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)

The activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) against untreated and previously treated metastatic breast cancer (documented in anthracycline-resistant disease and in extensively pretreated patients as well) has prompted investigations of the optimal doses and schedules of paclitaxel/doxorubicin combinations. With one exception, paclitaxel has been administered in either a 24- or a 3-hour infusion, while the administration times for doxorubicin vary from bolus injection to a 72-hour infusion. Results of these completed phase I and II trials are reviewed. Also reported are two ongoing European trials that have achieved promising preliminary results. In Milan, a phase I trial has achieved a preliminary response rate exceeding 90% in 30 chemotherapy-naive patients treated with an alternating schedule of paclitaxel over 3 hours and intravenous bolus doxorubicin. At doses of paclitaxel 200 mg/m2 and doxorubicin 60 mg/m2, the dose-limiting toxicity is leukopenia and mucositis. Furthermore, congestive heart failure has occurred in six patients. We are conducting a phase I/II study in minimally pretreated patients, with a 30-minute doxorubicin infusion preceding a 3-hour paclitaxel infusion every 3 weeks. Of 24 patients evaluable for response, five have achieved partial responses and three complete responses. (Another five partial and two complete responses need confirmation.) Of the two dose levels now given, all responses occurred at the higher paclitaxel/doxorubicin level, 175 and 60 mg/m2, respectively. Despite grades 3 and 4 neutropenia in 31% and 60% of courses, respectively, only six patients have been hospitalized for febrile neutropenia. Of concern, the left ventricular ejection fraction has decreased to below normal in six patients and two have developed symptomatic congestive heart failure. Whether lowering the peak doxorubicin concentration will preclude this effect, which has been observed only in the studies using short infusions of both drugs, is under investigation.
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PMID:Treatment of metastatic breast cancer with paclitaxel and doxorubicin. 864 64

Ifosfamide, carboplatin, cisplatin, etoposide, and paclitaxel are chemotherapeutic agents active in treating many malignant diseases. The ICE combination (ifosfamide/carboplatin [or cisplatin]/etoposide) has been studied in breast cancer, small cell and non-small cell lung cancer, testicular cancer, lymphoma, and other malignancies with promising results. We conducted a dose-escalation study of paclitaxel in combination with ICE (ICE-T) to evaluate the toxicity and define the maximum tolerated dose of paclitaxel. To date, 24 patients have been treated with ICE-T. Patients had to have no or minimal prior chemotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate bone marrow, liver, and kidney function. The doses of ICE were as follows: ifosfamide 1.25 g/m2/d days 1 to 3, carboplatin 300 mg/m2 day 1, and etoposide 80 mg/m2/d days 1 to 3. Paclitaxel was given at a dose of 120 mg/m2 to five patients, 135 mg/m2 to five patients, 150 mg/m2 to three patients, and 175 mg/m2 to 11 patients. All patients received granulocyte colony-stimulating factor support. The most common side effect was neutropenia. Grade 4 neutropenia and thrombocytopenia occurred during 34% and 20% of 94 cycles, respectively, with leukopenic fever occurring during 14% of cycles. No treatment-related death or sepsis occurred due to brief nadir durations of 3.5 days for neutropenia and thrombocytopenia. Other toxicities were mostly mild to moderate and did not require dose modification, although alopecia was universal. Nine patients (100%) with metastatic breast cancer and four (67%) with soft tissue sarcoma have attained documented objective responses with four complete remissions (one breast cancer and three sarcoma patients). The maximum tolerated dose of paclitaxel has not yet been defined, and the study is ongoing. In conclusion, this pilot study showed that ICE-T is safe and tolerable. The response to ICE-T is encouraging and warrants further study with this regimen.
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PMID:Ifosfamide, carboplatin, etoposide, and paclitaxel chemotherapy: a dose-escalation study. 867 54

The paclitaxel (TAXOL); Bristol-Myers Squibb Company) represents first agent from novel class of antineoplastic drugs--taxanes to enter routine clinical practice. Paclitaxel interferes with microtubular polymerization by promoting abnormal assembly of microtubules and inhibiting their subsequent disassembly. Pharmacokinetics of paclitaxel has been intensively studied. There are indications for nonlinear pharmacokinetics when paclitaxel is administered as a short infusion and at higher doses. Neurotoxicity, mucositis, and leukopenia correlate with some pharmacokinetic parameters. The clinical development of paclitaxel was initially hampered by hypersensitivity reactions. Current dosage regiments with premedication reduced the incidence of these events to 3%. The major dose-limiting adverse effect of paclitaxel is neutropenia. Significant activities were reported especially in patients with advanced ovarian, breast, non-small cell lung cancer (NSCLC), head and neck cancer and in other types of tumours. Long-term follow-up will also allow the effects of the drug on patient survival to be determined. At present combination of Taxol (paclitaxel) with cisplatin clearly improves the duration of progression-free survival and of overall survival compared with cyclophosphamide and cisplatin in women ovarian cancer. Recently was TAXOL (paclitaxel) registered in Czech republic for treatment of patients with advanced metastatic ovarian carcinoma and in patients with metastatic breast cancer after failure of the standard therapy.
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PMID:[Paclitaxel (Taxol)]. 870 79

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

Paclitaxel (Taxol) is a natural product with a broad spectrum of activity against various solid tumors. This report includes nineteen patients with advanced breast cancer who have not previously received chemotherapy for metastatic disease. Fifteen patients had received adjuvant chemotherapy, eight of which were doxorubicin based. Patients were treated with 135 mg/m2 over 24 hours by continuous infusion given every 21 days. There were 2 complete and 4 partial responses for an objective response rate of 32% (95% C.I.: 14%, 57%) and eight patients or 42% with stable disease. Three of eight patients (38%) who had received adjuvant doxorubicin did respond to paclitaxel. Responses occurred in lung, liver, and soft tissue. The primary toxicity was hematologic with 13 hospitalizations for febrile neutropenia in 180 cycles (7%). Paclitaxel has moderate activity in a small number of patients with metastatic breast cancer at the dose of 135 mg/m2 over 24 hours in this study.
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PMID:A phase II trial of paclitaxel (Taxol) as first line treatment in advanced breast cancer. 872 49

From January 1992 to July 1993, 28 patients with metastatic breast cancer were entered in a phase II trial to assess the activity and toxicity of the combination of mitoxantrone, 5-fluoruracil, and leucovorin. Patients were eligible if they had progressive disease after either adjuvant (2 patients) or previous chemotherapy for metastatic disease (26 patients). Twenty-five patients (89.2%) had received previous anthracycline-based therapy. Predominant site of metastatic disease was visceral in 22 patients, bone in 2 patients, soft tissue in 4 patients, and the majority of patients (89.2%) had two or more sites of disease. The regimen was administered according to the following schedule: Mitoxantrone 9-12 mg/m2 i.v. on day 1; L-Leucovorin 150 mg i.v. over 1 hour before 5-Fluorouracil 350 mg/m2 i.v. push days, 1, 2 and 3. Courses were repeated every 21 days. Twenty-six patients were evaluable for response. We observed 2 complete responses, 5 partial responses with a median duration of 38 weeks (range 23-68). The objective response rate was 27% (95% C.I., 10% to 44%). Myelo-suppression was the most frequent toxicity, but it was mild in the majority of patients. Nine episodes of fever and neutropenia occurred in six patients but none of these episodes was fatal. No clinical evidence of cardiotoxicity was observed. At a median follow-up of 78 weeks, the median time to progression was 20.5 weeks and the median overall survival was 48 weeks. We conclude that this regimen is well tolerated and in our experience the objective response rate is similar to other salvage chemotherapy regimens.
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PMID:Salvage chemotherapy in metastatic breast cancer: an experience with the combination of mitoxantrone, 5-fluorouracil, and L-leucovorin. 873 80

The present pilot study included 31 evaluable patients with metastatic breast cancer. All patients had disease progression following first-line treatment for their metastatic disease (by hormonal treatment or chemotherapy). Twenty patients had previously received Adriamycin as either adjuvant or palliative treatment. The patients were treated by Navelbine 25 mg/m2, Mitoxantrone 6 mg/m2 (both drugs on days 1 and 8) with 5-Fluorouracil (5-FU) 300 mg/m2 as continuous 24-hour infusion on days 1 to 14, and to be recycled on day 29. The overall response rate was 58%, and 50% for those who had received prior Adriamycin. The median time to progression was 8.5 months and the 1-year survival rate for the whole group was 45%. Grade III or IV neutropenia was the dose-limiting toxicity being encountered in 28% of the treatment courses with toxic death in 1 patient.
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PMID:Treatment of metastatic breast cancer by navelbine, mitoxantrone and continuous infusion 5-fluorouracil (FMN regimen): results of a pilot study. 880 59

The results of three multicentre phase II trials in which docetaxel (Taxotere) was used in previously treated patients with metastatic breast cancer resistant to anthracyclines or anthracenediones are summarized here. Docetaxel was given to a total of 134 patients who had evidence of disease progression while receiving anthracyclines or anthracenediones for metastatic disease or had relapsed during adjuvant therapy which included these agents. The overall response rate (ORR) across the three studies was 41% in an intent-to-treat analysis. The median duration of response varied from 24 to 28 weeks between studies and the median survival varied from 9 to 12 months. The response rate was well maintained in evaluable patients with visceral metastases (ORR 43%), or multiple (> 2) sites of disease (ORR 48%). These response rates are the highest ever reported for a single agent in patients with anthracycline-resistant disease. The recommended dose and schedule for docetaxel (100 mg/m2 intravenously over 1-h every 3 weeks), which was used in all three studies, was found to be well tolerated, with neutropenia as the most common toxicity (grade 4 in 90% of patients) and febrile neutropenia requiring hospitalisation occurring in only 4% of cycles of therapy.
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PMID:Treatment of patients resistant to anthracycline therapy. 886 4

The rationale for the development of new drug combinations is to combine optimal doses of drugs with single agent activity which are not cross-resistant and have non-overlapping toxicities. Anthracyclines are widely accepted as the agents of choice for first-line treatment of metastatic breast cancer and have been tested in combination with the taxoids, docetaxel (Taxotere) and paclitaxel (Taxol). Toxicity problems have emerged using anthracyclines and paclitaxel, with sequence- and schedule-dependent toxic effects including dose-limiting typhlitis and mucositis, as well as febrile neutropenia and, in one study, cardiomyopathy. The dose-limiting toxicities of the combination of docetaxel and doxorubicin are neutropenia and infection, and preliminary results indicate a response rate of 89%. There is a need to develop a combination treatment regimen which is non-cross-resistant with anthracyclines. Vinorelbine (Navelbine) has single agent activity against metastatic breast cancer and has been used in combination with taxoids. The dose-limiting toxicities of the vinorelbine-paclitaxel combination are febrile neutropenia, pelvic pain, fatigue and paraesthesias. The dose-limiting toxicities of the combination of docetaxel and vinorelbine are febrile neutropenia and mucositis. The overall response rate for this combination was 67% and studies are ongoing.
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PMID:Taxoids in combination chemotherapy for metastatic breast cancer. 886 12

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


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