Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Taxol is a unique mitotic inhibitor that has entered phase II investigation. Phase I studies demonstrated hypersensitivity reactions that were related to the cremophor vehicle and to the rate of drug infusion. As a result, the time span of intravenous (IV) infusion of taxol was routinely prolonged to 6 hours or beyond, and premedication with diphenhydramine, dexamethasone, and cimetidine was initiated. Early studies showed antitumor activity, especially against malignant melanoma and ovarian carcinoma. This phase I trial was performed giving taxol, as a 6-hour IV infusion every 21 days, without premedication. The purpose was to study the necessity of premedication and its impact on toxicity and pharmacokinetics. Thirty-one patients received 64 assessable courses of taxol. One patient had a hypersensitivity reaction, which was easily controlled using routine measures. Myelosuppression was dose-limiting, but sporadic, with two fatalities due to sepsis. Nonhematologic toxicity was of grade 1 and 2 except for one patient with grade 3 mucositis and two patients with grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias, requiring discontinuation of drug in two patients. Four partial responses were seen (three in patients with non-small-cell lung cancer, one in a patient with adenocarcinoma of unknown primary). Pharmacokinetic values were consistent with those previously reported. The occurrence of myelosuppression or neurotoxicity appeared to be associated with the area under the concentration x time curve (AUC) of taxol. The recommended phase II starting dose on this schedule is 225 mg/m2. Taxol merits broad investigation at the phase II level.
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PMID:A phase I trial of taxol given by a 6-hour intravenous infusion. 167 63

A dose-finding study was performed in 27 ovarian cancer patients to define the maximum tolerated dose of a 3-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with a fixed dose of carboplatin. The median age of the patients was 55 years (age range, 30 to 74 years), the median performance status was 0 (range, 0 to 2), and the sizes of tumors residual to first surgery were identified as > or = 1 cm (14 patients) or less than 1 cm (13 patients). All patients received carboplatin at a fixed dose of 300 mg/m2 over 1 hour. Paclitaxel was administered as a 3-hour infusion at five dose levels, starting at 150 mg/m2 and increasing in 25 mg/m2 increments to 250 mg/m2. In the absence of toxicity, courses were repeated every 4 weeks for a total of six cycles. Mild emesis, general alopecia, and moderate myalgias occurred. Hypersensitivity and cardiotoxicity were observed in 7.4% and 14.8% of patients, respectively. Moderate peripheral neuropathy was experienced by 30% of patients. Grade 3 and 4 neutropenia lasted less than 7 days; no patients required hospitalization for sepsis or febrile neutropenia, and no supportive treatment with granulocyte/granulocyte-macrophage colony-stimulating factor was needed. Twenty-one patients were evaluable for response. Overall response rate (complete response+partial response) was 81%, and responses were observed at all paclitaxel dose levels. The maximum tolerated dose was not achieved. In conclusion, with a fixed dose (300 mg/m2) of carboplatin, paclitaxel can be administered by 3-hour infusion at 250 mg/m2 with manageable toxicity and no supportive care is needed.
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PMID:Pilot study with fixed-dose carboplatin and escalating paclitaxel in advanced ovarian cancer. 855 81

Autologous and allogeneic bone marrow grafting both require cytoreductive therapy but only the allogeneic procedure requires immunosuppressive agents. Allogeneic bone marrow transplantation has been reported to be associated with a high incidence of both renal failure and veno-occlusive disease (VOD) of the liver, the combination of which is associated with a high morbidity and mortality. There is less known about the frequency and severity of these complications in patients undergoing autologous bone marrow transplantation. In the present study renal, hepatic and other complications were examined in 232 patients with Stages II/III and IV breast cancer who were treated with high-dose chemotherapy and autologous hematopoietic cell support with either marrow or peripheral blood progenitor cells. The post-treatment severity of the renal dysfunction was classified as follows: Grade 0, normal renal function [< 25% decrement in glomerular filtration rate (GFR)]; Grade 1. mild renal dysfunction (> 25% decrement in GFR but < a twofold increase in serum creatinine); Grade 2, > twofold rise in serum creatinine but no need for dialysis; Grade 3 > than twofold rise in serum creatinine and need for dialysis. There were 102 patients (44%) who were classified as Grade 0 and 81 patients (35%) who were classified as Grade 1 renal dysfunction. Severe renal dysfunction (Grades 2 and 3) was observed in 49 of the 232 patients (21%). This severe renal dysfunction of 21% compares with a previously reported 53% incidence of severe renal dysfunction for allogeneic bone marrow transplantation. Similarly, the frequency of hepatic VOD was less (4.7% or 11 of 232 patients) in this autologous bone marrow transplant study as compared to a reported incidence of hepatic VOD ranging from 22 to 53% in large series of allogeneic bone marrow transplant patients. The severe renal dysfunction (Grades 2 and 3) in the present autologous hematopoietic cell support study correlated most significantly with sepsis, liver and pulmonary dysfunction. The major fall in GFR occurred during chemotherapy but before hematopoietic cell support, thus primarily incriminating the cytoreductive therapy rather than the hematopoietic cell support. The only significant effect of different chemotherapy protocols was, at four weeks, the Taxol-treated group had a significantly lower creatinine clearance as compared to the BCNU treated group.
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PMID:Renal function in high dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer. 887 80

A dose-finding study involving 27 untreated patients with ovarian cancer was performed to define the maximum tolerated dose of a 3-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with a fixed dose of carboplatin. The median age of the study patients was 55 years (age range, 30 to 74 years), the median Eastern Cooperative Oncology Group performance status was 0 (range, 0 to 2), and residual tumor to first surgery was > or = 1 cm in 14 patients and less than 1 cm in 13 patients. All patients received carboplatin at a fixed dose of 300 mg/m2 over 1 hour. Paclitaxel was administered at five dose levels starting at 150 mg/m2 and increasing in 25-mg/m2 increments to 250 mg/m2. In the absence of toxicity, courses were repeated every 4 weeks for a total of six cycles. World Health Organization grade 1 hypersensitivity and cardiotoxicity were observed in 7.4% and 14.8% of patients, respectively. Moderate peripheral neuropathy was experienced by 29.6% of patients. Grades 3 and 4 neutropenia lasted less than 7 days; no patient required hospitalization for sepsis or febrile neutropenia, and no supportive treatment with granulocyte or granulocyte-macrophage colony-stimulating factor was needed. The maximum tolerated paclitaxel dose was not achieved.
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PMID:A phase I trial with fixed-dose carboplatin and escalating doses of paclitaxel in advanced ovarian cancer. 904 31

This study was performed to determine the activity and toxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 1-hour infusion plus carboplatin in the treatment of patients with advanced non-small cell lung cancer when used in a multicenter, community-based setting. The study population included 100 chemotherapy-naive patientswith stage IIIB or IV non-small cell lung cancer, Karnofsky performance status 70 to 100, measurable disease, and adequate kidney, liver, and bone marrow function. All patients received paclitaxel 225 mg/m2 intravenously by 1-hour infusion followed immediately by carboplatin at a targeted area under the concentration-time curve of 6.0 (Calvert formula). Cycles were repeated every 21 days. Colony-stimulating factors were not used routinely. Thirty-eight (38%) of 100 patients had objective responses (38 [40%] of 94 evaluable patients) to treatment (three complete responses, 35 partial responses). Thirty-two other patients had stable disease at initial re-evaluation. Weight gain during treatment occurred in 47% of those patients with objective response or stable disease. The median survival among all 100 patients was 8 months, with a 1-year survival rate of 42%. Leukopenia was common, but hospitalization for treatment of neutropenia and fever occurred in only 3% of courses. Cumulative peripheral neuropathy occurred consistently, but usually after the third or fourth course; it was severe (grade 3) in only 15% of patients. Other grade 3 and 4 toxicity was uncommon. One patient died as a result of treatment due to sepsis. This large, multicenter, community-based phase II trial demonstrates the efficacy of paclitaxel/carboplatin combination chemotherapy in advanced non-small cell lung cancer. This regimen is relatively well tolerated and when paclitaxel is given by 1-hour infusion, this treatment is easily administered in the outpatient setting.
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PMID:Paclitaxel (1-hour infusion) plus carboplatin in the treatment of advanced non-small cell lung cancer: results of a multicenter phase II trial. 933 Nov 13

Advanced transitional cell carcinoma (TCC) of the urothelial tract is usually fatal despite high response rates to platinum-based chemotherapy regimens. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated marked single-agent activity in TCC, and combinations of carboplatin and paclitaxel have been well tolerated in other solid tumors. Methotrexate is also active in TCC. Due to unexpectedly severe myelosuppression and mucositis when methotrexate and paclitaxel were combined, we undertook a phase I trial of paclitaxel, carboplatin, and escalating doses of methotrexate with granulocyte colony-stimulating factor and leucovorin support in advanced TCC to determine the feasibility of this combination. Nineteen previously untreated patients with locally advanced or metastatic TCC were eligible. Median age was 62 years. In sequence, paclitaxel 200 mg/m2 (3-hour infusion), carboplatin dosed to an area under the concentration-time curve of 6 mg/mL x min, and methotrexate 10 mg/m2, increasing in 10-mg/m2 increments, were administered on day 1 every 21 days. Granulocyte colony-stimulating factor 300 microg/d or 480 microg/d (in patients <60 kg or >60 kg, respectively) was administered on days 2 through 11 and leucovorin 15 mg orally every 6 hours for 3 days. At this time, the methotrexate dose has been escalated to 50 mg/m2. There were no dose-limiting toxicities in cycle 1. Sixty-eight cycles have been administered (range, one to eight cycles; median, three cycles). Significant hematologic toxicity including neutropenic sepsis (two episodes) occurred in subsequent cycles, but was infrequent. The major nonhematologic toxicity was neuropathy. Sixteen patients are evaluable for response. One patient has achieved a complete response, seven are partial responders, seven have stable disease, and one progressed on therapy. The overall response rate is 50% (95% confidence interval, 25% to 75%). The combination of paclitaxel, carboplatin, and methotrexate holds promise to be well tolerated and active in advanced TCC.
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PMID:Phase I trial of paclitaxel, carboplatin, and methotrexate with granulocyte colony-stimulating factor and leucovorin in advanced transitional cell carcinoma. 934 26

The purpose of this study was to evaluate the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin in patients with endometrial cancer known to be resistant to standard therapy. Subjects were taken from three groups: (1) recurrent or persistent disease following surgery and/or radiation, (2) advanced disease at diagnosis, and (3) high-risk histology. The combination of carboplatin (pharmacologically dosed at an area under the concentration-time curve of 5) and paclitaxel (135 to 175 mg/m2 over 3 hours) was given intravenously every 4 weeks for eight courses. Data about response, overall and progression-free survival, and toxicity were collected. Response and toxicity were evaluated by physical examinations, x-ray films, and blood tests. Twenty patients have participated to date, including eight considered evaluable for response. Due to limited follow-up, survival and progression-free intervals are not yet assessable. Of patients with measurable disease, five of eight (63%) have had significant reduction in the size of evaluable tumor masses, constituting a partial response. Although two patients had clinical and radiographic complete responses, occult disease was found at surgery. There were no complete responders. Fifteen patients had grade 3 or 4 hematologic toxicity, but none had neutropenic fever or hospitalization for sepsis. One patient was taken off study for grade 3 neuropathy. There was one possible treatment-related death. In this preliminary report, this combination is active against tumors of the endometrium, with acceptable levels of toxicity. Further follow-up will be required to determine the duration of response and whether progression-free and overall survival are influenced by treatment with these drugs.
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PMID:A trial of outpatient paclitaxel and carboplatin for advanced, recurrent, and histologic high-risk endometrial carcinoma: preliminary report. 934 28

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. We added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, 5-fluorouracil, and high-dose leucovorin. Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous infusion on day 1; mitoxantrone 10 mg/m2 by intravenous bolus on day 1; 5-fluorouracil 350 mg/m2 by intravenous bolus on days 1, 2, and 3; and leucovorin 300 mg intravenous over 30 to 60 minutes, immediately preceding 5-fluorouracil on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. Of 45 assessable patients, 23 (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. There were four treatment-related deaths, two sepsis, one congestive heart failure, and one sepsis and congestive heart failure, the last two after a large cumulative anthracycline dose. This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although how its activity compares with that of other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than had been anticipated based on previous results with the mitoxantrone/5-fluorouracil/high-dose leucovorin regimen or with single-agent paclitaxel administered at this dose and schedule. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with paclitaxel/doxorubicin combinations. We have embarked on a phase I/II trial of paclitaxel/mitoxantrone and have determined the maximum tolerated dose to be 200 mg/m2 and 10 mg/m2, respectively, without the use of cytokines. Fifteen patients have been treated at the maximum tolerated dose, and it is too early to assess results.
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PMID:Paclitaxel with mitoxantrone with or without 5-fluorouracil and high-dose leucovorin in the treatment of metastatic breast cancer. 937 96

Docetaxel (Taxotere) has been studied at a dose of 100 mg/m2 i.v. as a one hour infusion every 3 weeks, in four phase II trials in patients with extensively pretreated ovarian cancer. A total of 340 patients were treated, including 256 patients in two separate EORTC (European Organization for Research and Treatment of Cancer) trials and 84 patients in two trials in the U.S.A. All patients had received prior cisplatin or carboplatin therapy and the treatment-free interval was less than 4 months in 155 patients. The overall response rate using conventional UICC criteria was 30% among 315 evaluable cases (95% confidence interval: 24-36%). Among 155 patients whose disease was most refractory (i.e. treatment-free interval was less than 4 months), the overall response rate was 28% (95% confidence interval: 19-36%). Response duration ranged from 4 to 17 months. Grade IV neutropenia was a common finding and fluid retention was observed. The incidence of febrile neutropenia ranged from 8 to 44% of patients with two deaths (i.e. 0.6% of the total treated) related to neutropenic sepsis. Docetaxel and paclitaxel (Taxol) have comparable activities in ovarian cancer. Ongoing studies with docetaxel include its use in patients as part of first-line therapy, as well as in patients refractory to paclitaxel. To prevent the development of fluid retention, these now involve the routine use of steroid prophylaxis. It is expected that docetaxel will prove to be an important addition to the drugs available for the treatment of ovarian cancer.
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PMID:Phase II trials of docetaxel (Taxotere) in advanced ovarian cancer--an updated overview. 947 Aug 2

We report here the preliminary results of a large phase II multicenter study done in the community setting, using paclitaxel (Taxol) (given by 1-hour infusion) plus carboplatin (Paraplatin) to treat patients with advanced non-small-cell lung cancer (NSCLC). In this study, 155 chemotherapy-naive patients with stage IIIB, stage IV, or recurrent metastatic non-small-cell lung cancer received the two drugs in 21-day cycles. Paclitaxel 225 mg/m2 was given by 1-hour intravenous infusion followed immediately by carboplatin at a targeted area under the concentration-time curve of 6.0 (calculated according to the Calvert formula). Colony-stimulating factors were not used routinely. Objective responses occurred in 53 of 155 patients (34%) (53 of 144 [36%] evaluable patients) including three complete responses and 50 partial responses. Fifty-two other patients had stable disease at initial reevaluation. The median survival among all 155 patients was 8 months; the 1-year survival rate was 42%, and the 2-year survival rate was 20%. Leukopenia and cumulative peripheral neuropathy occurred consistently but rarely were severe or affected the course of therapy. One patient died due to sepsis. Other grade 3 and grade 4 toxicities were uncommon. This paclitaxel-carboplatin combination chemotherapy appears to be a relatively convenient, safe, and active regimen in advanced non-small-cell lung cancer.
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PMID:One-hour paclitaxel plus carboplatin for advanced non-small-cell lung cancer. 951 16


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