Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The North Central Cancer Treatment Group designed a phase II trial to assess the efficacy and toxicity of topotecan in patients with unresectable malignant pleural mesothelioma. Twenty-two previously untreated patients with unresectable pleural mesothelioma and good performance status (Eastern Cooperative Oncology Group performance status 0, 1, or 2) were enrolled on this trial from October 1993 through July 1994. Nineteen men and three women, median age 66 years (range, 44-78 years), were treated with topotecan 1.5 mg/m2 intravenously over 30 minutes daily for 5 days at 3-week intervals until toxicity, progression of disease, or a patient decided to discontinue treatment. There were seven patients with measurable disease and 15 with evaluable disease; all were assessable for response and toxicity. A total of 113 cycles of treatment were given, for a median of three cycles (range, 1-26 cycles). Myelosuppression was the most frequent toxicity. Eighteen of 21 patients (86%) experienced grade 3 or 4 neutropenia during the initial treatment cycle. The median neutrophil nadir was 0.5 x 10(3)/microl (range, 0.1-1.6 x 10(3)/microl), and the median platelet nadir was 127 x 10(3)/microl (range, 18-460 x 10(3)/microl). Other toxicities more than grade 2 included malaise (two patients), and anorexia, infection, fever, pulmonary, and cardiac in one patient each. There were no objective responses, and 18 patients had stable disease for a median of 74 days. The median survival for all patients was 230 days, with 23% alive at 1 year. Topotecan as administered in this trial is reasonably well tolerated; however, the response rate was insufficient to warrant additional study in pleural mesothelioma.
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PMID:Phase II trial of topotecan for the treatment of mesothelioma. 985 66

Prolonged exposure to topotecan in in vitro and in vivo experiments has yielded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged administration. Pharmacokinetic/pharmacodynamic relationships from four Phase I studies with different schedules of administration of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy were compared. Topotecan was administered as follows: (a) once daily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days every 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 days (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients). Pharmacokinetic analysis was performed in 55 patients using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. Totals of 109, 48, 64, and 59 courses were given, respectively. Dose-limiting toxicity consisted of granulocytopenia for the o.d. x 5-day dosage, a combination of myelosuppression and diarrhea in both of the 10-day schedules, and only diarrhea in the 21-day schedule. Pharmacokinetics revealed a substantial variation of the area under curve (AUC) of topotecan lactone in all of the dose schedules with a mean intrapatient variation of 25.4 +/- 31.0% (o.d. x 5), 34.5 +/- 25.0% (o.d. x 10), 96.5 +/- 70.1% (b.i.d. x 10), and 59.5 +/- 51.0% (b.i.d. x 21). Significant correlations were observed between myelotoxicity parameters and AUC(t) day 1 and AUC(t) per course of topotecan lactone. In all of the studies, similar sigmoidal relationships could be established between AUC(t) per course and the percentage decrease of WBCs. At maximum-tolerated dose level, no significant difference in AUC(t) per course was found [AUC(t) per course was 107.4 +/- 33.7 ng x h/ml (o.d. x 5), 145.3 +/- 23.8 ng x h/ml (o.d. x 10), 100.0 +/- 41.5 ng x h/ml (b.i.d. x 10), and 164.9 +/- 92.2 ng x h/ml (b.i.d. x 21), respectively.] For oral topotecan, the schedule rather than the AUC(t)-per-course seemed to be related to the type of toxicity. Prolonged oral administration resulted in intestinal side effects as a dose-limiting toxicity, and short-term administration resulted in granulocytopenia. On the basis of this pharmacokinetic study, no schedule preference could be expressed, but based on patient convenience, administration once daily for 5 days could be favored.
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PMID:A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin) 991 95

The topoisomerase I inhibitor topotecan had demonstrated good antitumor activity in several murine tumor systems and in human clonogenic assays by 1993. In that year, the Cancer and Leukemia Group B (CALGB) began a phase II trial to determine its activity in patients with breast cancer who had previously received one course of chemotherapy for advanced breast cancer. Between April 1993 and June 1994, 53 patients of performance status 0-2 entered the study, of whom 47 were eligible and 40 were evaluable. Topotecan was given at a dose of 1.5 mg/m2 over 30 minutes daily for 5 days every 21 days. In the absence of progression or withdrawal of consent, therapy was continued indefinitely. The median age was 58 years (range 30-79). There were no complete responses and four partial responses, resulting in an objective response rate of 10% (95% CI: 3-24%). Responses were noted in lymph nodes, liver, and skin. The median duration of response was 5 months. The median survival was 12 months. Life-threatening toxicities were almost exclusively hematologic. However, myelosuppression was not cumulative. It was concluded that topotecan has only modest activity among women with advanced breast cancer who have previously received one course of chemotherapy. Given its modest activity and predominant hematologic toxicity, it does not appear to be a promising drug for either single-agent or combination chemotherapy in the salvage setting of advanced breast cancer.
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PMID:Phase II trial of topotecan in advanced breast cancer: a Cancer and Leukemia Group B study. 1036 25

Topoisomerase I inhibitors are a new class of anticancer agents with a mechanism of action aimed at interrupting DNA replication in cancer cells, the result of which is cell death. Most if not all Topoisomerase I inhibitors are derivatives of the plant extract camptothecin. Irinotecan (CPT-11), a semi-synthetic derivative of camptothecin, is approved in the United States for the treatment of colorectal cancer. Ongoing clinical trials with CPT-11 show a 13% to 32% response rate when it is used singly or in combination with other chemotherapeutic agents such as 5-fluorouracil. The major dose-limiting toxicities of CPT-11 are myelosuppression and a dual phase diarrhea. Topotecan is another semi-synthetic analogue of camptothecin. It is approved for use in the United States for the treatment of cisplatin refractory ovarian carcinoma. Current clinical trials suggest antitumor activity against a variety of human tumor types. There is significant interindividual variability in the plasma disposition of this drug. The main dose-limiting toxicity is myelosuppression. There are other derivatives of camptothecin, as well as new formulations of the parent plant extract, that are in various stages of clinical trials. Some of these clinical trials are aimed at increasing the therapeutic benefits of the agents when used singly or in combination with other chemotherapeutic agent(s) or treatment modalities. The dose-limiting toxicity observed in most of these clinical trials is myelosuppression.
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PMID:Topoisomerase I Inhibitors. 1038 70

Topotecan (Hycamtin(R)) is a topoisomerase I inhibitor which demonstrated a wide spectrum of antitumor activity in preclinical models. During phase I assessment, evidence of activity was most promising when topotecan was administered on an i.v. daily x 5 schedule and a dose of 1.5 mg/m(2)/day was selected for phase II/III evaluation. This regimen has been shown to have activity in a wide range of tumor types, including recurrent ovarian cancer, relapsed small cell lung cancer (SCLC), non-small cell lung cancer, colon cancer, and breast cancer, as well as hematological malignancies. In patients with ovarian cancer who had failed standard therapy, topotecan demonstrated response rates of 13% to 25%, with median times to progression of 12 to 19 weeks. Compared with paclitaxel, the response rates were similar, 20.5% and 14.0%, respectively, as were median times to progression (19 weeks for topotecan versus 15 weeks for paclitaxel). Results in recurrent SCLC have also been encouraging. Patients sensitive to previous chemotherapy have shown response rates of 19% and 39%, and even patients resistant or refractory to previous chemotherapy have had responses of 3% and 7%. Survival ranged from 20 weeks in refractory disease to 12 months in both sensitive and resistant/refractory disease combined. The safety profile of topotecan is well established. The principal toxicity is noncumulative myelosuppression, and serious sequelae are uncommon. Nonhematological toxicities are generally mild. The use of topotecan in combination regimens is promising, although clinical results are currently at an early stage. To date, topotecan has demonstrated its activity in recurrent ovarian cancer and offers a valuable addition to treatment options in relapsed SCLC.
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PMID:Topotecan: An Oncologist's View. 1038 30

Topotecan was studied as a 72 h infusion given every 3 weeks. Treatment began at a dose of 1.0 mg/m2/day and was increased to 1.25 mg/m2/day after the first 6 patients tolerated this higher dose without excessive toxicities. Eighty-eight evaluable children were accrued in 6 strata. There were no complete nor partial responses. Twenty subjects had stable disease (astrocytoma 5/11, malignant glioma 5/13, medulloblastoma 0/12, brain stem tumor 4/19, ependymoma 5/17, and miscellaneous histologies 1/16). Two patients (astrocytoma, ependymoma) completed the maximum 18 topotecan courses. The remaining 68 children developed progressive disease within 2 months. Myelosuppression was the main toxicity. Grade 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 18, 32, 5, and 23 participants, respectively. It was concluded that topotecan as given according to this schedule showed insufficient activity to promote it to frontline protocol usage.
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PMID:Topotecan for the treatment of recurrent or progressive central nervous system tumors - a pediatric oncology group phase II study. 1044 70

Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.
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PMID:Cyclophosphamide, ara-C and topotecan (CAT) for patients with refractory or relapsed acute leukemia. 1078 92

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

Topotecan, a semi-synthetic derivative of the alkaloid camptothecin is an antitumor drug that like other camptothecin derivatives, targets DNA topoisomerase I, an enzyme that is present in cells in concentration relatively independent of the stage in the cell cycle. Topotecan stabilizes the complex formed between topoisomerase I and DNA, leading to DNA strand breakage and cell death. In accordance with preclinical studies, clinical efficacy of topotecan was documented in ovarian carcinoma, in small cell lung cancer and in childhood solid tumors. Myelosuppression is the dose-limiting toxicity and nonhematologic side effects are generally mild. The activity of topotecan against a number of hematological malignancies is now increasingly exploited as well as its role in high-dose chemotherapy programs with stem cell support. In both lymphoblastic and myeloid acute leukemias, topotecan has been widely utilised both as single agent or associated to other cytostatic drugs with proven efficacy in these diseases. Most of the published phase II studies demonstrated that heavily pre-treated, relapsing patients achieve a high percentage of overall responses with manageable toxicity. In myelodisplastic syndromes and acute myelomonocitic leukemias a recently published study shows positive results for the combination of topotecan and cytarabin. Topotecan seems to preferentially affect the abnormal cytogenetic clones and in patients achieving a complete response, a conversion from an aneuploid to a diploid karyotipe was documented. In non-Hodgkin lymphomas, several schedules have been tested in the phase I setting. When utilized alone and at very low dosage, the drug yielded 15% of objective responses and a lack of extrahematologic toxicity. Of particular interest seems to be the association of topotecan with taxanes that needs to be supported by growth factors. In multiple myeloma Topotecan has been utilized as single agent in heavily pre-treated patients. The obtained results show good activity and again myelosuppression as preminent toxicity. The use of topotecan in high-dose chemotherapy regimens for multiple myeloma has been proposed. The utilization of topotecan in high-dose chemotherapy is one of the newer and more interesting applications. Solid tumors (i.e. ovarian cancer and small cell lung cancer) are actually investigated by many authors, who have indicated that this drug can be used preferentially as a part of diversified programs containing overlimit dosages of different cytostatics. Furthermore, topotecan demonstrated to be an effective drug to mobilize CD34+ cells for autografting. A general conclusion is that topotecan is an interesting addition to the actual chemotherapy scenario, both because of its mechanism of action and its toxicity profile. The present review of the new possibility of utilization, give us the idea that topotecan has activity in several hematologic neoplasias; further investigations in these diseases (i.e., induction treatment, combination chemotherapy) are then warranted. The broad spectrum of antitumor activity and the characteristics of toxicity make it also interesting for use in both the circulating progenitor cell mobilization and in the consolidation phase of high-dose chemotherapy programs.
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PMID:[Topotecan: a new field of use]. 1078 97


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