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)

The combination of etoposide and cisplatin has become one of the standard treatments for small cell lung cancer. Ifosfamide, an analogue of cyclophosphamide, has demonstrated single-agent antitumor activity comparable with that of the most active agents used to treat small cell lung cancer. Because ifosfamide is relatively nonmyelosuppressive and its principal dose-limiting toxicity, urotoxicity, has largely been eliminated with the introduction of the uroprotective agent mesna, we undertook a phase II study of the combination of all three agents (etoposide/ifosfamide/cisplatin) in good-performance-status, extensive-disease patients 70 years of age or younger. Twenty-five patients (17 men and eight women; median age, 58 years) were treated with 75 mg/m2 etoposide, 20 mg/m2 cisplatin, and 1.0 g/m2/d ifosfamide administered intravenously for 5 days. Mesna (200 mg/m2) was given as a bolus prior to the first day of chemotherapy and then daily by continuous infusion (900 mg/m2 over 24 hours) between administrations of chemotherapy. Mesna was continued for 12 hours after the last dose of ifosfamide. Treatment cycles were planned every 4 weeks for four cycles. Due to severe toxicities in the first eight patients, subsequent patients received only 4 days of treatment (20% dose reduction). Of the 25 extensive-disease patients studied, 23 are evaluable for response. Seven (30%) achieved a complete response and 10 (43%) had a partial response (overall response rate, 73%). Five patients (22%) had stable disease (< 50% decrease and no evidence of disease progression for at least 4 weeks), and disease progressed in 1 patient (4%). The median survival time was 42 weeks (range, 2 to 160+ weeks). Granulocytopenia was dose-limiting: median granulocyte count was 0.486 x 10(9)/L, 21% of cycles had a granulocyte nadir below 0.2 x 10(9)/L, and four patients died of sepsis. Three patients required platelet transfusion and nine needed blood transfusion. Microscopic hematuria occurred in eight patients (11% of treatment cycles) but was reversible in all cases. A number of central nervous system symptoms were reported but could not be definitely attributed to ifosfamide/mesna. Gastrointestinal toxicity was generally mild, which is attributed to the use of an aggressive antiemetic program. The etoposide/ifosfamide/cisplatin regimen is active and produced a complete response rate of 30% in extensive small cell lung cancer; the duration of response and survival appears similar to that of other standard regimens. The 5-day schedule produced excessive toxicity in this patient population, necessitating a 20% dose reduction (by using a 4-day schedule). The method of administration required a minimum of 5 hospital days per cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A phase II study of ifosfamide in combination with etoposide and cisplatin in the treatment of extensive small cell lung cancer. 133 22

In this phase II trial, 105 eligible patients with no prior chemotherapy and advanced sarcoma received doxorubicin, ifosfamide, and dacarbazine (DTIC) with mesna uroprotection (MAID). Starting doses of these drugs were 60, 7,500, and 900 mg/m2 divided over 72 hours by continuous infusion, respectively. Mesna was given for 84 to 96 hours at 2,500 mg/m2/d. Myelosuppression was dose limiting, causing the only toxic death (sepsis). Nonhematologic toxicity consisted predominantly of anorexia and vomiting. Severe mucositis, macroscopic hematuria, renal tubular acidosis, renal failure, and CNS toxicity occurred in less than 5% of cycles. No cardiotoxicity was detected. The overall response rate (10% complete response [CR]) was 47% (95% confidence intervals, 5% to 18% and 37% to 57%, respectively). Most responses (approximately 70%) were observed within two cycles. Median times to progression were 10 and 9 months, respectively. Histologic high tumor grade, lesions less than 5 cm, and less than 1 year from diagnosis to study entry correlated with the probability of response. The median survival was 16 months. Time from diagnosis to study entry, performance status, and extent of disease, but not histologic grade, correlated with survival. Following CR, two patients remain disease-free at 32 and 16 months. Of the 15 additional patients rendered disease-free with surgery, two remain disease-free at 30 and 18 months with no further therapy. While most relapses occurred in sites of prior involvement, death from CNS metastases occurred in 11 of the 80 patients with high-grade sarcomas, of whom seven were still responding systematically (three complete responders). Because of its substantial response in this phase II trial, the MAID regimen is being compared with doxorubicin and DTIC alone in advanced sarcomas and to observation in the adjuvant treatment of high-grade sarcomas in randomized trials.
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PMID:Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. 250 90

Thirty-seven extensive disease SCLC patients were treated with ifosfamide 1.0 g/m2 (maximum 1.75 g), VP-16 (etoposide) 75 mg/m2 and cisplatin 20 mg/m2 (VIP) daily for 5 days in hospital. Mesna was given as a continuous infusion until 12 h after the last ifosfamide dose. Treatment was reduced to 4 days after the first 8 patients experienced serious myelotoxicity. 30 patients were evaluable for response. 8 (27%) achieved a complete response and 60% had a partial response. The median duration of response was 23 weeks. The median survival of all 37 patients was 41 weeks, and 47 weeks for the 30 evaluable patients. Fifty per cent and 26% of the evaluable treatment courses were associated with grade 4 and 3 granulocytopenia, respectively. There were eight febrile events including four treatment-related deaths from sepsis on the 5-day regimen. Although the response to VIP was generally rapid, the proportion achieving complete response (27% of evaluable patients) and the median survival is similar to standard chemotherapy regimens which are less toxic and less complex to administer.
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PMID:VP-16, ifosfamide and cisplatin (VIP) for extensive small cell lung cancer. 820 48

Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory peripheral neuropathy with similar distribution peaking around day +60. The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 micrograms/ml (25-55 micrograms/ml). Etanidazole significantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity using this schedule.
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PMID:Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support. 962 61

Purpose Because we had observed in the synovial sarcoma subgroup of a broad phase III advanced soft tissue sarcoma study a significantly greater objective regression rate from ifosfamide+doxorubicin (88%) than from doxorubicin alone (20%) (P = 0.02), the Eastern Cooperative Oncology Group (ECOG) decided to further assess this two drug combination in a subsequent Phase II study.Patients Between 1994 and 1999, twelve adult patients with advanced synovial sarcomas were enrolled to receive, as their initial chemotherapy, ifosfamide 7.5 gm/m(2) plus doxorubicin 60 mg/m(2), given intravenously over two consecutive days every 3 weeks.Methods Each day for 2 days doxorubicin 30 mg/m(2) was infused over 5 min through a running i.v., followed by ifosfamide 3750 mg/m(2) over 4 h. Continuous i.v. fluid was infused at 300 mL/h for 3 h on day 1, before chemotherapy was begun; then the infusion was continued at 100 mL/h for a total of 3 days. Mesna 750 mg/m(2) was given 15 min before ifosfamide and at 4 and 8 h after ifosfamide on days 1 and 2 of each treatment cycle. Filgrastim (G-CSF) 5 mug/kg was given subcutaneously each day for 14 days beginning on day 3 of each treatment cycle to limit the severity of neutropenia.Results Five of our 12 patients (42%) experienced partial regression of their advanced synovial sarcomas; however, this first stage result was borderline for proceeding to the second planned stage of accrual and our case accrual was quite poor. Thus, the study was closed after stage one accrual. Our patients received a median of four cycles of chemotherapy (range: 1 to 6). All patients experienced at least grade 3 neutropenia (grade 4 in nine of them), and one patient died of treatment-related sepsis following the initial cycle of chemotherapy. Median survival was 11 months.
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PMID:Phase II Study of Ifosfamide+Doxorubicin in Patients With Advanced Synovial Sarcomas (E1793): A Trial of the Eastern Cooperative Oncology Group. 1852 63