Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043352 (xerostomia)
 4,250 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Physicians are frequently pressured to make therapeutic decisions within a cost-effective framework to demonstrate value to managed care. Because cancer is a chronic disease, health care costs are known to be expensive and physicians must use their resources as efficiently as possible. Historically, economic analyses in oncology have emphasized survival as their clinical end point. Today, both government groups and professional organizations are moving toward making quality of life the clinical end point in determining the economics of chemotherapy. This report evaluates the cost and efficacy of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) use in the treatment of advanced ovarian cancer using two pharmacoeconomic analyses. A cost-utility analysis performed in the United States indicated that inclusion of amifostine therapy had both a favorable clinical and cost-utility profile compared with other medical therapies. A second cost-benefit analysis, conducted in Canada, suggested that use of amifostine in patients with advanced ovarian cancer would be cost saving. Amifostine is a novel agent that protects against both chemotherapy- and radiotherapy-induced toxicities, such as nephrotoxicity, neutropenia, thrombocytopenia, peripheral neuropathy, mucositis, and xerostomia. These toxicities are disturbing to both patients and physicians alike. The results of these studies support the use of amifostine as a valuable resource both economically and clinically.
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PMID:Pharmacoeconomics of amifostine in ovarian cancer. 1034 68

Amifostine (Ethyol), the first broad-spectrum cytoprotectant approved in many countries for clinical use, is an analog of cysteamine and was originally developed by the U.S. Walter Reed Army Institute of Research in the 1950s as a radioprotective agent. Studies have shown that amifostine selectively protects normal tissues of various organs from the effects of radiation and multiple cytotoxic chemotherapeutic drugs. Amifostine has demonstrated broad-spectrum cytoprotection against myelotoxicity, nephrotoxicity, xerostomia, and mucositis associated with various chemotherapy and radiation modalities. Amifostine has been evaluated in large comparative clinical trials in patients with advanced ovarian cancer, rectal cancer, and head and neck cancer, and in many phase 2 trials in patients with various neoplastic diseases. These trials have shown that amifostine delivers protection from the cytotoxic effects of cisplatin, cyclophosphamide, and radiation on various organs. Pretreatment with amifostine has also improved salivary gland tolerance of high-dose radioiodine treatment. Recent unique observations include improvement in cytopenia in patients with myelodysplastic syndrome. This review summarizes preclinical and clinical data on amifostine and includes trials that evaluated the drug's chemoprotective and radioprotective effects and other potential uses in clinical oncology.
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PMID:Chemoprotective and radioprotective effects of amifostine: an update of clinical trials. 1119 8

This phase II trial was designed to verify that subcutaneous (SC) administration of Amifostine (Ethyol) protects against radiation therapy (RT)-induced xerostomia and ameliorates amifostine-related side effects (including nausea, vomiting, and hypotension). Patients receiving amifostine SC plus RT had a 56% incidence of acute xerostomia, comparable with previous phase III data with intravenous administration of amifostine. There was good tolerability, with cutaneous toxicity as the most significant side effect. These data suggest that amifostine SC provided comparable protection against RT-induced acute xerostomia as amifostine intravenously.
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PMID:A phase II trial of subcutaneous amifostine and radiation therapy in patients with head and neck cancer. 1191 79

The degree of xerostomia has been reported to depend on the radiation dose and the salivary gland volume irradiated. Sparing salivary function can be achieved by reducing radiation dose to the salivary glands or using a radiation protector, such as amifostine (Ethyol). In this report, the author reviews clinical experiences in intensity-modulated radiation therapy (IMRT) for head and neck cancer. In experiences, the dosimetric advantage of IMRT did translate into significant reduction of late salivary toxicity in patients with oropharyngeal carcinoma. The author has found no adverse impact on tumor control and disease-free survival in patients treated with IMRT. Further, when studying the dose response of parotid gland after irradiation, it was found that the stimulated saliva flow 6 months after IMRT treatment reduced at approximately 4% per Gy exponentially of the mean parotid dose. The authors also review existing clinical data on the combination of amifostine and radiation and the potential therapeutic gain in combining IMRT with amifostine.
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PMID:Protection of salivary function by intensity-modulated radiation therapy in patients with head and neck cancer. 1191 80

Amifostine (Ethyol) has been evaluated clinically as a radioprotective agent for the prevention of xerostomia and mucositis for patients receiving radiotherapy (RT). Currently, amifostine is approved for the prevention of xerostomia in head and neck cancer patients receiving RT when administered intravenously (IV) before RT. For the clinician, there would be several advantages to administering the drug subcutaneously and to being able to show its protective effects on mucositis. The authors have developed a rat RT model to examine the protective effects of amifostine after IV and subcutaneous (SC) administration in a mucositis model. Rats (5 per group) were given 200 mg/kg (human dose equivalent of approximately 1,300 mg/m(2)) of amifostine either IV or SC, and their head and neck regions were exposed to 15.3 Gy of gamma radiation 0.5, 2, 4, and 8 hours after amifostine administration. For 10 days after treatment, the oral cavities of the rats were examined for signs of mucositis. Mucosal erythema and mucosal edema were scored according to 0 through 5 and 0 through 2 scales, respectively, with the scores added to indicate overall mucositis. The average mucositis score for the untreated animals was 3.5. Rats were protected from mucositis up to 4 hours when given amifostine either IV or SC. Rats that received amifostine SC, but not IV, were protected from mucositis 8 hours after administration. Preliminary pharmacokinetic data have revealed slightly higher active metabolite (WR-1065) levels in the parotid gland and small intestine in the rats given amifostine SC compared with IV and equivalent levels in the plasma and kidney. The data showed that SC administration of amifostine gave radioprotection comparable to IV administration up to 4 hours before RT and may be more effective than IV administration at longer pretreatment intervals.
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PMID:Preclinical modeling of improved amifostine (Ethyol) use in radiation therapy. 1191 93

Amifostine (Ethyol), an inorganic thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues that provides cytoprotection against ionizing radiation and chemotherapeutic agents, thus preserving the efficacy of radiotherapy and chemotherapy. This review summarizes the preclinical data and clinical experience with amifostine, and provides insight into future clinical directions. Amifostine, an inactive pro-drug, is transformed to an active thiol after dephosphorylation by alkaline phosphatase found in the normal endothelium. The absence of alkaline phosphatase in the tumoral endothelium and stromal components, and the hypovascularity and acidity of the tumor environment, may explain its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. Intravenous administration of amifostine 740-900 mg/m(2) before chemotherapy and 250-350 mg/m(2) before each radiotherapy fraction are widely used regimens. The US Food and Drug Administration has approved the use of amifostine as a cytoprotector for cisplatin chemotherapy and for radiation-induced xerostomia. Ongoing trials are being conducted to determine the efficacy of amifostine in reducing radiation-induced mucositis and other toxicities. Novel schedules and routes of administration are under investigation, and may further simplify the use of amifostine and considerably broaden its applications.
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PMID:Amifostine in clinical oncology: current use and future applications. 1198 63

Amifostine (Ethyol; MedImmune Oncology, Gaithersburg, MD) is a radio- and chemoprotective agent currently in clinical use. Based on experimental data showing the potential for mucosal protection and additional information in animal studies showing rapid uptake of amifostine in the salivary glands along with effective radioprotection, several investigators have tested this drug in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The first evidence that amifostine, administered at 200 mg/m(2)/d intravenously before each radiotherapy session, could effectively protect salivary function in patients with HNSCC was provided by McDonald et al in a limited series of HNSCC patients. On the basis of these phase I results, an international multicenter phase III radiotherapy trial with or without amifostine was carried out by Brizel et al in a series of 315 patients with head and neck tumors showing a reduction in xerostomia with no suggestion of tumor protection. Additional data have been obtained in patients with HNSCC regarding the potential protective effect of amifostine on the duration and severity of radio-induced mucositis. This effect was reported in small, randomized studies of patients receiving intensive accelerated radiotherapy (Bourhis et al) or combined radiochemotherapy (Buntzel et al). In conclusion, the experience obtained to date in HNSCC patients treated with radiotherapy supports the selective cytoprotective activity of amifostine to minimize radiation effects while apparently not diminishing tumor control.
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PMID:Radioprotective effect of amifostine in patients with head and neck squamous cell carcinoma. 1257 47

Locoregional recurrence remains a major obstacle to achieving cure of locally advanced head and neck cancers despite maximal resection and postoperative external beam radiation therapy (EBRT). Locoregional failure occurs in 30% to 40% of high-risk resected head and neck cancer patients after standard postoperative EBRT. In an effort to overcome this problem, a number of strategies have been designed to enhance the effectiveness of radiation including concurrent postoperative chemoradiation, accelerated radiation schedules, incorporation of targeted biologic therapies, and improved radiation delivery techniques such as intensity modulated radiation and high-dose rate (HDR) intraoperative radiation therapy. Intraoperative radiation therapy (IORT) represents an important approach to improve outcome in head and neck cancer patients treated with definitive surgery. High-dose rate IORT is defined as the delivery of a single, large dose of radiation at the time of surgery when the tumor bed is exposed. In conjunction with EBRT, HDR-IORT offers several advantages including: (1) conformal delivery of a large dose of radiation while the tumor bed is precisely defined, minimizing the risk of a geographic miss; (2) potential for subsequent dose reduction of EBRT; (3) shortening overall treatment time; and (4) dose-escalation. Because mucositis represents the dose-limiting acute toxicity and xerostomia ranks as the most common long-term quality-of-life complaint, a reduction of the EBRT dose may provide an important benefit in reducing toxicity, especially when combined with the radioprotectant amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD). The purpose of this article is to review the rationale for integrating HDR-IORT with a reduced dose of postoperative EBRT combined with amifostine to improve locoregional control and quality of life outcomes in advanced-stage resected head and neck cancer patients.
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PMID:Rationale for integrating high-dose rate intraoperative radiation (HDR-IORT) and postoperative external beam radiation with subcutaneous amifostine for the management of stage III/IV head and neck cancer. 1472 39

The major salivary glands produce about 90% of salivary secretions; the minor salivary glands produce the remainder. Standard conventional radiation therapy for advanced oropharyngeal tumors typically involves administering high radiation dose to the major salivary glands bilaterally. In most cases, this causes a marked reduction in oral saliva output. Xerostomia is the most prevalent late side effect of radiation for head and neck malignancies and is cited by patients as the major cause of decreased quality of life. The degree of xerostomia has been reported to depend on the radiation dose and salivary gland volume irradiated. Several studies show dose volume response relationships in the salivary glands, suggesting the possibility of significant improvement in saliva production post radiation as well as quality of life if radiation techniques can spare the salivary glands. In recent years, conformal radiation techniques have evolved, which may allow radiation of tumor targets in the head and neck area while sparing substantial portions of salivary glands. It has been shown that in using these techniques, adequate irradiation of the targets while sparing major salivary glands is feasible. Early clinical experience showed substantial sparing of salivary flow following radiation and suggested an improvement of tumor control and of xerostomia over that achieved with standard radiation techniques. We hypothesize that the addition of a radioprotector may further improve salivary function over that obtained with intensity modulated radiation therapy alone. To test this hypothesis, we initiated a pilot clinical trial whose principal objective is to compare measurements of unstimulated and stimulated salivary flow rates 6 months after intensity modulated radiation therapy plus amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) (study patients) with those obtained in historical controls treated with intensity modulated radiation therapy alone.
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PMID:Pilot study of subcutaneous amifostine in patients undergoing postoperative intensity modulated radiation therapy for head and neck cancer: preliminary data. 1472 49

Amifostine (Ethyol) is a cytoprotective drug approved for the reduction of xerostomia in head and neck cancer when administered to patients receiving postoperative radiation therapy. Although amifostine is approved for intravenous infusion, the off-label subcutaneous route of administration has become more prevalent. Although human patient data indicate higher plasma bioavailability of the active metabolite (WR-1065) following intravenous compared to subcutaneous administration, there are no corresponding data showing human tissue levels of WR-1065 following either route of administration due to the difficulty in obtaining human specimens. In our study we compared plasma and tissue pharmacokinetics of WR-1065 in primates following both routes of administration. Monkeys received amifostine at a dose of 260 mg/m2 either intravenously or subcutaneously. Plasma samples were analyzed for total WR-1065 by reverse-phase high-pressure liquid chromatography (HPLC) and fluorescence detection up to 4 h after amifostine administration. Tissues were analyzed for free WR-1065 by reverse-phase HPLC and electrochemical detection 30 and 60 min after administration. Following intravenous administration, plasma WR-1065 levels peaked rapidly and showed a bi-exponential decline, while following subcutaneous administration WR-1065 levels rose slowly and declined exponentially. The relative plasma bioavailability of WR-1065 given subcutaneously was lower at 30 and 60 min. Interestingly, after 30 min, tissues showed equal or slightly greater concentrations of WR-1065 following subcutaneous administration. Levels following 60 min were comparable following both routes. The plasma bioavailability studies performed in primates confirm human plasma data. Expanding the study to evaluate primate tissue levels of WR-1065 revealed that despite lower plasma bioavailability following subcutaneous administration, tissue levels of the active metabolite were surprisingly greater than or equal to those measured in animals that received the drug intravenously. These studies strengthen the argument for subcutaneous administration of amifostine in radiation oncology.
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PMID:Tissue levels of WR-1065, the active metabolite of amifostine (Ethyol), are equivalent following intravenous or subcutaneous administration in cynomolgus monkeys. 1555 77


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