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)

Taxol, a novel antimicrotubule agent that enhances tubulin polymerization and microtubule stability, was administered to adults with refractory leukemias as a 24-h i.v. infusion in a Phase I study. The primary objectives were to determine the maximum tolerated dose of taxol administered on this schedule to patients with acute leukemias and describe the nonhematological toxicities which became dose limiting. The starting dose, 200 mg/m2, was based on the maximum tolerated dose in solid tumor trials, in which myelosuppression precluded dose escalation. Seventeen patients received 28 evaluable courses at 200, 250, 315, and 390 mg/m2. Severe mucositis limited further dose escalation. Other nonhematological effects included peripheral neuropathy, alopecia, myalgias, arthralgias, nausea, vomiting, diarrhea, and an acute pulmonary reaction that was presumptively due to taxol's Cremophor vehicle. Mean peak taxol plasma concentrations at all dose levels were in the range of concentrations that were previously demonstrated to induce microtubule bundles, a morphological effect associated with cytotoxicity, in leukemia cells in vitro. Pretreatment blasts from 12 patients were incubated with taxol ex vivo. Taxol-induced microtubule bundles were apparent in the blasts of eight patients who also had cytoreduction of tumor, and sensitivity to bundle formation was related to the magnitude of antitumor activity. In contrast, taxol did not induce microtubule bundles ex vivo in the blasts of the other four total nonresponders. Based on this study, the maximum tolerated doses and recommended Phase II doses for taxol, limited by nonhematological toxicity and administered as a 24-h i.v. infusion to patients with refractory leukemias, are 390 and 315 mg/m2. Phase II trials at these myelosuppressive doses are required to determine taxol's activity in the treatment of leukemias. In addition, further evaluation of microtubule bundle formation ex vivo in Phase II studies is necessary to determine the ultimate utility of this assay in assessing tumor sensitivity to taxol.
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PMID:Phase I and pharmacodynamic study of taxol in refractory acute leukemias. 256 75

Taxol is a plant product derived from the western yew, Taxus brevifolia. We have conducted a phase I clinical study of Taxol used intravenously daily for 5 days at 3-week intervals. The starting dose was 5 mg/m2 daily, and the highest dose used was 40 mg/m2 daily for 5 days. The daily dosage of Taxol was mixed in 250 mL of intravenous fluid and infused over a period of 1 hour. A total of 20 patients with metastatic solid tumors refractory to standard therapy received 45 courses of therapy. Taxol was generally well tolerated and caused no significant nausea or vomiting. A mild degree of diarrhea was reported by six patients, and a moderate degree of stomatitis at the higher dose levels developed in four patients. All patients treated in the dosage range of 20 mg/m2 to 40 mg/m2 experienced nearly complete alopecia. Myelosuppression, predominantly in the form of leukopenia, was the dose-limiting toxicity. The nadir of leukopenia was reached between days 8 and 12 followed by complete recovery between days 15 and 21. Leukopenia was first observed following the Taxol dosage level of 20 mg/m2/d, was moderately severe at the dosage level of 30 mg/m2/d, and was severe at the dosage level of 40 mg/m2/d. No objective tumor regression was observed. A starting dosage level of 30 mg/m2/d for 5 days is recommended for phase II trials using this schedule.
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PMID:Phase I study of taxol using a 5-day intermittent schedule. 287 Nov 37

Combination antimicrotubule therapy with estramustine phosphate (EMP) and vinblastine has reproducible activity in metastatic hormone-refractory prostate cancer (HRPC) with an objective response rate of 31%. Although paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion was inactive in HRPC, 0.5 to 1.0 nmol/L concentrations of paclitaxel combined with EMP exerted synergistic cytotoxicity in DU-145 androgen-independent human prostate cancer cell lines. Based on these results, we treated 24 patients with HRPC using the combination of paclitaxel 120 to 140 mg/m2 by 96-hour intravenous infusion every 3 weeks plus daily oral EMP at 600 mg/m2/d. Of seven patients with measurable soft tissue metastases, three have attained partial responses and a fourth patient is nearing partial response status. Of 16 patients with bone-only disease evaluated by change in serum prostate-specific antigen levels, 11 patients (68.8%) have had decreases of > or = 50% from pretreatment baseline. The prostate-specific antigen decrease has exceeded 80% in six of 16 (37.5%) patients. For all 23 evaluable patients, the prostate-specific antigen has decreased by > or = 50% in 15 (65.2%) and by > or = 80% in eight (34.7%). Grade 4 leukopenia occurred in one of 21 patients treated at the paclitaxel dose of 120 mg/m2/96 hr and one of three patients treated at 140 mg/m2/96 hr. The incidence of nausea (50%) and peripheral edema (37.5%) was similar to that associated with single-agent EMP. These results demonstrate that 96-hour paclitaxel plus EMP is active in HRPC and provide further evidence that the rational combination of antimicrotubule agents leads to synergistic antitumor activity in HRPC.
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PMID:Paclitaxel plus estramustine in metastatic hormone-refractory prostate cancer. 748 60

An ongoing phase I/II trial in patients with chemotherapy-naive metastatic breast cancer (one adjuvant chemotherapy regimen is allowed) uses a 3-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 90 mg/m2 followed by a 3-hour infusion of cisplatin 60 mg/m2 every 2 weeks given with standard premedications. The protocol called for the escalation of paclitaxel in 10 mg/m2 increments to as much as 130 mg/m2 combined with a fixed 60 mg/m2 cisplatin dose without granulocyte colony-stimulating support in the phase I portion of the trial, but dose-limiting neutropenia identified the initial 90 mg/m2 paclitaxel dose as the maximum tolerated in this biweekly schedule. The phase II portion is continuing to accrue patients and results are preliminary. Twenty-two patients have been enrolled thus far. Of the 16 evaluable for response, four (25%) have had a complete and II (69%) a partial response, for an overall response rate of 94%. Eighteen patients are evaluable for toxicity. Significant neutropenia has been dose limiting, but the mean duration of the absolute neutrophil nadir (< 0.5 x 10(9)/L) is only 2 days. Nonhematologic toxicity has been generally mild, with no grade 4 and few grade 3 toxicities occurring. Nausea, most likely attributable to cisplatin, has occurred frequently, as have mild hypersensitivity reactions. Other nonhematologic toxicity (arthralgias, fatigue, neurologic symptoms) also has been mild.
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PMID:Biweekly paclitaxel and cisplatin: a phase I/II study in the first-line treatment of metastatic breast cancer. 759 26

Estramustine phosphate is a unique antimitotic agent that binds to tubulin and microtubule-associated proteins. Preclinically, estramustine combined with other microtubule inhibitors, like vinblastine or paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), produced additive or greater antimitotic and cytotoxic effects. Clinically, the estramustine/vinblastine combination has significant activity in hormone-refractory prostate cancer. We have begun a phase I study of paclitaxel by 96-hour continuous infusion every 3 weeks combined with daily oral estramustine (600 mg/m2). Eighteen patients with refractory solid tumors have received paclitaxel doses ranging from 80 to 140 mg/m2. Grade 3 or 4 granulocytopenia occurred in one of seven and two of four patients treated at the 120- and 140-mg/m2 dose levels, respectively. The latter two patients experienced grade 3 mucositis and had mean plasma paclitaxel levels exceeding 0.1 mumol/L. Other toxicities, principally nausea and hepatic function abnormalities, have been mild. The apparent steady-state concentrations of paclitaxel 100 and 120 mg/m2 administered with estramustine are similar to those reported for single-agent paclitaxel administered as a 96-hour infusion at doses of 100 and 120 mg/m2. In contrast, at the 140 mg/m2 dose level, paclitaxel concentrations increased throughout the infusion, and steady state was not reached in three of the four patients treated. Objective responses have been observed in two of three patients with adenocarcinoma of the esophagus and in two patients with hormone-resistant prostate cancer and measurable soft tissue metastases. Two additional patients with prostate cancer have been treated with the estramustine/paclitaxel combination, one achieving a major response and the other stable disease. The recommended phase II dose for 96-hour infusional paclitaxel with daily oral estramustine is at least 120 mg/m2. Studies to determine the effect of estramustine on paclitaxel pharmacokinetics are continuing. The antitumor activity observed merits phase II studies of this combination in hormone-resistant prostate cancer and other malignancies.
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PMID:Phase I study of paclitaxel and estramustine: preliminary activity in hormone-refractory prostate cancer. 759 35

Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/II trial in outpatients: high-dose 5-FU (24-hour infusion)/FA (2-hour infusion preceding 5-FU) is given for 6 weeks (days 1, 8, 15, 22, 29, and 36), with paclitaxel (3-hour infusion) administered on days 1 and 22; 2 weeks' rest follows. Folinic acid 500 mg/m2 was administered throughout; the respective 5-FU doses for dose levels 1 through 3 were 1.5, 1.8, and 2.0 g/m2 with paclitaxel 135 mg/m2. Dose level 4 (500 mg/m2 FA, 2.0 g/m2 5-FU, and 175 mg/m2 paclitaxel) was chosen for phase II evaluation. To date, 46 patients with bidimensionally measurable disease (four each at dose levels 1, 2, and 3, and 34 at dose level 4) have been entered. The 12 patients treated at dose levels 1 through 3 were titrated to level 4 doses when phase II began; 35 patients are evaluable for response. The median age is 46 years, and the median number of metastatic sites is 2.5. Fourteen patients had received adjuvant chemotherapy, nine chemotherapy for metastasis, and 23 chemotherapy both adjuvantly and for metastasis. Of 31 anthracycline-treated patients, 27 had anthracycline-resistant disease. No dose-limiting toxicity appeared until dose level 4, when grade 3 or 4 leukopenia and diarrhea occurred in 15 and eight, respectively, of 108 cycles. Mild to moderate mucositis, hand-foot syndrome, myalgia, and nausea/vomiting occurred in 20% to 40% of cycles. One (3%) of the 35 patients had a complete response, 18 (51%) had partial responses, 14 (40%) had stable disease, and two (6%) had disease progression. Eleven (55%) of 20 evaluable patients with anthracycline-resistant disease responded (95% confidence interval, 34% to 76%). Median time to maximum response was 2 months, and the remission duration was 8+ months. Median survival time has not been reached. Paclitaxel and weekly high-dose 5-FU/FA was well tolerated and highly effective, even in patients with anthracycline-resistant metastatic breast cancer. The regimen can be administered safely to outpatients.
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PMID:Phase I/II study with paclitaxel in combination with weekly high-dose 5-fluorouracil/folinic acid in the treatment of metastatic breast cancer: an interim analysis. 855 83

The activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been documented in untreated and previously treated metastatic breast cancer, including both patients with anthracycline-resistant disease and those with extensive pretreatment. Such activity has prompted investigations of the optimal doses and schedules of paclitaxel/doxorubicin combinations. With one exception, paclitaxel has been administered as either a 24- or a 3-hour infusion, while the administration times for doxorubicin vary from bolus injection to 72-hour infusion. Results of these completed phase I and II trials are reviewed. Also reported are two European trials that have achieved promising results. In Milan, a phase I/II trial has shown a preliminary response rate exceeding 90% in 32 chemotherapy-naive patients treated with an alternating schedule of paclitaxel given over 3 hours and intravenous bolus doxorubicin. At doses of paclitaxel 200 mg/m2 and doxorubicin 60 mg/m2, the dose-limiting toxicities were neutropenia, oral mucositis, myalgias, and peripheral neuropathy. Congestive heart failure occurred in six patients. A phase I/II study of a 30-minute doxorubicin infusion preceding a 3-hour paclitaxel infusion every 3 weeks in minimally pretreated patients also is reported. Of 29 patients evaluable for response, 17 have achieved partial responses and seven complete responses, for an overall response rate of 83% (95% confidence interval, 79% to 99%). Toxicities observed were grades 3 to 4 neutropenia and moderate paresthesias, nausea/vomiting, alopecia, myalgia, and mucositis. Cardiotoxicity also occurred, as 15 patients had a significant decrease in left ventricular ejection fraction measured by isotope cardiography. Six of these developed congestive heart failure. This effect has been observed only in studies using short infusions of both drugs, and it is now being investigated whether lowering the peak doxorubicin concentration will preclude it.
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PMID:Paclitaxel and doxorubicin, a highly active combination in the treatment of metastatic breast cancer. 862 30

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is an effective drug in the treatment of metastatic breast cancer (MBC). In the salvage setting, 5-fluorouracil (5-FU) and folinic acid have proved to be effective against MBC as well. Recent preclinical data suggest that paclitaxel plus 5-FU has additive cytotoxicity. Given these observations, we initiated a phase II trial in which 38 women with MBC have been treated with a combination of all three drugs. All patients are currently evaluable for toxicity and 34 are evaluable for response. All women had histologically proven and assessable disease. Patients with prior exposure to paclitaxel were ineligible. Patient characteristics include a median age of 51 years (age range, 31 to 73 years) and a median performance status of 1 (range, 0 to 2). Thirty-three patients have received prior chemotherapy, of whom 23 had adjuvant chemotherapy only. Fifty-eight percent of the patients (22 of 38) had received prior doxorubicin or mitoxantrone; four patients had only hormonal therapy. Four patients had bone-only disease, and three patients had lymphangitic spread or cytologically positive pleural effusion as the only evaluable disease. Treatment consisted of paclitaxel 175 mg/m2 over 3 hours (day 1 only), followed by folinic acid 300 mg over 1 hour, followed by 5-FU 350 mg/m2 on days 1 to 3. Patients received standard paclitaxel premedications. To date, 175 cycles have been administered (median cycle length, 29 days; median number of cycles per patient, five). Toxicities included grade 3/4 infections in nine cycles (5%), grade 3/4 mucositis in three cycles, grade 3/4 nausea/vomiting in three cycles, grade 1 paresthesias in 12 patients (32%), alopecia 100%, and 17 cycles (10%) associated with dose reduction. Based on Cancer and Leukemia Group B toxicity criteria, arthralgia/myalgias were modest and graded mild (32 cycles), moderate (nine cycles), or severe (two cycles). There were two major hypersensitivity reactions, prompting removal of those patients from further protocol treatment. Four patients are unassessable for response due to hypersensitivity reactions (two) and unevaluable disease (two). Among the 34 patients evaluable for response, there were three complete responses, 18 partial responses, one minor response, nine stable disease, and three progressive disease (response rate, 62%). Responses were seen in patients who had received prior doxorubicin or mitoxantrone (11 of 22 patients) and in anthracycline/naive patients (10 of 16 patients). Responses were observed in all metastatic sites: soft tissue, viscera, and bone. Paclitaxel/5-FU/folinic acid appears to be an effective and well-tolerated outpatient regimen for women with MBC, even after failure of anthracycline-containing therapy.
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PMID:Paclitaxel and 5-fluorouracil in metastatic breast cancer: the US experience. 862 38

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is active against advanced breast cancer and anthracycline-resistant breast cancer. We assessed the efficacy and toxicity of doxorubicin followed by a 3-hour infusion of paclitaxel in women with advanced breast cancer. Participants could have received at most one prior adjuvant chemotherapy regimen, but no previous exposure to anthracyclines or taxanes was permitted. The patients were treated every 3 weeks with doxorubicin (50 or 60 mg/m2) followed 30 minutes later by paclitaxel (155, 175, or 200 mg/m2). After reaching the maximum cumulative doxorubicin dose, treatment could be continued with paclitaxel alone. Thirty women were included, of whom 29 were evaluable for response. The overall response rate was 83% (95% confidence interval, 64% to 94%), with 24% of patients attaining complete remission. Median response duration for complete responders was 8+ months (range, 4 to 13 months) and median time to progression was 9 months (range, 2 to 18 months). Main toxicities were neutropenia, paresthesia, nausea/vomiting, alopecia, myalgia, and cardiotoxicity. In 15 patients (50%), the left ventricular ejection fraction decreased to below normal levels; six patients (20%) developed congestive heart failure. In conclusion, the combination of doxorubicin and paclitaxel is highly active; dose-limiting toxicities are neutropenia, neuropathy, and cumulative cardiotoxicity.
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PMID:Doxorubicin and paclitaxel, a highly active combination in the treatment of metastatic breast cancer. 889 95

We performed a clinical phase II trial of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin in patients with locally advanced (stage IIIB) or metastatic non-small cell lung cancer (NSCLC), using a 3-hour infusion of paclitaxel followed by a 1-hour infusion of cisplatin. Treatment was repeated every 21 days, for a maximum of six cycles. The patients received paclitaxel 175 mg/m2 followed by cisplatin 75 mg/m2. At present, 52 chemotherapy-naive patients with stage IIIB (17.3%) or stage IV (82.7%) NSCLC have been entered into this ongoing trial. Ten (19%) of the patients are women and 42 (81%) are men. With 197 courses of chemotherapy given, all 52 patients are evaluable for toxicity. Hematologic toxicities were moderate: World Health Organization (WHO) grade 3 or 4 neutropenia occurred in 38.7% of the cycles (47.7% of patients), and WHO grade 3 or 4 thrombocytopenia was observed in 1.5% of cycles (3.8% of patients). Other toxicities consisted mainly of WHO grade 2 or 3 alopecia and nausea/vomiting. World Health Organization grade 1 or 2 polyneuropathy occurred in 30.4% and grade 3 or 4 only in 1% of all courses. Of 40 patients evaluable for response, a complete remission was noted in one patient, a partial remission occurred in 13 patients (32.5%), stable disease was seen in 14 patients (35%), and disease progressed in 12 patients (30%). These results suggest that the combination of paclitaxel and cisplatin is active and tolerable in the treatment of NSCLC. The efficacy of the combination seems high in this poor-prognosis population.
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PMID:Paclitaxel and cisplatin in patients with non-small cell lung cancer: results of a phase II trial. 894 3


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