Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anthracyclines and taxanes are currently the most effective drugs in the treatment of metastatic breast carcinoma. The aim of this study was to determine the efficacy and toxicity of paclitaxel and doxorubicin combination in the first-line treatment of metastatic breast cancer. Forty-five women with metastatic breast cancer were recruited in the study. Median age was 49 years (range, 33-70). Treatment protocol: doxorubicin (50 mg/m2/day, 30-min infusion) followed by paclitaxel (200 mg/m2/day, 3-hr infusion) every 3 weeks. Response rates included complete response in 13 (28.9%) patients and partial response in 19 (42.2%) patients, with an overall response rate of 71%. Five (11%) patients had stable disease and 8 (18%) patients had progressive disease. At a median follow-up of 19.7 months, median time to progression for all patients was 19.9 months (95% confidence interval, 12.8 to 27 months). Median overall survival time was 28.4 months. Grade 3-4 nausea/vomiting and hematological toxicities were observed in 12 (26%) and 6 (13.3%) patients, respectively. Cardiac toxicity was observed in 2 (4.4%) patients. In this trial, paclitaxel and doxorubicin combination was demonstrated to be a favorable and active regimen in the first-line treatment of metastatic breast cancer.
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PMID:Paclitaxel and doxorubicin combination in the first-line treatment of metastatic breast cancer. 1219 57

Patients with hormone-sensitive breast cancer who have responded to tamoxifen may receive additional benefit from a second endocrine agent following progression or relapse after tamoxifen therapy. Fulvestrant (Faslodex((R)), ICI 182780, AstraZeneca Pharmaceuticals; Wilmington, Delaware) is a selective antagonist of estrogen designed to have no estrogenic effects. Lack of aqueous solubility led to the development of a parenteral formulation for monthly intramuscular administration. Fulvestrant has been shown to inhibit the proliferative effects of estrogen on sensitive tissues in vitro and in vivo, and is without apparent measurable estrogenic activity. The data upon which marketing approval for fulvestrant was based are summarized below. Eight hundred fifty-one postmenopausal women with advanced breast cancer were enrolled in two phase III studies, 400 in a North American double-blind study and 451 in a European open-label study, comparing the efficacy and safety of fulvestrant with anastrozole. Four hundred twenty-eight patients were randomized to receive fulvestrant 250 mg monthly by intramuscular injection and 423 patients were to receive anastrozole 1 mg daily. Patients were considered hormone sensitive either by receptor status or previous response to endocrine therapy. Over 96% of patients had previously received tamoxifen, either in the adjuvant setting or as treatment for metastatic disease. The primary study end points were response rate and time to progression. Response rates for patients treated with fulvestrant were 17% and 20% in the North American and European trials, respectively, compared with 17% and 15% in the anastrozole treatment arms. There were no statistically significant differences in response rates, time to progression, or survival between treatment arms in either study. The most common adverse events attributed to the treatment (>10%) were injection-site reactions and hot flashes. Common events (1%-10%) included asthenia, headache, and gastrointestinal disturbances (nausea, vomiting, and diarrhea), as well as rash and urinary tract infections. A small increase in joint disorders was reported in the anastrozole-treated patients. On April 25, 2002, fulvestrant 250 mg by monthly intramuscular injection was approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Approval was based on similarity of response rates and time to progression between fulvestrant and anastrozole.
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PMID:FDA drug approval summaries: fulvestrant. 1249 Jul 35

Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).
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PMID:Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. 1251 69

Docetaxel has consistently demonstrated its high activity as an antineoplastic agent in the treatment of metastatic breast cancer. However, 90% of patients receiving the recommended dose of 100 mg/m2 every 3 weeks will develop grade 3 or 4 neutropenia. Recent data suggest that the safety profile of a weekly docetaxel regimen compared favorably with the standard 3-week schedule. Thus, we initiated a phase II study to assess the efficacy and toxicity of weekly docetaxel in pretreated patients with metastatic breast cancer. Twenty patients with advanced, anthra-cycline-refractory breast cancer were included in this phase II trial. Docetaxel was administered at a starting dose of 40 mg/m2, repeated once a week for 3 consecutive weeks followed by a 1-week rest period (1 cycle). Patients were evaluated for tumor response every 8 weeks (after every other cycle). Therapy was continued for a maximum of six courses in patients showing tumor response or stable disease. Twenty patients received a total of 204 weekly infusions of docetaxel. The mean number of treatments was 10.2 (range 1-18). Eighteen patients were assessable for response. Five patients achieved a partial response and six patients showed either stable disease or a minor response. Seven patients had disease progression. The median survival was 7.8 months. Grade 3/4 leukopenia occurred in two patients. No other grade 3 or 4 hematologic toxicities were observed. The following grade 3/4 non-hematologic toxicities were seen: nausea/vomiting (one patient), infection (one patient), mucositis (two patients) and diarrhea (one patient). Three patients withdrew from the study due to dose-limiting toxicities (one due to severe neutropenia and two due to mucositis). We conclude that administration of docetaxel at a dose of 40 mg/m2 was effective and well tolerated even in heavily pretreated patients with metastatic breast cancer. This regimen is associated with only mild myelosuppression.
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PMID:Weekly docetaxel in patients with pretreated metastatic breast cancer: a phase II trial. 1263 18

Despite the widespread use of trastuzumab in the management of patients with HER2-overexpressing metastatic breast cancer, its optimal duration of administration is unknown. We retrospectively reviewed the medical records of 80 such patients who received trastuzumab monotherapy or combination chemotherapy beyond disease progression in order to register their clinical course. Median age of the patients was 54 years. Ninety-one percent had 3+ HER2 overexpression and 9% had 2+ HER2 overexpression. Fifty-six percent of patients had previously been treated with chemotherapy for advanced disease. The most commonly used combinations in first- and second-line treatments were trastuzumab with paclitaxel and trastuzumab with vinorelbine, respectively. In total, 32 responses were observed, most of them during the second or third line of treatment. Severe toxicities frequently seen (in = 5% of patients) were neutropenia (25%), thrombocytopenia (11.5%), infection (10%), peripheral neuropathy (9%), nausea/vomiting (6%), stomatitis (6%), diarrhea (6%), constipation (6%), edema (6%), and myalgias/arthralgias (5%). Median survival from diagnosis of advanced disease was 43.4 months (range, 6.4-91.7+), whereas median survival from disease progression after trastuzumab administration was 22.2 months (range, 0.01-32.9+). In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic breast cancer is feasible and safe. Randomized studies are warranted.
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PMID:Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the hellenic cooperative oncology group. 1286 40

The purpose of this study was to evaluate the efficacy and toxicity of weekly docetaxel in metastatic breast cancer. Fifty-seven patients were enrolled in this study of weekly docetaxel given at 25 mg/m(2)/week as a 1-h infusion in out-patient setting. Each cycle consisted of 3 weeks of therapy followed by 1-week treatment break, and the patients received a median of 24 infusions with a median cumulative dose of 600 mg/m(2). Overall response rate was 30% [95% confidence interval (CI), 18-42%], and 31% (18-42%) of patients had stable disease for at least 6 months. With a median follow-up of 16 months, the median time to treatment failure was 11 months (6-14 M), and 3-year survival rate was 60%. There was no grade 4 toxicity, and myelosuppression, fatigue, nausea, vomiting was mild, thus the regimen was generally well tolerated. On the other hand, 44% of patients had grade 1-2 nail change, 21% had grade 3 pleural effusion, 17% had grade 1-2 tearing, and these became more common with prolonged administration of docetaxel. Thus, a weekly schedule of docetaxel at low dose maintains activity and is less myelosuppressive, however, one should be careful about cumulative toxicities.
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PMID:Protracted administration of weekly docetaxel in metastatic breast cancer. 1288 27

A phase II study was conducted to assess the toxicity and response rate of vinorelbine (NavelbineR) combined with epirubicin and fluorouracil (NEF) in metastatic breast cancer. Vinorelbine was delivered at a dose of 25 mg/m2 on days 1 and 8, epirubicin at 60 mg/m2 on day 1 and fluorouracil at 600 mg/m2 on day 1, at 3-week intervals. Forty consecutive ambulant patients with breast cancer with measurable metastases were treated with a total of 310 cycles (median 8) as first-line therapy. The objective response rate was 83% (95% CI 71-95) (6/40 CR 15%, 27140 PR 68%). In 3 patients, CNS metastases were detected during NEF therapy those who had a partial response in their visceral metastases. Median time to progression was 13 months (95% CI 7-19) and estimated median survival time was 32 months. The main dose-limiting adverse effect, grade III-IV haematological toxicity, was reported in 92% of patients. One patient died of neutropenic sepsis. Grade III infections requiring hospitalization were observed in 8 patients (20%). Half of the patients complained of mild constipation, nausea or stomatitis, which were easily managed. Almost all patients had grade III alopecia. One patient with previous adjuvant anthracycline therapy (CEF x 9 two years earlier) developed fatal grade IV cardiac failure associated with pulmonary emboli 2 months after completion of NEF therapy (PR with 6 cycles). In line with the observations of others conducting phase II first-line trials combining vinorelbine and epirubicin, it is concluded that the NEF regimen is effective in metastatic breast cancer. Haematological toxicity, however, requires dose reductions in many patients. Furthermore, careful monitoring of cardiac function is necessary, particularly in patients who received prior adjuvant anthracycline therapy.
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PMID:Vinorelbine, epirubicin and fluorouracil as first-line therapy in metastatic breast cancer--a phase II trial. 1289 2

With the development of highly effective, well-tolerated third-generation aromatase inhibitors (AIs), these drugs will probably play an increasingly important role in all phases of breast cancer treatment. As a result, the impact of such hormonal agents on patients' quality of life bears rigorous investigation. In a randomized, multicenter, single-blind cross-over study, the AIs letrozole and anastrozole were evaluated for quality of life, toxicity, and patient preference. A total of 72 patients were enrolled and were treated with each drug for a 4-week period, with a 1-week drug-free washout period before cross-over to the alternate agent. Assessments included the FACT-ES, toxicity, and patient preference. The FACT-ES is a validated questionnaire designed to measure quality of life of women with breast cancer who are being treated with endocrine therapies. Letrozole was superior to anastrozole with respect to both quality of life and toxicity evaluations. In addition, at the conclusion of the trial, reduced nausea, hot flashes, and abdominal discomfort caused almost twice as many patients to prefer to continue with letrozole therapy than with anastrozole. Data from this recent trial indicate that letrozole is better tolerated and provides better quality of life than anastrozole for women with metastatic breast cancer.
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PMID:Examining quality of life issues in relation to endocrine therapy for breast cancer. 1290 76

Many attempts have been made to achieve good selectivity to targeted tumor cells by preparing specialized carrier agents that are therapeutically profitable for anticancer therapy. Among these, liposomes are the most studied colloidal particles thus far applied in medicine and in particular in antitumor therapy. Although they were first described in the 1960s, only at the beginning of 1990s did the first therapeutic liposomes appear on the market. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome (Nexstar, Boulder, CO, USA), used as an antifungal drug, and Myocet (Elan Pharma Int, Princeton, NJ, USA), a doxorubicin-containing liposome, used in clinical trials to treat metastatic breast cancer. The second-generation liposomes ("pure lipid approach") were long-circulating liposomes, such as Daunoxome, a daunorubicin-containing liposome approved in the US and Europe to treat AIDS-related Kaposi's sarcoma. The third-generation liposomes were surface-modified liposomes with gangliosides or sialic acid, which can evade the immune system responsible for removing liposomes from circulation. The fourth-generation liposomes, pegylated liposomal doxorubicin, were called "stealth liposomes" because of their ability to evade interception by the immune system, in the same way as the stealth bomber was able to evade radar. Actually, the only stealth liposome on the market is Caelyx/Doxil (Schering-Plough, Madison NJ, USA), used to cure AIDS-related Kaposi's sarcoma, resistant ovarian cancer and metastatic breast cancer. Pegylated liposomal doxorubicin is characterized by a very long-circulation half-life, favorable pharmacokinetic behavior and specific accumulation in tumor tissues. These features account for the much lower toxicity shown by Caelyx in comparison to free doxorubicin, in terms of cardiotoxicity, vesicant effects, nausea, vomiting and alopecia. Pegylated liposomal doxorubicin also appeared to be less myelotoxic than doxorubicin. Typical forms of toxicity associated to it are acute infusion reaction, mucositis and palmar plantar erythrodysesthesia, which occur especially at high doses or short dosing intervals. Active and cell targeted liposomes can be obtained by attaching some antigen-directed monoclonal antibodies (Moab or Moab fragments) or small proteins and molecules (folate, epidermal growth factor, transferrin) to the distal end of polyethylene glycol in pegylated liposomal doxorubicin. The most promising therapeutic application of liposomes is as non-viral vector agents in gene therapy, characterized by the use of cationic phospholipids complexed with the negatively charged DNA plasmid. The use of liposome formulations in local-regional anticancer therapy is also discussed. Finally, pegylated liposomal doxorubicin containing radionuclides are used in clinical trials as tumor-imaging agents or in positron emission tomography.
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PMID:From conventional to stealth liposomes: a new frontier in cancer chemotherapy. 1290 76

Fulvestrant, a novel antiestrogen classified as an estrogen receptor antagonist without known agonist effects, was recently approved in the United States for the treatment of postmenopausal, hormone receptor-positive women with progressive metastatic breast cancer after antiestrogen therapy. In a phase II trial, monthly administration of fulvestrant, 250 mg intramuscularly, conferred clinical benefit (partial response or stable disease for >or= 24 weeks) in 69% of patients with tamoxifen-resistant advanced breast cancer. Furthermore, the median duration of response and survival for this population (26 and 54 months, respectively) was twice as high as those documented for a megestrol acetate-treated historical cohort (14 months and 30 months, respectively). Comparative phase III trials conducted in North America and internationally, which used time to progression as the primary endpoint, demonstrated fulvestrant's tolerability and equivalence to anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer, which led to its approval in this setting. Vasodilation and nausea were the principal treatment-related adverse events in the fulvestrant arms, and mild injection-site reactions occurred in 4.6% and 1.1% of monthly fulvestrant courses given in the North American and international trials, respectively. Recent subanalyses of the pivotal phase III data have found that fulvestrant produces a 30% longer mean duration of response compared with anastrozole and that fulvestrant-induced estrogen receptor downregulation does not preclude response to subsequent hormonal therapy. Ongoing trials in patients with advanced breast cancer will provide further insight into the relative merits of fulvestrant versus tamoxifen as first-line therapy for metastatic disease, the use of fulvestrant within combination and sequential regimens, and the efficacy of fulvestrant specifically in premenopausal women. Research efforts focusing on alternate administration schedules for fulvestrant and its potential as an adjuvant hormonal therapy are also anticipated.
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PMID:Fulvestrant: an estrogen receptor antagonist that downregulates the estrogen receptor. 1461 22


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