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)

Gemcitabine is a fluorine-substituted cytarabine analog with broad experimental antitumor activity. It's activity was explored in chemotherapy-naive patients with advanced progressive renal-cell carcinoma. A total of 39 patients were included in the study, of whom 37 were fully evaluable. In five patients the primary tumor remained in situ. Gemcitabine at 800 mg/m2 was given as a weekly 30-min infusion for 3 consecutive weeks followed by 1 week of rest. One complete response and two partial responses were observed giving a response rate of 8.1% [95% confidence interval (CI), 2-22%]. The duration of the responses is currently 32, 15, and 19 months, respectively. The median survival for all patients was 12.3 months. Gemacitabine was generally well tolerated, with nausea and vomiting (20.5% grade III) and neutropenia (5.3% grade III) being the most significant side effects. Gemcitabine given at this dose level and on this schedule has only limited activity in advanced renal-cell carcinoma.
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PMID:Gemcitabine: a phase II study in patients with advanced renal cancer. 859 74

Gemcitabine is a nucleoside analogue with activity in non-small-cell lung cancer (NSCLC). Phase I trials have determined the best tolerated dose of gemcitabine in chemotherapy-naive patients to be 1250 mg/m2 given as a 30-minute infusion weekly x 3 every 4 weeks. The single-agent efficacy of gemcitabine has been assessed in 4 phase II trials (361 patients) at dose of 800-1250 mg/m2/weekly x 3 every 4 weeks. Single-agent response rates (externally verified by Oncology Review Board) were > 20%, with duration of response 7.6-12.7 months and median survival 8-9 months. Dose-limiting toxicity was neutropenia, but this was rare, even at the highest dose levels. In 3 Japanese studies, response rates of 16.3%, 26% and 20.9% were seen in untreated patients. Pooled data from all NSCLC studies shows that responses were seen in stages IIIA, IIIB and IV disease, and were similar in adeno and squamous cell types. Gemcitabine has also been studied in combination with other drugs active in NSCLC. In one study 50 patients were treated with gemcitabine and cisplatin given weekly x 3 every 4 weeks, cisplatin at a dosage of 25-30 mg/m2 and gemcitabine at doses escalating from 1000 mg/m2 in steps of 250 mg/m2 per cycle, 38 of 50 patients have been evaluated to date, with an overall response rate of 31.6%. Dose limiting toxicity was rare, but there was evidence of cumulative haematological toxicity with grade 4 granulocytopenia and thrombocytopenia becoming more frequent with repeated administration. Similar activity was seen when gemcitabine (1000 mg/m2) was combined with monthly cisplatin (60, 75, 100 mg/m2). Other studies have shown that gemcitabine can enhance radiosensitivity in NSCLC and other solid tumour types such as pancreas/breast and colorectal cancer cell lines.
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PMID:Gemcitabine in the treatment of non-small-cell lung cancer. 861 18

Gemcitabine (2',2'difluoro-2'deoxycytidine, dFdC) is a synthetic antimetabolite of the cellular pyrimidine nucleotide metabolism. In a first series of in vitro experiments, the drug showed a strong effect on the proliferation and colony formation of the human androgen-sensitive tumor cell line LNCaP and the androgen-insensitive cell lines PC-3 and DU-145. Maximal inhibition occurred at a dFdC concentration as low as 30 nM. In contrast to the cell lines which were derived from metastatic lesions of prostate cancer patients, no inhibitory effects were found in normal primary prostatic epithelial cells at concentrations up to 100 nM. The effect of gemcitabine was reversed by co-administration of 10-100 microM of its natural analogue deoxycytidine. In view of a future clinical application of this anti-tumor drug in advanced prostatic carcinoma, we have compared the effect of gemcitabine on prostatic tumor cells with that on bone marrow granulopoietic-macrophage progenitor cells, because neutropenia is a common side effect of gemcitabine treatment. The time course of action on the two kinds of cells was markedly different. Colony formation of tumor cells was inhibited by two thirds at a gemcitabine concentration of about 3.5 nM. The same effect on granulopoietic-macrophagic progenitor cells required a concentration of 9 nM. Co-administration of deoxycytidine to gemcitabine-treated tumor cell cultures completely antagonized the effect of gemcitabine whereas addition of deoxycytidine after 48 hr of gemcitabine treatment could not prevent gemcitabine action on the tumor cells. In contrast, more than half of the granulopoietic-macrophagic progenitor cells could still be rescued by deoxycytidine administration after 48 hr. These findings and the marked difference in the susceptibility of neoplastic and normal prostatic cells suggest that gemcitabine is a promising substance which should be further evaluated as to its efficacy in the treatment of advanced prostatic carcinoma.
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PMID:Inhibitory effects of the nucleoside analogue gemcitabine on prostatic carcinoma cells. 862 20

A phase I study to determine the maximum tolerated dose and toxicity of gemcitabine when given as a 24 h infusion to patients with inoperable non-small-cell lung cancer (NSCLC). A total of 24 patients with unresectable stage IIIa-IV NSCLC were entered into the study. Gemcitabine was administered as a 24 h infusion on days 0, 7 and 14. Courses of therapy were repeated every 28 days. There were 16 males and 8 females with a median age of 51 years (range 40-73 years). The WHO performance score was 1 (21 patients) or 2 (3 patients). The TNM stage was IIIa (6), IIIb (10) and IV (8). Three patients were entered at each dose level with six at the maximum tolerated dose (MTD). Dose levels were 10, 20, 40, 80, 120, 180 and 210 mg m-2. The MTD was 180 mg m-2 and dose-limiting toxicity was neutropenia and lethargy. Partial response was observed in five (21%) patients (95% CI 7-42%) lasting 10, 14, 18, 47 and 51 + weeks. The maximum tolerated dose of gemcitabine given as a 24 h infusion was 180 mg m-2.
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PMID:A phase I study of a 24 hour infusion of gemcitabine in previously untreated patients with inoperable non-small-cell lung cancer. 869 65

Although chemotherapy costs have not been highlighted traditionally, there is increasing pressure to demonstrate the value of new treatments within the health care budget. Pharmaceutical companies are assessing the economic value of their products before launch. Gemcitabine is a nucleoside analogue developed for use in solid tumours. The purpose of this model was to investigate the clinical outcomes and potential cost savings for gemcitabine used as monotherapy compared to cisplatin and etoposide combination therapy in late stage non-small cell lung cancer (NSCLC), in a palliative (as opposed to aggressive) chemotherapy setting. Gemcitabine treatment data were taken from a large NSCLC study and data from retrospective chart reviews identified through the National Oncology Data Base. The model population and effectiveness of the two regimens were judged to be similar, except for baseline performance status. If drug costs were not included, the probability distribution resulting from the simulation showed median cost savings per cycle ranging from $US 1504 to $US 7425, with a medium value of $US 2154. The model suggested that gemcitabine would result in cost savings per cycle more than 90% of the time. Outpatient versus inpatient drug administrations accounted for the majority of potential cost savings. Most of the remaining cost savings were attributable to the difference in febrile neutropenia and antiemetic use. This economic model showed susbstantial savings if gemcitabine was used instead of cisplatin and etoposide combination therapy in the United States' community care setting. Some savings would be realized even if the location of treatment for both regimens was mostly outpatient. Assessment of the product's economic value before launch has assisted in our understanding of the potential areas of cost savings for gemcitabine and has guided us in the design of prospective randomized studies which included pharmacoeconomic endpoints.
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PMID:Economic value of gemcitabine compared to cisplatin and etoposide in non-small cell lung cancer. 869 16

The experience with single-agent gemcitabine in advanced or metastatic breast cancer is reviewed. In all studies, gemcitabine was administered as a 30 min intravenous infusion in cycles once a week for 3 weeks followed by 1 week of rest. In the first European study (gemcitabine 800 mg/m2/week), of 40 evaluable patients, 14 were chemo-naive, 7 had received adjuvant chemotherapy, and 19 had received chemotherapy for metastatic disease. There were 3 complete responders and 7 partial responders (all independently validated by an external Oncology Review Board) for an overall response rate of 25.0% (95% CI: 12.7%-41.2%). The median time to declaration of response was 1.9 months and the median duration of survival for all 40 efficacy-evaluable patients was 11.5 months. Haematological and non-haematological toxicities were particularly mild. WHO grade 3 and 4 toxicities included leukopenia (6.8% and 2.3% of patients), neutropenia (23.3% and 7.0%), AST (6.8% and 2.3%), ALT (18.2% and 0%), infection (0% and 2.3%), nausea and vomiting (25.0% and 2.3%), alopecia (2.3% and 0%). There was no grade 3 or 4 creatinine, proteinuria or haematuria. In the smaller US study (18 evaluable patients, all but one having received prior chemotherapy for stage IV disease) there were no responders. However, the mean dose delivered was very low (577 mg/m2/injection). In an ongoing European trial, with a starting dose of 1000 mg/m2, a number of partial responders have been seen in soft tissue, lung and liver. Gemcitabine's modest toxicity profile and single-agent activity make it an attractive candidate for trial in combination therapy in advanced breast cancer where treatment is currently given to palliate symptoms and improve quality of life.
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PMID:Gemcitabine in advanced breast cancer. 871 26

Gemcitabine has shown phase II activity against a range of solid tumor malignancies. This study evaluated a combination of gemcitabine and carboplatin in a phase I trial in 13 chemotherapy-naive patients with non-small cell lung cancer to determine the maximum tolerated dose of carboplatin in combination with gemcitabine. Gemcitabine at a dose of 1,000 mg/m2 was administered on days 1, 8, and 15 of a 28-day cycle and carboplatin was given as a 30. minute infusion immediately before gemcitabine on day 1. Carboplatin dosing was escalated and determined using the Calvert formula, and three patients were treated at the initial predicted dose of area under the curve (AUC) 4 mg/mL/min. Subsequently the carboplatin dose was escalated to a predicted AUC 5.2 mg/mL/min. Pharmacokinetic studies were performed measuring gemcitabine and carboplatin (total platinum) concentrations. Responses were assessed following two cycles of treatment and patients with stable disease or objective responses proceeded to receive a maximum of six cycles. Dose-limiting myelosuppression was identified at a predicted carboplatin AUC 5.2 mg/mL/min, with two patients developing grade 4 neutropenia and two patients grade 4 thrombocytopenia. However, these grade 4 toxicities were not associated with any serious sequelae. In this preliminary study, four partial responses were observed and the median length of survival for all patients was 45 weeks. Pharmacokinetic parameters for gemcitabine were similar to those in patients receiving 1,000 mg/m2 as a single agent, and for carboplatin showed that the delivered dose was slightly below the calculated dose. There was one treatment-related death due to cerebral edema. The combination was well tolerated by the majority of patients, and symptomatic toxicity was similar to single-agent gemcitabine. The combination of gemcitabine and carboplatin is well tolerated in patients with non-small cell lung cancer, with myelosuppression being the dose-limiting toxicity. Symptomatic toxicities were rare and outpatient treatment was easy. In view of the antitumor activity observed, further examination of this combination is warranted. In the first instance, alternate sequencing of the combination with gemcitabine followed by carboplatin is planned in an extended phase I study prior to phase II evaluation.
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PMID:A phase I study of gemcitabine and carboplatin in non-small cell lung cancer. 889 83

Two phase II breast cancer studies have been completed with gemcitabine in patients with locally advanced or metastatic breast cancer. Gemcitabine was administered as a 30 minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. In a European study of 44 patients, 40 patients were evaluable for response, 26 having received chemotherapy (seven in the adjuvant setting). The mean number of completed cycles administered was 2.7 and 81% of doses were delivered as scheduled. There were three complete responses and seven partial responses, giving an overall response rate of 25.0% (95% confidence interval, 12.7% to 41.2%). Four patients were not evaluable for efficacy: one had insufficient therapy, two had no bidimensionally measurable disease, and one had insufficient therapy and no bidimensionally measurable disease. The median duration of survival was 11.5 months. Hematologic toxicity was generally mild, with World Health Organization grade 3 and 4 leukopenia occurring in 6.8% and 2.3% of patients and neutropenia in 23.0% and 7.0% of patients, respectively. Nonhematologic toxicity was minimal. Flu-like symptoms were mild and transient. Only one patient developed alopecia. In a US study, 18 of 21 heavily pretreated patients were evaluable, all of whom had stage IV disease. The median number of cycles administered was two, with 12% of injections omitted and 31% reduced by 50%. No responses were observed in this smaller study. The safety profile was similar to that in the European study, although myelosuppression was greater in the US study, in which patients were heavily pretreated. The differing results observed from single-agent studies of gemcitabine in advanced breast cancer may be explained in part by the amount of prior chemotherapy received and the lower mean dose of chemotherapy administered in the US study. Responses have been observed in both chemotherapy-naive and previously treated patients. The drug was extremely well tolerated in both studies, even in heavily pretreated patients. In view of its modest toxicity profile and its novel mechanism of action, gemcitabine deserves further evaluation in breast cancer patients and, in particular, because of its relative lack of myelotoxicity would be an ideal candidate for combination chemotherapy.
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PMID:Phase II activity of gemcitabine in advanced breast cancer. 889 87

Although cost considerations traditionally have not been important in cancer treatment decision making, there is increasing concern worldwide about the economic impact of therapeutic alternatives in the field of oncology. In particular, there is greater pressure for pharmaceutical companies to assess the economic value of new products. We have investigated and compared the clinical outcomes and corresponding cost savings of a novel nucleoside analog, gemcitabine, with other chemotherapy options in three different health care settings: Germany, the United States, and Spain. To date, most of the work with gemcitabine has been done in non-small cell lung cancer. Most non-small cell lung cancer patients present with advanced disease that is unsuitable for surgery and, in many cases, unsuitable for potentially curative chemotherapy. Chemotherapy for the majority of patients is therefore administered with palliative intent. For this reason, the comparative agents chosen for the economic models were palliative treatments (cisplatin/etoposide and ifosfamide/etoposide). As is customary with oncolytics, gemcitabine was investigated first as a single agent in noncomparative trials. Since data were not available from a comparator trial, we estimated comparative data from the literature sources and expert opinion (German and Spanish cost models) and from retrospective chart reviews (US cost model). In all three models, the efficacy was assumed to be equal, so a cost-minimization approach was used. Gemcitabine monotherapy showed cost savings compared with both cisplatin/etoposide and ifosfamide/etoposide in all treatment settings. The majority of these savings were due to differences in hospitalization for drug administration, and the incidence and treatment of nausea and vomiting and febrile neutropenia.
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PMID:Economic value of gemcitabine in non-small cell lung cancer. 889 89

Thirty-eight women with epithelial ovarian cancer were treated with gemcitabine, a new antimetabolite. All had previously received platinum, and 27 had also received paclitaxel. Four patients had a partial response giving a response rate of 13% in assessable patients (n = 31) and 11% for all patients entered. Additionally, 6 patients had stable disease with >50% reduction in CA-125 for at least 3 months. Activity was seen in patients resistant to both platinum and paclitaxel. Gemcitabine was well tolerated, with uncomplicated neutropenia the main hematological toxicity. Nonhematological toxicities were generally mild and included fatigue, myalgias, and skin rash. Gemcitabine has some activity in heavily pretreated ovarian cancer patients and deserves further investigation in this malignancy.
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PMID:Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. 889 75


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