Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ifosfamide, a cytostatic drug highly active in vivo, has slight superiority over cyclophosphamide. It proved effective in experimental tumor systems including the C3H mammary carcinoma. Clinical studies of ifosfamide as monotherapy in breast cancer, begun in 1974 by Ahmann et al., reported a 20% objective response. Subsequent trials were conducted from 1974 through 1977 using ifosfamide as monotherapy, and ifosfamide was also combined with other chemotherapeutic agents. In 1975, Hartwich and coworkers used the combination ifosfamide/vincristine with a 25% overall response. With the introduction of the uroprotector mesna, more studies were instituted. In 1984, using the IMF combination (ifosfamide/methotrexate/5-fluorouracil), we reported a 25% overall response. Other groups also reported good results for ifosfamide-containing combinations, with overall responses ranging from 25% to 79%. Recently, Sanchiz and Milla used high-dose ifosfamide to treat metastatic breast cancer, with a 40% overall response. In conclusion, ifosfamide's efficacy in breast cancer has been confirmed and the drug is highly recommended in combination chemotherapy as a first-line treatment.
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PMID:Use of ifosfamide in the management of breast cancer. 139 Mar 13

Ifosfamide is an alkylating agent that has clearly demonstrated efficacy against advanced breast cancer. In broad phase II trials, ifosfamide produced response rates of approximately 15% to 20%, and up to 30% in patients without exposure to previous chemotherapy. In subsequent studies, in which ifosfamide was evaluated in higher doses with mesna uroprotection in advanced breast cancer patients with or without prior chemotherapy, the combined complete and partial response rate was 28%. Ifosfamide has also been used in combination regimens. The ifosfamide/methotrexate/5-fluorouracil (IMF) combination has produced efficacy similar to that of the cyclophosphamide/methotrexate/5-fluorouracil (CMF) combination in both previously treated and untreated metastatic breast cancer. Combinations of ifosfamide/epirubicin, ifosfamide/mitoxantrone, and ifosfamide/etoposide have shown encouraging results. Response rates of approximately 70% have been obtained with regimens that include ifosfamide/doxorubicin or ifosfamide/epirubicin. The dose-limiting toxic reactions of ifosfamide, with administration of mesna uroprotection, are myelosuppression, renal tubular acidosis, and renal insufficiency. Additional studies are needed to determine the role of ifosfamide in well-defined patient subsets, to assess its cross-resistance with other alkylating agents, and to determine the slope of the dose-response curve in patients with breast cancer. Further, the role of ifosfamide in front-line combinations needs to be defined.
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PMID:Activity of ifosfamide in breast cancer. 148 73

Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is a prodrug metabolised in the liver by cytochrome P450 mixed-function oxidase enzymes to isofosforamide mustard, the active alkylating compound. Mesna, a uroprotective thiol agent, is routinely administered concomitantly with ifosfamide, and has almost eliminated ifosfamide-induced haemorrhagic cystitis and has reduced nephron toxicity. Therapeutic studies, mostly noncomparative in nature, have demonstrated the efficacy of ifosfamide/mesna alone, or more commonly as a component of combination regimens, in a variety of cancers. In patients with relapsed or refractory disseminated nonseminomatous testicular cancer, a salvage regimen of ifosfamide/mesna, cisplatin and either etoposide or vinblastine produced complete response in approximately one-quarter of patients. As a component of both induction and salvage chemotherapeutic regimens, ifosfamide/mesna has produced favourable response rates in small cell lung cancer, paediatric solid tumours, non-Hodgkin's and Hodgkin's lymphoma, and ovarian cancer. Induction therapy with ifosfamide/mesna-containing chemotherapeutic regimens has been encouraging in non-small cell lung cancer, adult soft-tissue sarcomas, and as neoadjuvant therapy in advanced cervical cancer. As salvage therapy, ifosfamide/mesna-containing combinations have a palliative role in advanced breast cancer and advanced cervical cancer. Ifosfamide/mesna can elicit responses in patients refractory to numerous other antineoplastic drugs, including cyclophosphamide. With administration of concomitant mesna to protect against ifosfamide-induced urotoxicity, the principal dose-limiting toxicity of ifosfamide is myelosuppression; leucopenia is generally more severe than thrombocytopenia. Reversible CNS adverse effects ranging from mild somnolence and confusion to severe encephalopathy and coma can occur in approximately 10 to 20% of patients after intravenous infusion, and the incidence of neurotoxicity may be increased to 50% after oral administration because of differences in the preferential route of metabolism between the 2 routes of administration. Other adverse effects of ifosfamide include nephrotoxicity, alopecia, and nausea/vomiting. In general, intravenously administered mesna is associated with a low incidence of adverse effects; however, gastrointestinal disturbances are common following oral administration. Thus, ifosfamide/mesna is an important and worthwhile addition to the currently available range of chemotherapeutic agents. It has a broad spectrum of antineoplastic activity and causes less marked myelosuppression than many other cytotoxic agents. At present, the role of ifosfamide/mesna in refractory germ cell testicular cancer is clearly defined; however, its overall place in the treatment of other forms of cancer awaits delineation in future well-controlled comparative studies.
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PMID:Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. 172 Mar 82

Four courses of ifosfamide with mesna given by intravenous infusions were combined with bolus doxorubicin in a phase II trial to treat patients with breast cancer. Ifosfamide can deplete intracellular glutathione levels and because doxorubicin resistance may be associated with elevated levels of intracellular glutathione these drugs were combined in an attempt to overcome clinical cytotoxic drug resistance. There were 31 women with poor prognosis advanced breast cancer in the study. Forty-five percent were younger than 40 years old, 68% had visceral dominant disease, 59% had more than two disease sites, and each of the five women tested had increased expression of primary tumor epidermal growth factor receptor. The objective response rate was 71% with manageable toxicity (95% confidence interval, 54% to 85%). The response rate in 22 patients not given prior chemotherapy was 72% and in 9 patients with cancers resistant to previous mitoxantrone monotherapy it was 67%. The high antitumor activity of this combination suggests further exploration of its use in breast cancer.
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PMID:Phase II study of doxorubicin plus ifosfamide/mesna in patients with advanced breast cancer. 211 Aug 60

A sixty-year-old woman with advanced breast cancer, previously treated with cisplatin, developed an irreversible lethal renal failure with anuria, the day after 5 g/m2 bolus ifosfamide. Postrenal failure was excluded by echography. A prerenal component could have contributed to renal failure because of a transient hypotension, due to an increasing ascitis, occurring just before anuria. However, correction of the hemodynamic parameters did not improve renal function. Ifosfamide is a known nephrotoxic drug with demonstrated tubulopathies. We strongly suspect that this lethal anuria was mainly due to ifosfamide, occurring in a patient having received previous cisplatin chemotherapy and with poor kidney perfusion due to transient hypotension. We recommend careful use of ifosfamide in patients pretreated with nephrotoxic chemotherapy and inadequate renal perfusion.
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PMID:Lethal anuria complicating high dose ifosfamide chemotherapy in a breast cancer patient with an impaired renal function. 232 Aug

Ifosfamide has definite efficacy in many malignant tumours, including breast cancer. In the present study we substituted cyclophosphamide with ifosfamide in the combination CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) regimen in 25 patients with breast cancer whose disease was refractory to CMF or who had relapsed after previous response. Ifosfamide was given in an i.v. infusion at a dose of 1.2 g/m2 daily for 5 days, together with mesna as a uroprotector (at 20% of the ifosfamide dose). Methotrexate was given at a dose of 40 mg/m2 and 5-fluorouracil was given at 600 mg/m2, both by i.v. push. Courses were repeated every 21 days. The 24 evaluable patients received 3-12 courses (average, 5 courses); results included a complete remission in 3 patients (12.5%) and a partial remission in 3 (12.5%). Among the remaining patients, improvement was seen in 4 (16.6%); stable disease, in 7; and progressive disease, in 7 (29.2%). The complete responses lasted for 11+, 13+, and 15+ months, and partial remissions, for 2, 6, and 9 months. The responses were detected in soft-tissue as well as visceral lesions, but not in bony lesions. The responders remain under follow-up. This study shows the efficacy of ifosfamide-containing chemotherapy in breast cancer. As toxicities were tolerable, higher doses of ifosfamide could safely be used in these patients. Use of this combination as first-line therapy in breast cancer could be considered for a future study.
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PMID:Ifosfamide, methotrexate, and 5-fluorouracil: effective combination in resistant breast cancer. 234 57

Thirty-five patients with a median age of 55 years (range, 28 to 68 years) and a median Karnofsky status of 80% (range, 40% to 100%) were treated with ifosfamide (1.5 g/m2 plus mesna), methotrexate (40 mg/m2), and 5-fluorouracil (600 mg/m2) intravenously (IV) days 1 and 8 at intervals of 4 weeks. Thirty-four patients had received previous chemotherapy, including anthracyclines in 28 patients. All patients were evaluable for response. A partial remission was achieved in six patients (17%), stable disease in 13 patients (37%), and 16 patients (46%) were unresponsive. Median time to progression was 7 months (range, 4 to 13 months) for partial responders, and 4 months for patients with stable disease. Median survival was 9 months for all patients, 13 months for partial responders, 16 months for no change, and 3 months for progressive disease. Toxicity was tolerable, with myelotoxicity being a dose-limiting factor, mainly in heavily pretreated patients. No treatment-related death occurred. In conclusion, this combination is effective and well tolerated. Ifosfamide is suggested for further evaluation in advanced breast cancer.
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PMID:Ifosfamide, methotrexate, and 5-fluorouracil in advanced pretreated breast cancer. 249 68

Ifosfamide (IFO) at a dose of 5 g/m2, was administered as a 24-h infusion to 15 patients with metastatic (12) or locally advanced (3) breast cancer (age range 33-59 years, median 46). Concurrent chemotherapy was doxorubicin (40 mg/m2) or epirubicin (60 mg/m2). Ifosfamide and its metabolites were measured in plasma and urine during and for 24 h after the infusion using a high performance thin layer chromatography (HPTLC) technique. Patients' haematological toxicity and biochemistry were monitored during treatment and patients were followed for up to 2 years after therapy. At the time of evaluation, 5 of the patients were alive, 2 of whom had not relapsed. A marked variation was observed in the pharmacokinetics and metabolism of ifosfamide in the evaluable patients. Clearance, volume of distribution and half-life of the drug were 3.48 +/- 0.88 1/h/m2, 0.56 +/- 0.22 l/kg and 4.68 +/- 2.01 h, respectively. There was no apparent correlation between these pharmacokinetic variables and patient age, weight or renal function. AUCs of the ultimate alkylating species isophosphoramide mustard (IPM) varied over 6-fold, as did those of the inactivated metabolite carboxyifosfamide (CX). AUCs of dechloroethylated metabolites varied 4-fold (3-dechloroethylifosfamide, 3-DCI) or 8-fold (2-DCI), while that of the parent compound varied only 2.5-fold. Variation in recovery of the metabolites in urine varied over an even wider range, total recovery varying from 17.5 to 81.8% of the dose administered. There was little apparent correlation between pharmacokinetic and metabolite parameters of IFO and haematological toxicity. However, there was a marked negative correlation between both progression-free interval and survival and the AUCs of the products of IFO activation (IPM and CX). In addition, the recovery of IPM in urine was higher in patients experiencing a partial response compared to those with progressive or stable disease. Recovery of dechloroethylated metabolites correlated positively with survival, if 1 poor prognosis patient was excluded. Although far from conclusive, these results give some insight into a possible mechanism of action of ifosfamide and indicate that some species other than IPM, as measured systemically, is responsible for the pharmacological effects of this drug.
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PMID:Pharmacokinetics, metabolism and clinical effect of ifosfamide in breast cancer patients. 769 82

Ifosfamide has single agent activity in advanced breast cancer and may potentiate the activity of doxorubicin. The combination of ifosfamide 5 g/m2 and doxorubicin 40 mg/m2 every 3 weeks for 4 cycles was used to treat 77 patients with advanced breast cancer. Fifty three patients had not received prior chemotherapy. All patients had one or more poor prognostic features, including tumor expression of epidermal growth factor receptor in 11/12 tested. The overall response rate was 74% (95% confidence intervals 62%-83%). The median survival was 9.4 months. The principal toxicities were febrile neutropenia and ifosfamide encephalopathy each in 6% of patients. A high percentage of the projected dose intensity was administered. This is a highly active combination with acceptable toxicity in advanced breast cancer, although the long term survival remains poor. Further exploration of ifosfamide in combination chemotherapy for advanced breast cancer is warranted.
Breast Cancer Res Treat 1994
PMID:Results of chemotherapy using ifosfamide with doxorubicin in advanced breast cancer. 804 61

In MX1 human breast cancer xenografts grown on the hind paw of thymusaplastic nude mice the effect of ifosfamide on tumor oxygenation, tumor pH and the concentration of lactic acid have been determined at mean tumor temperatures of 32 degrees C, 37 degrees C and 41 degrees C. For histological studies tumors were shock-frozen or fixed with formalin or glutaraldehyde. Treatment with Ifosfamide (250 mg/kg b.w.) reduced intratumoral laser Doppler flow, oxygenation and pH. This suggests that ifosfamide or its metabolites may have an effect on tumor vasculature.
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PMID:The effect of ifosfamide on tumor oxygenation at different temperatures. 807 51


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