Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When administered as a single agent to previously treated patients with advanced breast cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has good activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line treatment for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive either paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles over 24 weeks or standard treatment with oral cyclophosphamide 100 mg/m2/d days 1 to 14, intravenous methotrexate 40 mg/m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisone 40 mg/m2 daily days 1 to 14 (CMFP) for six cycles over 24 weeks. Patients whose disease progressed or relapsed were recommended for second-line therapy with epirubicin. Accrual has been completed with 209 patients randomized, and an interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by the linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP, with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months with paclitaxel and 6.4 months with CMFP, with a median survival of 17.3 months for patients treated with paclitaxel and 11.3 months for those given CMFP. Grades 3 and 4 neutropenia occurred in 64% of patients with paclitaxel and 63% with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% with CMFP. Major infections (World Health Organization grade 4) were seen in 7% of patients treated with CMFP, but in none of those given paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel and 27% of CMFP patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results for those treated with paclitaxel compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides control of metastatic cancer comparable to that of CMFP combination therapy when used as front-line therapy in an outpatient setting.
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PMID:A randomized study of paclitaxel versus cyclophosphamide/methotrexate/5-fluorouracil/prednisone in previously untreated patients with advanced breast cancer: preliminary results. Taxol Investigational Trials Group, Australia/New Zealand. 937 84

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane used in routine clinical practice, has aroused considerable interest for its high single-agent activity against breast cancer and for its novel mechanism of action. Epirubicin, the 4' epimer of doxorubicin, is another agent with a high activity against breast cancer and is known for its lower rate of toxic side effects, especially toxic cardiac events, compared with its mother compound. The combination of paclitaxel and doxorubicin yielded response rates between 63% and 93% in phase I/II studies. In these studies, however, the investigators reported severe cardiac toxic events. The rationale for the current study was therefore to evaluate the combination of paclitaxel/epirubicin, focusing mainly on cardiac toxicity. In two groups, 85 patients with metastatic breast cancer entered the study. Approximately 20% of the patients had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication in group A consisted of epirubicin 60 mg/m2 given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2-blockers. In group B, epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2, given in the same manner as in group A. Dose escalation to 225 mg/m2 paclitaxel was planned in both groups. The main toxicity in both groups was neutropenia (73% World Health Organization grade 3/4 in group A and 93% in group B). Other hematologic side effects were rare. No febrile neutropenia was reported in group A, but two episodes occurred in group B. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grades 1 and 2). Alopecia was universal. In group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in seven patients. Dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac events were reported in group A. In group B, the paclitaxel dose could be escalated to 200 mg/m2 in only one patient, and no patient reached 225 mg/m2. Three patients needed a dose reduction. In this group, one patient had a greater than 10% decrease in the left ventricular ejection fraction with no clinical signs. In group A, 43 patients were evaluable for response; in group B, 25 patients were evaluable. Thirteen patients were out of protocol with only bone metastasis, and two patients had more than one prior chemotherapy for metastatic disease. The response rate was identical in both groups, with five complete remissions and 24 partial remissions in group A and three complete responses and 14 partial remissions in group B. The duration of response was 8.2 months in both groups. The median cumulative epirubicin dose was 420 mg/m2 in group A and 630 mg/m2 in group B. The combination of paclitaxel 175 mg/m2 and epirubicin 60 or 90 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of this combination-line treatment of metastatic breast cancer is warranted.
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PMID:Phase II study of paclitaxel and epirubicin as first-line therapy in patients with metastatic breast cancer. 937 90

Epirubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is an active combination for the treatment of metastatic breast cancer. A multicenter pilot phase II trial evaluated this combination in 35 patients treated with epirubicin 75 mg/m2 given as a 1-hour infusion, immediately followed by paclitaxel 200 mg/m2 given as a 3-hour infusion every 3 weeks. All patients had metastatic disease and had received a maximum of one chemotherapy regimen for advanced disease. A 43% response rate was observed in 30 evaluable patients, with two complete responses (7%) and 11 partial responses (37%). All patients were evaluable for toxicity. Hematologic toxicity was common and dose limiting. All patients underwent blood counts three times weekly. Grade 4 neutropenia was extremely common (91%), occurring at approximately days 10 to 12 and resolving rapidly in most cases. Thrombocytopenia was rare. Dose reductions were necessary in 10 patients, primarily for myelosuppression, but due to neuropathy in two patients. Alopecia was universal. Cardiac function was measured in all patients every two cycles. Among the first 24 evaluable patients, left ventricular ejection fraction decreased to below 40% in three patients, all of whom had received prior anthracyclines. Treatment was discontinued in one patient, who experienced no further deterioration. Under the auspices of the United Kingdom Coordinating Committee for Cancer Research, a randomized phase III study has been initiated in the United Kingdom to compare this combination of epirubicin/paclitaxel with combination epirubicin/cyclophosphamide. The primary end point of this study is progression-free survival, and the intention is to recruit 350 to 700 patients over the next 2 years.
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PMID:A phase II trial of epirubicin plus paclitaxel in metastatic breast cancer. United Kingdom Coordinating Committee for Cancer Research Breast Cancer Sub-Committee. 937 92

The primary aim of this study was to define the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion and cyclophosphamide given by intravenous bolus every 3 weeks in patients with breast cancer. Patients had received a maximum of one prior chemotherapy for advanced disease. The maximum tolerated dose of the combination was also determined with granulocyte colony-stimulating factor (G-CSF) support. The 80 women who took part in this study received 347 fully evaluable courses of therapy. Starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2; G-CSF support (5 microg/kg subcutaneously) was added at the subsequent cycle if specific dose-limiting toxicities had occurred during the previous cycle. Febrile neutropenia and severe thrombocytopenia defined the maximum tolerated doses as paclitaxel 200 mg/m2 and cyclophosphamide 2,000 mg/m2, with or without G-CSF support, in patients with or without a prior chemotherapy. Recommended doses were paclitaxel 200 mg/m2 and cyclophosphamide 1,750 mg/m2 in these two groups of patients. The overall response rate was 25% among patients who had received prior therapy for metastatic disease and 50% in patients who had not been previously treated. Complete remissions were reported in 9% of patients, but only among those who were previously untreated.
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PMID:Dose-finding study of paclitaxel and cyclophosphamide in women with advanced breast cancer. 937 94

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil (5-FU)/leucovorin (LV) in intensively pretreated patients with metastatic breast cancer prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the regimen for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin to the regimen for first-line treatment. Twenty-eight patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with high-dose 5-FU 2 g/m2 (24-hour infusion) plus LV 500 mg/m2 (2-hour infusion before 5-FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 before high-dose 5-FU/LV, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems (SIMS Deltec Inc, St Paul, MN) and portable pumps. Neutropenia was common but mild to moderate and of short duration in most patients. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle with mild to moderate expression. In 28 patients with bidimensionally measurable disease, 25% (seven of 28) attained a complete response, 57% (16 of 28) achieved a partial response, 11% (three of 28) had stable disease, and 7% (two of 28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). We conclude that the combination of paclitaxel/cisplatin with weekly high-dose infusional 5-FU/LV appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.
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PMID:Infusional 5-fluorouracil/leucovorin plus paclitaxel and cisplatin in the first-line treatment of metastatic breast cancer: results of a phase II study. 937 95

Current chemotherapeutic approaches to recurrent or metastatic head and neck cancer have yielded response rates of 10% to 20% for single agents and 30% to 40% for combination chemotherapy. Median survival for patients with recurrent or metastatic disease treated with single agents or combination chemotherapy is between 4 and 6 months. Investigation of new drugs, therefore, has high priority among clinicians and researchers. One new agent that has been effective as single-agent therapy is paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). We tested the combination of paclitaxel, ifosfamide, and cisplatin in recurrent or metastatic head and neck cancer. The starting dose of paclitaxel was 175 mg/m2 as a 3-hour infusion on day 1, ifosfamide 1 g/m2 as a 2-hour infusion on days 1 to 3, and cisplatin 60 mg/m2 via 2-hour infusion on day 1. This schedule was repeated every 3 weeks. Sixty-five patients were entered into the study and 62 patients are currently evaluable for response and toxicity in the phase I and phase II portions of this study. We observed 10 (16%) complete responses and 24 (39%) partial responses. The overall response rate was 55% in phases I/II of this interim analysis. In the phase II part alone, we have observed eight (16%) complete responses and 22 (44%) partial responses to date among 50 evaluable patients. Median survival times were 8.9 months for all patients and 9.7 months for patients in the phase II part of the study. Preliminary results demonstrate significant antitumor activity in patients with recurrent or metastatic head and neck cancer. The paclitaxel/ifosfamide/cisplatin regimen was well tolerated. Chemotherapy with paclitaxel/ifosfamide/cisplatin should be tested as an induction regimen in patients with locally advanced head and neck cancer. It also warrants testing in a randomized setting to compare it with a standard regimen, such as the combination of 5-fluorouracil and cisplatin.
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PMID:Recent advances in paclitaxel-containing chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck. 942 63

We evaluated the efficacy and toxicity of a novel chemotherapy regimen that included paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), carboplatin, and long-term, continuous-infusion 5-fluorouracil in the treatment of cancers of the upper aerodigestive tract. In the preoperative treatment of patients with localized esophageal cancer, we administered this regimen concurrently with radiation therapy. Thirty-eight patients with biopsy-proven cancers of the head and neck or esophagus entered this trial between January 1996 and November 1996. Patients with head and neck cancers considered curable with local treatment modalities were excluded. All patients received the following chemotherapy regimen: paclitaxel 200 mg/m2 via 1-hour intravenous infusion on days 1 and 21, carboplatin at an area under the concentration-time curve of 6.0 intravenously on days 1 and 21, and 5-fluorouracil 225 mg/m2/d via continuous infusion on days 1 to 42. Patients with localized esophageal cancer also received radiation therapy beginning on day 1 (1.8 Gy/d; total dose, 45 Gy). Patients were re-evaluated at week 6; responding patients received a repeat course of treatment, except for those with localized esophageal cancer, who underwent resection at week 10. Twenty-five of 29 evaluable patients had major responses to treatment. Four of five patients with locally advanced head and neck cancer had complete clinical responses, while eight of 11 patients with metastatic disease responded. All 13 evaluable patients with localized esophageal cancer underwent resection, and nine (69%) had a pathologic complete response. Toxicity was moderate, with brief grade 3/4 leukopenia occurring in 19 patients (66%). Esophagitis occurred in five of 13 patients receiving concurrent chemotherapy and radiation therapy, but was reversible and generally occurred during the last week of radiation therapy. Other grade 3/4 toxicity was uncommon. This novel regimen of paclitaxel, carboplatin, and long-term 5-fluorouracil infusion is feasible and highly active in patients with cancers of the upper aerodigestive tract. It can be used concurrently with radiation therapy before resection for localized esophageal cancer. The high overall response rates, and particularly the high pathologic complete response rates in resected patients with esophageal cancer, are encouraging and warrant further evaluation of this regimen.
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PMID:Paclitaxel, carboplatin, and long-term continuous 5-fluorouracil infusion in the treatment of upper aerodigestive malignancies: preliminary results of phase II trial. 942 64

The goal of this National Cancer Institute-sponsored phase I trial is to determine the feasibility, toxicity, and pharmacokinetics of continuous-infusion (24 hr/d, 7 d/wk, 7-week total) intravenous paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with standard curative radiotherapy (RT) for previously untreated, locally advanced head and neck squamous cell cancers. Eligible patients have squamous cell cancers of the head and neck with expected 5-year survival rates of < or =25%; a good performance status; adequate hematologic, hepatic, and renal functions; and no distant metastases. All patients receive 70 Gy megavoltage RT in 7 weeks (2 Gy/d x 5 d/wk). Paclitaxel is delivered by protracted venous infusion starting 48 hours before RT and continuing for its duration. Biopsies for cell-cycle distribution analyses and paclitaxel tissue levels are obtained, if possible, before beginning paclitaxel and after 48 hours just before RT begins. The dose of paclitaxel is escalated in cohorts of three patients. Eighteen patients are evaluable for toxicity. Treatment has been completed through the 6.5 mg/m2/d dose level and is ongoing at 10.5 mg/m2/d. There has been no dose-limiting toxicity thus far. With the exception of anemia, toxicity is commensurate with what would be expected from RT alone. A slowly progressive normocytic anemia with no renal dysfunction was found to be associated with an acquired hypoerythropoietin state. Tumor biopsies have suggested the possibility of paclitaxel-induced mitotic arrest. This therapy is feasible and has been well tolerated through current dose levels with no dose-limiting toxicity. There is a suggestion of biologic activity evidenced by the anemia and the possibility of alteration in cell-cycle distributions. Dose escalation is ongoing.
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PMID:Seven-week continuous-infusion paclitaxel with concurrent radiotherapy for locally advanced head and neck squamous cell cancer: a phase I study. 942 70

We demonstrated in an earlier trial that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has substantial antineoplastic activity, with acceptable toxicity, in patients with advanced metastatic esophageal cancer. Preclinical and clinical data from studies in other tumors indicate substantial additive or even synergistic activity for paclitaxel/cisplatin combination chemotherapy. We encountered substantial toxicity with a cisplatin/paclitaxel/5-fluorouracil combination. To maximize paclitaxel dose, we initiated a phase II trial using cisplatin and paclitaxel alone. This report summarizes preliminary data from that trial. Paclitaxel 200 mg/m2 is given as a continuous, 24-hour infusion on day 1. On day 2, cisplatin 75 mg/m2 is given. Courses are repeated every 21 days. Dose adjustments are based on myelosuppression, neurotoxicity, and (for cisplatin) renal or auditory toxicity. All patients receive recombinant human granulocyte colony-stimulating factor to minimize the risk of neutropenic fever. The primary end point of the study is tumor regression. Secondary end points include duration of response and toxicity. Two groups of patients are being studied. Those with advanced metastatic disease receive chemotherapy alone as palliative treatment. The second group has locoregional disease that is potentially resectable. These patients receive combined-modality therapy involving induction paclitaxel/cisplatin chemotherapy followed by surgery. To date, 37 evaluable patients have been treated. Twenty had advanced metastatic disease and 17 were treated before planned surgery. Twenty-seven patients had adenocarcinoma and 10 had epidermoid carcinoma. Major objective responses were seen in 49% of all patients, with similar response rates for patients with metastatic and locoregional disease. The median duration of response for patients with metastases is 4+ months. Among 14 patients treated before surgery, one experienced a complete pathologic response, and the neoplasms of 43% were downstaged. Primary toxicity was neutropenia, which was tolerable. Surgical morbidity or mortality did not increase. Cisplatin plus paclitaxel is an active combination in the treatment of patients with advanced or locoregional esophageal cancer. Further studies with this combination both in metastatic and locally advanced disease are indicated.
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PMID:A phase II trial of paclitaxel and cisplatin in patients with locally advanced metastatic esophageal cancer: a preliminary report. 942 72

Several recent reports support administering preoperative chemotherapy and radiotherapy to improve the outcome of patients with resectable esophageal malignancies. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), 5-fluorouracil (5-FU), and cisplatin are known radiosensitizers, and paclitaxel has demonstrated single-agent activity in patients with metastatic esophageal cancer. This study sought to define the maximum tolerated dose of paclitaxel given with 5-FU, cisplatin, and 60 Gy radiotherapy before esophagectomy to patients with potentially resectable lesions. Seventeen patients so treated underwent esophagectomy. Three patients with metastatic disease, treated to obtain more information about the toxicity of the combined-modality regimen, did not undergo surgery. Over 6 weeks, 60 Gy radiation was administered in 2-Gy fractions. During radiation treatment, continuous intravenous infusions of 5-FU 225 mg/m2/d were administered, with paclitaxel given weekly as a 1-hour intravenous infusion immediately preceding a 1-hour cisplatin infusion. Surgery was performed 4 to 6 weeks after the completion of radiotherapy. The 27 patients, one of whom was a woman, had a median age of 58 years and an Eastern Cooperative Oncology Group performance status of 0 (10 patients) or 1. Three patients had a squamous cell histology, while 22 had adenocarcinoma; two had other histologies. The paclitaxel dose levels were 25 mg/m2 in four patients, 40 mg/m2 in five patients, 60 mg/m2 in nine patients, and paclitaxel 50 mg/m2 with 5-FU reduced to 200 mg/m2 in nine patients. The latter proved to be the maximum tolerated dose combination, with cisplatin held constant at 25 mg/m2. This level represents weekly dose intensities of 9.6 Gy radiation, 48 mg/m2 paclitaxel, 24 mg/m2 cisplatin, and 192 mg/m2 5-FU. Diarrhea in four patients, mucositis and dehydration in seven, electrolyte wasting in two, gram-positive catheter-related infection in three, and neuropathy in one proved dose limiting. Hematologic toxicity was relatively mild, with three episodes of nonneutropenic bacteremia, one of which was fatal. Postoperative chemotherapy consisting of four cycles of paclitaxel 175 mg/m2 over 3 hours and cisplatin 75 mg/m2 over 1 hour every 3 weeks was planned but rarely feasible due to postoperative morbidity and poor tolerability of postoperative chemotherapy. Therefore, the use of two induction cycles of this regimen given before the combined-modality study regimen is currently being investigated. Of 17 patients whose surgical specimens were assessed pathologically, three had complete remissions and 14 had partial remissions, five of which were characterized as very good, showing only microscopic foci and marked radiation effects. The median follow-up of the 17 patients who underwent surgery is 50 weeks (range, 5 to 111 weeks). Three relapses occurred at 26, 33, and 43 weeks. We conclude that this is an intense combined-modality preoperative regimen for patients with esophageal cancer. Determining the efficacy of this regimen will require further follow-up and the performance of phase II trials.
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PMID:Combined-modality therapy for esophageal cancer: phase I trial of escalating doses of paclitaxel in combination with cisplatin, 5-fluorouracil, and high-dose radiation before esophagectomy. 942 76


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