the given dose intensity topotecan shows activity in advanced paclitaxel- and platinum-resistant ovarian cancer based on CA-125 measurements.
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PMID:Effect of topotecan on serum CA-125 in patients with advanced epithelial ovarian cancer. 1083 46

From October 1995 to March 1997, a phase II trial of topotecan was carried out in chemotherapy-naive women with advanced, persistent, or recurrent uterine leiomyosarcomas. Thirty-six patients were entered. Median age was 53 years. Performance status was 0 (50%) in 18, 1 (36%) in 13, and 2 (14%) in 5. Most patients, 33 (92%), had undergone prior surgery, and 8 (22%) prior radiation therapy. Topotecan, 1.5 mg/m2. was administered intravenously daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. Patients received 1 to 13 courses with a median of 3 courses. The most frequent grade 4 adverse effects were neutropenia in 28 (78%), leukopenia in 8 (22%), thrombocytopenia in 3 (8%), and anemia in 3 (8%). Complete response was seen in 1 (3%), partial response in 3 (8%), stable disease in 12 (33%), and increasing tumor in 20 (56%). Thus topotecan at this dose and schedule does not appear to have major activity in uterine leiomyosarcomas.
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PMID:Phase II trial of topotecan in patients with advanced, persistent, or recurrent uterine leiomyosarcomas: a Gynecologic Oncology Group Study. 1095 63

24 patients were enrolled into a phase I-II study conducted to determine the maximum tolerated doses of topotecan-gemcitabine in sequential combination and the response rate in platinum/paclitaxel resistant ovarian cancer patients. A total of 83 courses are evaluable, with a median number of three cycles administered per patients (range 2-7). Topotecan was administered on days 1-5 by 30 min i.v. infusion immediately after gemcitabine given by 30 min i.v. on days 1 and 3; cycles were repeated every 28 days. The starting doses were topotecan 0.7 mg/m(2) and gemcitabine 200 mg/m(2). Following dose levels were 08/400; 0.9/600; 0.9/800 for topotecan and gemcitabine, respectively. The maximum tolerated dose (MTD) was reached at dose level 3, the dose-limiting toxicity being represented by febrile neutropenia and thrombocytopenia. After the MTD was reached, granulocyte-colony-stimulating factor was administered in 27% of cycles. Mild and manageable was non hematological toxicity. All patients are so far evaluable for response. Among them 2 complete responses (8.3%; 95% CI: 2.6-19), 1 partial response (4.2%; 95% CI: 3.8-12), 9 no change (37.5%; 95% CI: 18-56.8) and 12 progressions (50%; 95% CI: 30-70) have been registered. Based on these data, there is no evidence that combining topotecan and gemcitabine is better than using either of the two drugs used separately.
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PMID:Topotecan and gemcitabine in platinum/paclitaxel-resistant ovarian cancer. 1115 Sep 3

Recurrent or metastatic squamous carcinoma of the head and neck (RMSCHN) is a modestly chemoresponsive tumor; however, currently available agents have failed to improve survival. New active agents are needed for the treatment of this disease. Topotecan is a topoisomerase inhibitor that demonstrated initial promising activity in squamous carcinoma of the head and neck. The Eastern Cooperative Oncology Group conducted a phase II trial of topotecan to determine the efficacy and toxicity of a weekly treatment schedule in patients with RMSCHN. Patients with metastatic or locally recurrent squamous carcinoma of the head and neck were treated with topotecan 1.5 mg/m2 x 24 hours by continuous infusion on days 1, 8, 15, and 22 of each 35-day cycle. Patients were stratified in two cohorts: chemonaive and previously treated. Sixteen chemonaive and 16 previously treated patients were registered on study. Grade III/IV neutropenia and anemia occurred in 16% and 18% of patients, respectively. No responses were observed in either cohort. Median survival for previously untreated patients was 4.6 months and 3.2 months for previously treated patients. Topotecan failed to demonstrate efficacy in patients with RMSCHN. Further evaluation of this agent is not planned.
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PMID:Lack of efficacy of topotecan in the treatment of metastatic or recurrent squamous carcinoma of the head and neck: an Eastern Cooperative Oncology Group Trial (E3393). 1123 52

The activity and toxicity of topotecan in women with recurrent cervical cancer are described from a case series of women with recurrent cervical cancer who had measurable disease and were not amenable to cure by surgery or radiation. All patients had prior platinum-based chemotherapy and developed progressive disease. Topotecan was given as 1 mg/m2/day over 30 min for 5 days every 3 weeks until progression of disease or prohibitive toxicity. Between July 1998 and July 1999, 12 patients received a total of 20 cycles of topotecan. Median age was 41 years (range 21-62), and 11 (92%) patients had prior whole pelvic radiation. The mean number of topotecan cycles was 1.5 (median 1, range 1-3). There were two partial responses (16.7%; 95% CI, 2% to 48%), both in prior radiation fields. Five patients required red blood cell transfusions, four had grade II nausea and vomiting, two developed sepsis (one with neutropenia), one developed fever, and one reported hyperpigmentation. There were no treatment-related mortalities. Although topotecan appears to exhibit modest activity in recurrent cervical cancer after radiation and platinum-based therapy, bone marrow toxicity may limit the utility of this regimen without hematopoietic growth factor support.
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PMID:Topotecan for recurrent cervical cancer after platinum-based therapy. 1124 Jun 88

Topotecan, a drug typically used to treat cancer, has shown promising in vitro results against the JC virus. The JC virus causes progressive multifocal leukoencephalopathy (PML). SmithKline Beecham is planning to announce phase II placebo-controlled trials for PML. There is currently no known treatment for PML, although it sometimes responds to anti-HIV drugs, alpha-interferon, and peptide T. AIDS advocates are questioning why SmithKline Beecham did not perform animal and pre-clinical studies to see if topotecan would be effective and tolerable among HIV/AIDS patients. Topotecan treatment has resulted in minimum success fighting ovarian cancer, however, its toxic effects are dangerous and powerful. Advocates advise that any patient considering a trial of topotecan have their blood monitored very carefully, particularly for neutropenia. Participants should consider pre- and post-treatment with G-CSF (Neupogen) to boost white blood cells.
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PMID:Topotecan and PML: the limits of pharmaceutical industry research. 1136 13

Combining antineoplastic analogues may increase efficacy by increasing the serum and intracellular concentration of the cytotoxic moiety shared by the analogues. Topotecan and irinotecan are two camptothecan analogues that are active in different human tumors (topotecan in ovary; irinotecan in colon) and in different experimental tumor systems. These data suggest that different mechanisms of drug resistance may be operative for the two agents, and if incomplete cross-resistance exists between analogues, concomitant administration may be advantageous. The objectives of this phase I study were 1) to determine in a phase trial design whether topotecan and irinotecan administered concomitantly on a weekly schedule can be delivered at the same dose intensity as that of single-agent topotecan or irinotecan delivery; and 2) to determine whether hematologic and/or nonhematologic toxicity is increased with topotecan and irinotecan administered together as a prelude to a possible phase II trial in responsive tumor categories. Irinotecan was administered for 30 to 45 minutes weekly x 4 at four dose levels: 50, 75, 100, and 125 mg/m(2)/wk. Topotecan was administered for 30 minutes (after irinotecan administration) at two dose levels within each of the irinotecan dose levels (1.0 and 1.5 mg/m(2)). Concomitant single-dose granulocyte-macrophage colony-stimulating factor (G-CSF) was used for leukocyte counts between 1,000 cells/mm(3) and 3,500 cells/mm(3) to maintain schedule. Maximum tolerated dosage (MTD) for the topotecan and irinotecan combination was defined as that which permitted 4 weeks of topotecan and irinotecan administration with G-CSF at or near the dose intensity reported for each single agent. Twenty-one patients received 32 4-week cycles. Dose-limiting toxicity was hematologic with grade IV leukopenia and neutropenia occurring at all dose levels. There was no apparent increase in the diarrhea syndrome associated with irinotecan. The MTD for irinotecan (at 125 mg/m(2)/wk) is the same MTD as with single-agent irinotecan use. The MTD for concomitant topotecan (1.5 mg/m(2)/wk) is 60% of the single-agent topotecan dose for the 5-day topotecan schedule (at 2.5 mg/m(2)/wk) but only 30% of the single-agent topotecan dose for the weekly schedule (5 mg/m(2)/wk). The topoisomerase I inhibitor dose is increased minimally when the analogues are administered concomitantly on a weekly schedule. Comparative trials of single-agent topotecan and irinotecan versus the combination of topotecan and irinotecan would be necessary to provide the proof of principle that combining analogues can increase therapeutic effectiveness.
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PMID:Phase I clinical trial of weekly combined topotecan and irinotecan. 1147 56

Pharmacodynamic measures of neutropenia, such as absolute neutrophil count at nadir and neutrophil survival fraction, may not reflect the overall time course of neutropenia. We developed a pharmacokinetic-pharmacodynamic model to describe and quantify the time course of neutropenia after administration of topotecan to children and to compare this with nonhuman primates (NHPs) as a potential preclinical model of neutropenia. Topotecan was administered as a 30-min infusion daily for 5 days, repeated every 21 days. As part of a Phase I Pediatric Oncology Group study, topotecan was administered at 1.4 and 1.7 mg/m(2)/day without filgrastim (POG), and at 1.7, 2, and 2.4 mg/m(2)/day with filgrastim (POG+G). In NHPs, topotecan was administered at 5, 10, and 20 mg/m(2)/day without filgrastim. A pharmacokinetic-pharmacodynamic model was fit to profiles of topotecan lactone plasma concentrations and neutrophil survival fraction from cycle 1 and used to calculate topotecan lactone area under the plasma concentration-versus-time curve from 0 to 120 h (AUC(LAC)) and the area between the baseline and treatment-related neutrophil survival fraction (ABC) from 0 to 700 h. The mean +/- SD neutrophil survival fraction at nadir for the POG, POG+G, and NHP groups was 0.12 +/- 0.09, 0.11 +/- 0.17, and 0.09 +/- 0.08, respectively (P > 0.05). The mean +/- SD for the ratio of ABC to AUC(LAC) for the POG and NHP groups was 1.02 +/- 0.38 and 0.16 +/- 0.09, respectively (P < 0.05). The model estimate of ABC and the ratio of ABC to AUC(LAC) in children and NHPs may better reflect sensitivity to chemotherapy-induced neutropenia.
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PMID:Pharmacodynamic model of topotecan-induced time course of neutropenia. 1148 5


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