UMLS:C0027947 - FACTA Search

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Query: UMLS:C0027947 (neutropenia)
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Topotecan (Hycamtin, SmithKline Beecham, Philadelphia, PA) was approved by the U.S. Food and Drug Administration in 1996 for use in relapsed ovarian cancer and in 1999 for platinum-sensitive small-cell lung cancer. Hematologic toxicity has been the predominant side effect associated with its use. Patients who have had extensive platinum-based therapy have exhibited increased degrees of thrombocytopenia and more severe neutropenia. These adverse events can be managed by identifying high-risk patients (i.e., those with more than six cycles of chemotherapy containing an alkylating agent or radiation to more than 25% of marrow-bearing bones, patients with a history of myelosuppression or renal impairment) and by recommending appropriate dose modifications based on the creatinine clearance measurement. By reducing the topotecan dose, myelosuppressive effects, as evidenced by neutropenia and thrombocytopenia, may be lessened or prevented without reducing the antitumor response.
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PMID:Nursing considerations for managing topotecan-related hematologic side effects. 1189 7

Topotecan is a topoisomerase-I inhibitor, a drug that stabilizes a covalent complex of enzymes and causes strand cleavage of DNA. 5-Fluorouracil (5FU) is an antimetabolite that interferes with DNA synthesis. Preclinical studies using human cancer cell line models have shown potential therapeutic synergy between these two drugs by showing the maximum cytolytic effect using sequential 5FU followed by topotecan. In the current study, 5FU was used at a fixed dose of 375 mg/m2 given intravenously for five consecutive days on a 28 day cycle. Topotecan was dose-escalated in cohorts of patients from 0.5 to 1.0 mg/m2 given intravenously for 5 days after the 5FU dose. Eleven patients were entered at different dose levels. Both hematological and gastrointestinal toxicity were dose limiting. Diarrhea was the dose-limiting toxicity at the dose of 0.75 mg/m2 of topotecan. Two cases of grade 4 neutropenia were also observed at this dose level. One patient with small cell lung cancer had a complete response, while one patient with metastatic colorectal cancer had a partial remission. Three other patients had stable disease, lasting between 6 and 8 months. Overall, the regimen was well tolerated. A phase II study using a dose of 5FU at 375 mg/m2 followed by topotecan at 0.75 mg/m2 intravenously over 5 days every 28 days is recommended.
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PMID:Phase I study of sequential administration of topotecan and 5-fluorouracil in patients with advanced malignancies. 1219 19

Ovarian cancer is the fifth leading cause of cancer death in women. Most patients with ovarian cancer respond to first-line chemotherapy, but many relapse within 18 to 22 months. The development of efficacious salvage therapies that increase overall survival while maintaining quality of life is a great challenge in the treatment of this disease. Topotecan, a novel topoisomerase I inhibitor, is currently indicated for the treatment of recurrent metastatic carcinoma of the ovary. In patients with relapsed ovarian cancer, the overall response rates on treatment with topotecan range from 19%-33% in platinum-sensitive patients, 14%-18% in platinum-resistant patients, and 5%-11% in platinum-refractory patients. The proportion of patients achieving stable disease ranges between 17% in refractory and 48% in sensitive patients. In phase III studies, topotecan was shown to be equivalent in efficacy to both paclitaxel and liposomal doxorubicin as second-line therapy in patients with relapsed ovarian cancer. Further, non-cross-resistance between topotecan and paclitaxel was demonstrated in a third-line, phase III crossover study, suggesting that topotecan may be effective in the first-line setting with paclitaxel and/or platinum. Hematologic toxicities include neutropenia, thrombocytopenia, and anemia; however, these toxicities are usually short lived, noncumulative, and manageable with dose modifications, including low-dose topotecan regimens. Nonhematologic toxicities are usually mild to moderate in severity. These data support the use of topotecan for second-line therapy and suggest that topotecan may also be effective in first-line therapy. Further studies with topotecan alone and in combination with other agents are needed to fully characterize the role and sequencing of topotecan in the salvage and first-line settings.
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PMID:Update on the role of topotecan in the treatment of recurrent ovarian cancer. 1232 28

Extensive-stage small cell lung cancer (SCLC) is an aggressive disease with a median survival of approximately 8 months. Although current combination chemotherapy regimens provide high initial tumor response rates, they have not translated into large gains in survival. Topotecan and paclitaxel have nonoverlapping mechanisms of action and are active agents in SCLC. Additionally, these two agents demonstrate in vitro synergy in animal and human tumor models. We investigated the maximum tolerated dose of 3-day topotecan in combination with paclitaxel in previously untreated patients with extensive SCLC. Seventeen patients were enrolled in an open-label, phase I, dose-escalation study and were treated with intravenous paclitaxel 135-175 mg/m(2) over 1 hour on day 1, followed by intravenous topotecan 1.25-1.5 mg/m(2) over 30 minutes on days 1-3 of a 21-day course. Sixty-nine courses of therapy were administered with no delays due to hematologic toxicity. Prophylactic hematologic support was required for 24% of patients. The topotecan/paclitaxel combination was well tolerated, with 24%, 12%, and 6% of patients experiencing grade 3/4 neutropenia, anemia, or thrombocytopenia, respectively. Dose-limiting neutropenia was seen in three of five patients treated with topotecan 1.5 mg/m(2) and paclitaxel 175 mg/m(2). Therefore, topotecan 1.5 mg/m(2) with paclitaxel 135 mg/m(2) was determined to be the maximum tolerated dose. Of the 17 evaluable patients, 53% achieved a partial response and 18% achieved stable disease. In summary, we have identified a regimen of topotecan 1.5 mg/m(2) and paclitaxel 135 mg/m(2) that was well tolerated and active in this patient group. Additional studies of topotecan and paclitaxel at these dose levels are needed to fully elucidate the efficacy of this combination in extensive SCLC.
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PMID:Phase I study of paclitaxel and topotecan for the first-line treatment of extensive-stage small cell lung cancer. 1260 34

Our purpose was to establish the maximum tolerated dosage (MTD) of daily i.v. topotecan with conventionally fractionated radiotherapy (XRT) for patients with intrinsic pontine glioma of childhood. Topotecan was given as a 30-min i.v. infusion 30-60 min before each XRT treatment given daily for 33 days. Total XRT dose was 59.4 Gy. Dose escalation of topotecan was carried out using a standard phase I design. Dose limiting toxicity (DLT) was defined as an absolute neutrophil count (ANC) of < or =500/mm(3) for > or =7 days; platelets of < or =50,000/mm(3) for > or =7 days; >7 days platelet transfusions; fever and neutropenia (ANC < or =500/mm(3) for > or =7 days); and/or any > or=grade 3 non-hematologic toxicity. In this multi-institutional phase I study, 17 patients <21 years with intrinsic pontine glioma were enrolled. Sixteen patients completed treatment. An ANC < or =500/mm(3) for > or =7 days occurred in 2/5 patients at 0.50 mg/m(2) of topotecan, which was the DLT. The remaining 14 patients received topotecan without experiencing DLT. One patient at 0.40 mg/m(2) died of disease progression while on treatment. There were 6 other grade 4 hematologic events (5 ANCs <500/mm(3), 1 hemoglobin <6. 5 g/dl) not meeting DLT criteria. No significant non-hematologic toxicities were seen. The actuarial median survival time is 15 months (95% confidence interval, 9.6-19 months); 1-year survival is 53%. DLT of daily topotecan with cranial XRT is grade 4 neutropenia for > or =7 days at 0.50 mg/m(2) x 33 (total dosage = 16.5 mg/m(2)); the recommended safe MTD of daily topotecan for further phase II testing is 0.40 mg/m(2) x 33 (total dosage = 13.2 mg/m(2)).
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PMID:A phase I study of topotecan as a radiosensitizer for brainstem glioma of childhood: first report of the Children's Cancer Group-0952. 1262 28

A randomized two-stage, phase II study was conducted to assess the antitumor activity of two different schedules of topotecan in the treatment of extensive-stage small-cell lung cancer (SCLC) in chemotherapy-naive patients. A total of 40 eligible patients were randomized to receive either the daily schedule, with topotecan being administered intravenously at 1.5 mg/m2 daily for 5 days every 3 weeks, or the continuous-infusion schedule, with topotecan administered intravenously at a dosage of 1.3 mg/m2 per day over 72 hours every 4 weeks. Randomization to the continuous-infusion schedule was discontinued due to inactivity, and an additional 20 patients were treated on the daily schedule. Patients received an average of 5 courses (range: 1-13) of the daily schedule compared to an average of 2 courses (range: 1-7) of the continuous-infusion schedule (p < 0.01). Confirmed response rates for the daily and continuous-infusion schedules are 62.5% (90% CI: 49-75%) and 15% (90% CI: 1-29%), respectively. Toxicity was predominantly hematologic with 92% (55/60) having greater than or equal to grade III neutropenia and 58% (35/60) reporting greater than or equal to grade III leukopenia for both IV schedules. Nonhematologic toxicity was very mild, with only 10% (6/60) patients experiencing grade IV toxicities. One patient died of infection on the continuous-infusion arm. Median times to progression for the daily and continuous-infusion schedules are 5 months (90% CI: 4.4-7.2) and 2 months (90% CI: 1.1-2.1), respectively. Estimated 1-year survival rates for patients receiving daily and continuous-infusion schedules are 63% (90% CI: 51-76%) and 55% (90% CI: 39-77%), respectively. Fifty percent (30/60) of patients received second-line therapy with etoposide and cisplatin. Forty-three percent (13/30) of patients who received second-line therapy achieved a confirmed response. Topotecan showed significant activity in the treatment of extensive stage SCLC when administered as a brief daily IV repeated every 3 weeks.
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PMID:Randomized phase II study of daily versus continuous-infusion schedules of topotecan in the treatment of extensive-stage small cell lung cancers. 1279 91

In a previous study of prevalidation, a standard operating procedure (SOP) for two independent in vitro tests (human and mouse) had been developed, to evaluate the potential hematotoxicity of xenobiotics from their direct and the adverse effects on granulocyte-macrophages (CFU-GM). A predictive model to calculate the human maximum tolerated dose (MTD) was set up, by adjusting a mouse-derived MTD for the differential interspecies sensitivity. In this paper, we describe an international blind trial designed to apply this model to the clinical neutropenia, by testing 20 drugs, including 14 antineoplastics (Cytosar-U, 5-Fluorouracil, Myleran, Thioguanine, Fludarabine, Bleomycin, Methotrexate, Gemcitabine, Carmustine, Etoposide, Teniposide, Cytoxan, Taxol, Adriamycin); two antivirals (Retrovir, Zovirax,); three drugs for other therapeutic indications (Cyclosporin, Thorazine, Indocin); and one pesticide (Lindane). The results confirmed that the SOP developed generates reproducible IC90 values with both human and murine GM-CFU. For 10 drugs (Adriamycin, Bleomycin, Etoposide, Fludarabine, 5-Fluorouracil, Myleran, Taxol, Teniposide, Thioguanine, and Thorazine), IC90 values were found within the range of the actual drug doses tested (defined as the actual IC90). For the other 10 drugs (Carmustine, Cyclosporin, Cytosar-U, Cytoxan, Gemcitabine, Indocin, Lindane, Methotrexate, Retrovir, and Zovirax) extrapolation on the regression curve out of the range of the actual doses tested was required to derive IC90 values (extrapolated IC90). The model correctly predicted the human MTD for 10 drugs out of 10 that had "actual IC90 values" and 7 drugs out of 10 for those having only an extrapolated IC90. Two of the incorrect predictions (Gemcitabine and Zovirax) were within 6-fold of the correct MTD, instead of the 4-fold range required by the model, whereas the prediction with Cytosar-U was approximately 10-fold in error. A possible explanation for the failure in the prediction of these three drugs, which are pyrimidine analogs, is discussed. We concluded that our model correctly predicted the human MTD for 20 drugs out of 23, since the other three drugs (Topotecan, PZA, and Flavopiridol) were tested in the prevalidation study. The high percentage of predicitivity (87%), as well as the reproducibility of the SOP testing, confirm that the model can be considered scientifically validated in this study, suggesting promising applications to other areas of research in developing validated hematotoxicological in vitro methods.
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PMID:Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics. 1288 91

Several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer. The TAX 317 trial found that patients treated with docetaxel (Taxotere) 75 mg/m2 had significantly longer survival than those treated with best supportive care alone. In addition, symptom control was better for patients who received chemotherapy. The TAX 320 trial found that treatment with docetaxel 75 or 100 mg/m2 resulted in significantly higher response rates than treatment with vinorelbine (Navelbine) or ifosfamide (Mitoxana), and the 1-year survival rate was also significantly better for patients treated with docetaxel 75 mg/m2. A large randomized trial compared pemetrexed (LY-231514 or Alimta) 500 mg/m2 with docetaxel 75 mg/m2. Response and survival rates were similar in the two treatment arms, however, the toxicity profile of pemetrexed was superior to that of docetaxel with significantly less Grade 3/4 neutropenia and febrile neutropenia. Fewer patients in the pemetrexed arm required hospitalization. Topotecan (Hycamtin) 2.3 mg/m2/day orally for 5 days has been compared with docetaxel 75 mg/m2 in a large 800-patient study. The results of this trial are awaited. Gemcitabine (Gemzar) and irinotecan (Campto) have been evaluated both as single agents and in combination with each other and study results do not suggest that either of these drugs is superior to docetaxel or pemetrexed. The vinca alkaloid vinorelbine has proved to be inferior to docetaxel in a randomized trial. The epidermal growth factor receptor inhibitors gefitinib (ZD1839, Iressa) and erlotinib (CP-358774, OSI 774, Tarceva) have been evaluated in Phase II trials in the second- and third-line setting. Both drugs have demonstrated interesting response rates ranging from 10 to almost 20%. The results of placebo-controlled randomized trials of this family of drugs are awaited. In summary, several studies have now found a definite role for the second-line treatment of patients with non-small cell lung cancer.
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PMID:Second-line chemotherapy for non-small cell lung cancer. 1293 56

Although current treatments for small-cell lung cancer (SCLC) yield objective response rates exceeding 50%, most patients relapse. Hence, research into the identification of novel agents and combinations that may improve therapy is ongoing. Topotecan, an established treatment for patients with recurrent SCLC, is being investigated as first-line therapy for SCLC because of its novel mechanism of action, non-cumulative toxicity and in vitro synergy with other active agents. Several phase II studies of doublet and triplet combination therapy with other agents, including paclitaxel, cisplatin, carboplatin and etoposide, have reported promising results for first-line treatment of SCLC. For example, in combination with paclitaxel, complete and overall responses were 3-67% and 45-100%, respectively, in extensive-stage disease. Furthermore, two studies of the triplet combination of topotecan with paclitaxel plus carboplatin yielded impressive complete response rates of 37-51% in limited-stage SCLC. The most frequent adverse events associated with topotecan-based regimens have been reported as neutropenia and thrombocytopenia so growth factor support is often incorporated into treatments. Several ongoing phase III studies will help to clarify the role of topotecan in the first-line treatment of SCLC.
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PMID:Topotecan as first-line therapy for small cell lung cancer. 1456 9

Topotecan, a novel topoisomerase I inhibitor, is an established treatment for patients with recurrent small-cell lung cancer (SCLC), with antitumor response rates of approximately 20% and median survival of approximately 32 weeks in patients with extensive-stage disease. Topotecan's comparable activity relative to other agents used in SCLC and its novel mechanism of action, noncumulative toxicity, and in vitro synergy with other active agents have provided the rationale for investigating topotecan in first-line therapy. Furthermore, topotecan penetrates the blood-brain barrier and is potentially useful for the relatively large subset of patients with SCLC and brain metastases. In early studies of topotecan in brain metastases, encouraging antitumor activity has been observed. In several feasibility and phase II studies of topotecan as single-agent therapy in patients with extensive- and limited-stage tumors and as part of novel first-line combination regimens, overall response rates have ranged from 42% to 100%. Complete responses of 3%-67% and partial responses of 33%-80% have been observed in first-line therapy. Furthermore, the median overall survival in patients receiving topotecan in first-line therapy has ranged from approximately 8 months (extensive-stage disease) to 20 months (limited-stage disease). The most frequent adverse events associated with topotecan-based regimens include grade 3/4 neutropenia and thrombocytopenia that often require the incorporation of growth factor support into the treatment regimen. Nonhematologic adverse events associated with topotecan-based combination regimens have been mild or primarily attributed to other agents in the combination. Alternative doses and schedules (3 consecutive days and weekly) are being explored because they appear to be associated with considerably less myelosuppression. Although several trials have established the feasibility and activity of topotecan in first-line therapy of patients with SCLC, randomized phase III studies with comparison to standard therapy will be required to confirm a potential role for this active agent and to determine the optimal dosing regimen.
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PMID:Emerging role of topotecan in first-line therapy of small-cell lung cancer. 1460 45

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