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)

Cetuximab is a chimeric monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is over-expressed by 25-80% of colorectal cancer tumours and associated with advanced disease. Cetuximab induces a broad range of cellular responses in tumours expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. In a large, randomised, open-label, multicentre study in adult patients with irinotecan-refractory, metastatic colorectal cancer expressing EGFR, cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly plus irinotecan (various doses) produced a greater rate of partial response and disease control (partial response plus stable disease), and increased time to disease progression, compared with cetuximab monotherapy; survival was similar in both groups. The same dosage of cetuximab combined with irinotecan, fluorouracil and folinic acid (various regimens) produced partial responses in 43-58% of patients, a complete response in 5% of patients (one study only) and stable disease in 32-52% of patients with treatment-naive metastatic colorectal cancer expressing EGFR in three small, open-label trials. The most common grade 3/4 adverse events associated with cetuximab monotherapy were acne-like rash, asthenia, abdominal pain and nausea/vomiting. In patients receiving cetuximab plus irinotecan, these were diarrhoea, asthenia, leucopenia and neutropenia.
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PMID:Cetuximab: in the treatment of metastatic colorectal cancer. 1472 61

Based on nonoverlapping toxicity profiles and at least additive cytotoxicity in preclinical models, chemo-therapy regimens have been developed that feature the combination of irinotecan and a taxane drug. In the first study, the optimal doses of paclitaxel and irinotecan were 75 mg/m2 and 50 mg/m2, respectively, when chemotherapy was administered weekly for 4 consecutive weeks, followed by a 2-week rest. The dose-limit-ing toxicity for this regimen was neutropenia, and the most prominent nonhematologic toxicities were mild diarrhea and fatigue. Pharmacokinetic studies failed to demonstrate any sequence-dependent interaction be-tween these agents on the metabolism of irinotecan or its major metabolite. This regimen has been modified, with chemotherapy given on day 1 and day 8 every 3 weeks, and is being tested further in previously un-treated advanced non small-cell lung cancer (NSCLC). In a second trial, irinotecan was combined with docetaxel on a weekly schedule. When chemotherapy was given weekly for 4 weeks, followed by a 2-week rest, the recommended doses of docetaxel and irinotecan were 35 mg/m2 and 50 mg/m2, respectively. Low-grade gastrointestinal toxicity and asthenia were the dose-limiting toxicities. The treatment schedule was modified, with chemotherapy given on days 1 and 8 of a 21-day cycle, and patients are currently being treated with docetaxel 35 mg/m2 and irinotecan 65 mg/m2. Among the 10 evaluable patients with NSCLC in this second study, there was one partial response lasting 24 weeks and four patients with stable disease, including one patient who had progressive disease on a prior paclitaxel-containing regimen. The combinations of irinotecan and a taxane on a weekly schedule are active and well tolerated and deserve further evaluation in the treatment of NSCLC.
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PMID:Irinotecan and taxane combinations for non small-cell lung cancer. 1472 26

Both docetaxel and gemcitabine are active against chemotherapy-pretreated non small-cell lung cancer (NSCLC). We previously demonstrated that weekly gemcitabine can be safely combined with monthly docetaxel with promising antineoplastic activity. In a recently completed phase II trial, 38 NSCLC patients failing upfront chemotherapy were treated with gemcitabine 800 mg/m2 on days 1, 8, and 15 and docetaxel 100 mg/m2 on day 1 every 4 weeks. The intent-to-treat response rate was 33% (95% CI: 19%-55%), with one complete and 11 confirmed partial responses. Responses were seen at all disease sites and in 31% of patients refractory to front-line chemotherapy. The median time to disease progression for the responders was 8 months, and two have remained progression-free for longer than a year. Hematological toxicities included grade 4 neutropenia in half of patients, febrile neutropenia in 10%, and grade 3-4 thrombocytopenia in 25%. The most prominent nonhematological toxicity was asthenia. We conclude that this doublet is active and safe, producing durable responses at all disease sites and in patients with platinum-refractory NSCLC.
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PMID:Docetaxel and gemcitabine combinations in chemotherapy-pretreated non small-cell lung cancer. 1472 38

Second-line chemotherapy with the newer active anticancer drugs like docetaxel may confer some benefit in patients with non small-cell lung cancer (NSCLC) who failed front-line treatment with cisplatin-contain-ing chemotherapy regimens. However, young patients with good performance status need further efforts for palliation and, probably, survival prolongation. Phase II trials have shown that gemcitabine, a new nucleoside analogue, is effective as second-line treatment with a 7%-25% objective response and a 22- to 33-week median survival in patients with NSCLC. Paclitaxel also seems to be active as second-line treatment with a 3%-38% objective response and 17- to 40-week median survival. The antitumor activity of second-line paclitaxel seems to be dose related. The combination of gemcitabine (900 mg/m2 on days 1 and 8) and paclitaxel (175 mg/m2 on day 8) every 3 weeks was administered in 49 patients pretreated with cisplatin- and/or docetaxel-based chemotherapy. Objective responses were observed in 18% (95% confidence interval: 4%-24%) of the patients (one complete response and eight partial responses); three of the responses were observed in patients who failed to respond to front-line chemotherapy. The median survival was 44 weeks. The toxicity profile of the regimen was mild with grade 3/4 neutropenia and thrombocytopenia occurring in 12% and 2% of the patients, respectively. There was only one episode of neutropenic fever. Grade 2 and 3 neurotoxicity occurred in 24% and 8% of the patients, respectively, and 51% of the patients reported grade 2 and 3 asthenia. In conclusion, the combination of gemcitabine/paclitaxel is an effective and well-tolerated second-line chemotherapy regimen which can be given on an outpatient basis.
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PMID:The role of gemcitabine and paclitaxel as second-line chemotherapy for the treatment of advanced non small-cell lung cancer (NSCLC). 1473 36

We examined the safety and efficacy of the docetaxel/cisplatin combination in patients with advanced, previously untreated NSCLC and evaluated changes in quality of life over time. Docetaxel was administered before cisplatin (both 75 mg/m2, 1-hour infusions) every 3 weeks to 47 patients with stage IIIB or stage IV NSCLC. Patients also received premedication of oral dexamethasone. The median age (range) of patients was 62 (45-78) years and 26 patients (55.3%) had adenocarcinoma. Of the 40 patients evaluable for response, one achieved a complete response and 14 had partial responses; the response rate was 37.5% (95% confidence intervals; 22.5, 52.5). In the intent-to-treat population the overall response rate was 31.9%. Time to response ranged from 3 to 20 weeks, and the median duration of response was 34.6 weeks. Median survival and median time to progression were 11.3 months and 18.9 weeks, respectively. One-year survival was 40%. Grade 3 or 4 neutropenia and febrile neutropenia were observed in 74.4% and 12.8% of patients, respectively. Severe asthenia was seen in 14.9% of patients. Other grade 3 or 4 toxicities included nausea (eight patients), vomiting (five), neurosensory effects (six), neuromotor effects (five), diarrhea (four), and infection (three). There was an improvement in emotional well-being; however, the overall quality of life score did not change with treatment. Docetaxel administered in combination with cisplatin is an active regimen in patients with NSCLC. This regimen of docetaxel (75 mg/m2) and cisplatin (75 mg/m2) repeated at 3-week intervals is being evaluated in an ongoing Eastern Cooperative Oncology Group (ECOG) randomized study in patients with advanced and metastatic NSCLC.
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PMID:Docetaxel and cisplatin in patients with advanced non small-cell lung cancer (NSCLC): a multicenter phase II trial. 1473 66

Azimilide dihydrochloride (or azimilide) is a class III antiarrhythmic drug currently under investigation that has been tested in atrial fibrillation in four randomized, placebo-controlled clinical trials to assess efficacy and dose range. These investigational trials showed that doses of azimilide 100 and 125 mg once daily prolonged the time to symptomatic arrhythmia recurrence in patients with a history of symptomatic atrial fibrillation, atrial flutter or both. Doses of 75 mg or less were not useful in this indication. Safety of azimilide has been examined in several different types of studies. In a large randomized clinical trial of post-infarct patients, azimilide neither increased nor decreased mortality risk. In patients with supraventricular arrhythmias, the most common adverse effects reported by patients on azimilide were approximately equal in frequency with those on placebo: headache, asthenia, infection, diarrhea and dizziness. Infrequent cases of torsade de pointes and severe neutropenia were reported in patients taking azimilide. Azimilide is an investigational antiarrhythmic drug that has shown efficacy in patients with atrial fibrillation.
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PMID:Azimilide for atrial fibrillation: clinical trial results and implications. 1473 16

Docetaxel is one of the most active drugs in second-line therapy for non-small-cell-lung-carcinoma (NSCLC). The aim of this multicenter study was to evaluate the safety and efficacy of weekly low-dose docetaxel. Forty-two patients with advanced NSCLC pretreated with cisplatinum-based chemotherapy were enrolled. Docetaxel was administered at a dose of 25 mg/m(2) weekly for 12 consecutive weeks. A total of 386 doses were given with a median number of 10 doses per patient (range: 3-12). Treatment showed low incidence of hematologic toxicity and modest non-hematologic toxicity. An episode of grade 4 thrombocytopenia was reported but no episodes of grade 3 or 4 neutropenia. Most frequent non-hematologic toxicities were asthenia and alopecia. Response rate was 10.5% and median survival time (MST) was 12.8 weeks. Weekly treatment with 25 mg/m(2) docetaxel for 12 consecutive weeks appears to be a feasible and active regimen with mild toxicity in heavily pretreated NSCLC patients.
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PMID:Second line therapy with weekly low-dose docetaxel for pretreated non-small-cell lung carcinoma patients: a multicenter Italian phase II study. 1475 67

The aim of this study was to define the maximum tolerated dose (MTD) and the pharmacological profile of the paclitaxel analogue BMS-184476 given once every 3 weeks, or on days 1 and 8 every 3 weeks (d1&8), in combination with a fixed dose of 50 mg/m(2) of Doxorubicin (Doxo) administered on day 1 of a 21-day cycle. Adult patients with advanced solid malignancies received escalating doses of BMS-184476 infused over 1 h after bolus Doxo. Pharmacokinetics (PK) of BMS-184476, Doxo and metabolites were investigated. The effect of BMS-184476 on doxorubicinol formation was studied in the cytosol from human myocardium. The MTD of 3-weekly BMS-184476 was 30 mg/m(2). The MTD/recommended Phase II dose was 35 mg/m(2)/week (70 mg/m(2) per cycle) in the d1&8 schedule. The dose-limiting toxicity was neutropenia for both schedules. Other toxicities were loss of appetite, asthenia, and mild, cumulative peripheral neuropathy. The objective response rate in 17 previously untreated or minimally pretreated patients with breast cancer treated at 35 mg/m(2)/week of BMS-184476 was 59% (95% Confidence Interval (CI): 33-82%). Two of the 7 patients not responding to the study regimen later responded to Doxo and paclitaxel. Plasma disposition of BMS-184476 at 30, 35 and 40 mg/m(2) was linear without evidence of a PK interaction with Doxo. In studies with cytosol from human myocardium, the formation of cardiotoxic doxorubicinol was not enhanced by BMS-184476. Dosing of BMS-184476 for 2 consecutive weeks allowed the administration of larger doses of the taxane with a promising antitumour activity in patients with untreated or minimally pretreated breast cancer. The higher than expected myelotoxicity of the 3-weekly schedule is unexplained by the investigated interactions. Lack of enhanced doxorubicinol formation in human myocardium is consistent with the cardiac safety of the regimen.
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PMID:Phase IB and pharmacological study of the novel taxane BMS-184476 in combination with doxorubicin. 1496 24

Aprepitant (Emend) is the first commercially available drug from a new class of agents, the neurokinin NK(1) receptor antagonists. Oral aprepitant, in combination with other agents, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy in adults. In three randomised, double-blind, placebo-controlled trials comparing aprepitant (125 mg day 1, 80mg once daily on days 2 and 3 or 2-5) plus standard therapy (intravenous ondansetron and oral dexamethasone) with standard therapy plus placebo, overall complete responses (primary endpoint, defined as no emesis and no rescue therapy) were seen in significantly more patients in the aprepitant arms (63-73% versus 43-52%, p < 0.01 for all comparisons). Complete responses and complete protection during the acute and delayed phase, and overall complete protection were also observed in significantly more patients in the aprepitant arms. The difference between treatment groups was more marked in the overall and delayed phases than in the acute phase. The antiemetic efficacy of aprepitant plus standard therapy in the prevention of CINV was maintained for up to six cycles of chemotherapy. Where assessed, more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis. Aprepitant is generally well tolerated. The most common adverse events in randomised trials were asthenia or fatigue. Other adverse events experienced by aprepitant recipients include anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups. In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of CYP2C9. Thus, aprepitant has the potential to interact with other agents metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence of serious infection or febrile neutropenia in the aprepitant plus standard therapy arm than the standard therapy plus placebo arm; this was attributed to a pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent trials, a modified dexamethasone regimen was used. In conclusion, when added to standard therapy (a serotonin 5-HT(3) receptor antagonist and a corticosteroid), aprepitant is effective and generally well tolerated in the prevention of CINV associated with highly emetogenic chemotherapy in adults. Despite marked advances in the prevention of CINV, standard therapy does not protect all patients. The addition of aprepitant to standard therapy provides an advance in the prevention of both acute and delayed CINV in adults with cancer.
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PMID:Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting. 1502 55

We studied factors predicting docetaxel-related toxicity in 113 unselected patients with metastatic cancer treated under routine daily practice. Docetaxel was administered in either a weekly, bi-weekly or tri-weekly schedule. All patients received prophylactic dexamethasone. Twenty-six patients were aged 70 or more, and 28 (24.8%) had an ECOG performance status (PS) score > or = 2. Primary tumors were mainly in breast, lung, and stomach (58, 25, and 14 patients, respectively). Most patients had metastases at two or more sites and were heavily pretreated. NCI-CTC graded toxicities were mild. Grade 3/4 leucopenia and neutropenia occurred in 19.4% and 10.6% of patients, respectively, with febrile neutropenia in 2 patients. Severe nonhematologic toxicities were rare, except for asthenia (8 patients). Complete alopecia occurred in 26.6% of patients. A proportional-odds regression analysis demonstrated that the tri-weekly schedule and older age represented independent risk factors for all-grade leucopenia, whereas a poor PS for anemia. Primary tumor in breast, tri-weekly schedule, an abbreviated and low dose of corticosteroids premedication, and high duration and cumulative dose of docetaxel were factors predicting asthenia. Risk factors for alopecia and vomiting were tri-weekly schedule and high docetaxel cumulative dose, respectively. In conclusion, in daily clinical practice docetaxel toxicity may be correlated with factors related to patient, disease, and treatment characteristics. Taking into account these variables could be a first step toward individualizing treatment.
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PMID:Factors predicting docetaxel-related toxicity: experience at a single institution. 1507 5


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