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Michael I. Koukourakis - One of the best experts on this subject based on the ideXlab platform.
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normal tissue radioprotection by Amifostine via warburg type effects
Scientific Reports, 2016Co-Authors: Michael I. Koukourakis, Alexandra Giatromanolaki, Christos E Zois, Dimitra Kalamida, Stamatia Pouliliou, Ilias V Karagounis, Tzulan Yeh, Martine I Abboud, Timothy D W ClaridgeAbstract:The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of Amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption and of carbon dioxide emission in cancer patients receiving Amifostine. Glucose levels significantly decreased and lactate levels increased in patient venous blood. Although Amifostine in vitro did not inhibit the activity of the prolyl-hydroxylase PHD2, experiments with mouse liver showed that on a short timescale WR-1065 induced expression of the Hypoxia Inducible Factor HIF1α, lactate dehydrogenase LDH5, glucose transporter GLUT2, phosphorylated pyruvate dehydrogenase pPDH and PDH-kinase. This effect was confirmed on normal mouse NCTC hepatocytes, but not on hepatoma cells. A sharp reduction of acetyl-CoA and ATP levels in NCTC cells indicated reduced mitochondrial usage of pyruvate. Transient changes of mitochondrial membrane potential and reactive oxygen species ROS production were evident. Amifostine selectively protects NCTC cells against radiation, whilst HepG2 neoplastic cells are sensitized. The radiation protection was correlates with HIF levels. These findings shed new light on the mechanism of Amifostine cytoprotection and encourage clinical research with this agent for the treatment of primary and metastatic liver cancer.
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radiochemotherapy with cetuximab cisplatin and Amifostine for locally advanced head and neck cancer a feasibility study
International Journal of Radiation Oncology Biology Physics, 2010Co-Authors: Michael I. Koukourakis, Pelagia G Tsoutsou, Antonios Karpouzis, Maria Tsiarkatsi, Ilias Karapantzos, Vassilios Daniilidis, Constantinos KouskoukisAbstract:Purpose Radiotherapy (RT) combined with cisplatin or cetuximab is the standard of care for patients with locally advanced head/neck cancer (LA-HNC). The feasibility of radiochemotherapy with cisplatin and cetuximab, supported with Amifostine, was herein investigated. Methods and Materials Forty-three patients with LA-HNC were recruited. Conformal hypofractionated/accelerated RT with Amifostine cytoprotection (2.7 Gy/fraction, 21 fractions in 4 weeks) was combined with cisplatin (30 mg/m 2 /week) and cetuximab (standard weekly regimen) therapy. The dose of Amifostine was individualized according to tolerance. Results A high daily Amifostine dose (750–1,000 mg) was tolerated by 41.8% of patients, and a standard dose (500 mg) was tolerated by 34.9% of patients. A high Amifostine dose was linked to reduced RT delays ( p = 0.0003). Grade 3 to 4 (3-4) mucositis occurred in 7/43 (16.2%) patients, and fungal infections occurred in 18/43 (41.8%) patients. Radiation dermatitis was not aggravated. Interruption of cetuximab due to acneiform rash was necessary in 23.3% of patients, while Amifostine-related fever and rash were not observed. Severe late radiation sequelae consisted of laryngeal edema (9% laryngeal cases) and cervical strictures (33% of hypopharyngeal cases). Good salivary function was preserved in 6/11 (54.5%) nasopharyngeal cancer patients. The complete response rate was 68.5%, reaching 77.2% in patients with minor radiotherapy delays. The 24-month local control and survival rates were 72.3% and 91%, respectively (median follow-up was 13 months.). Conclusions In this feasibility study, weekly administration of cisplatin and cetuximab was safely combined with accelerated RT, supported with Amifostine, at the cost of a high incidence of acneiform rash but a reduced incidence of Amifostine-related fever/rash. A high daily dose of Amifostine allows completion of therapy with minor delays.
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individualization of the subcutaneous Amifostine dose during hypofractionated accelerated radiotherapy
Anticancer Research, 2006Co-Authors: Michael I. Koukourakis, Ioannis Abatzoglou, Leonidas Sivridis, Maria Tsarkatsi, Helen DelidouAbstract:Background: Individualization of the daily dose of Amifostine may prove of value in achieving maximum cytoprotection during radiotherapy. Patients and Methods: Using an algorithm based on: i) the gradual increase of the Amifostine dose, ii) an Amifostine tolerance-recording scale and iii) the intermittent administration of dexamethasone, the individualization of the subcutaneous Amifostine dose was prospectively attempted in a large cohort of 132 cancer patients, treated with 12-15 consecutive fractions of 3.4-3.5 Gy (hypofractionated accelerated radiotherapy with cytoprotection, HypoARC). Results: Using the above algorithm, a daily dose of 1000 mg of Amifostine was successfully delivered in 62% of patients. An additional 20% of patients tolerated well a mean daily dose of 750-975 mg. Nausea and fatigue were minimal, while fever/rash enforced Amifostine interruption in 7% of cases. Conclusion: Individualization of the Amifostine dose allowed an up to two-fold increased daily-dose administration of Amifostine and can be tested as a support to aggressive radio-chemotherapy schemes aiming at improving the cure rates of cancer patients, while avoiding excess toxicity. Amifostine is a broad spectrum cytoprotective agent that
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Individualization of the subcutaneous Amifostine dose during hypofractionated / accelerated radiotherapy.
Anticancer research, 2006Co-Authors: Michael I. Koukourakis, Ioannis Abatzoglou, Leonidas Sivridis, Maria Tsarkatsi, Helen DelidouAbstract:Background: Individualization of the daily dose of Amifostine may prove of value in achieving maximum cytoprotection during radiotherapy. Patients and Methods: Using an algorithm based on: i) the gradual increase of the Amifostine dose, ii) an Amifostine tolerance-recording scale and iii) the intermittent administration of dexamethasone, the individualization of the subcutaneous Amifostine dose was prospectively attempted in a large cohort of 132 cancer patients, treated with 12-15 consecutive fractions of 3.4-3.5 Gy (hypofractionated accelerated radiotherapy with cytoprotection, HypoARC). Results: Using the above algorithm, a daily dose of 1000 mg of Amifostine was successfully delivered in 62% of patients. An additional 20% of patients tolerated well a mean daily dose of 750-975 mg. Nausea and fatigue were minimal, while fever/rash enforced Amifostine interruption in 7% of cases. Conclusion: Individualization of the Amifostine dose allowed an up to two-fold increased daily-dose administration of Amifostine and can be tested as a support to aggressive radio-chemotherapy schemes aiming at improving the cure rates of cancer patients, while avoiding excess toxicity. Amifostine is a broad spectrum cytoprotective agent that
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Amifostine induces anaerobic metabolism and hypoxia-inducible factor 1α
Cancer Chemotherapy and Pharmacology, 2004Co-Authors: Michael I. Koukourakis, Alexandra Giatromanolaki, Wen Chong, Costantinos Simopoulos, Alexandros Polychronidis, Efthimios Sivridis, Adrian L. HarrisAbstract:Purpose The cytoprotective mechanism of Amifostine (WR-2721) implies free radical scavenging and DNA repair activities. We investigated additional cytoprotective pathways involving intracellular hypoxia and the activation of the hypoxia-inducible factor (HIF) pathway, a key transcription factor regulating glycolysis, angiogenesis and apoptosis, which is also linked with radioresistance. Materials and methods The glucose and oxygen levels in the peripheral blood of patients receiving 1000 mg Amifostine were determined at various time-points in order to investigate the metabolic changes induced by Amifostine. MDA468 breast tumor cell lines were incubated with a high Amifostine concentration (10 m M ) to overcome the natural resistance of cancer cells to influx of the non-hydrolyzed WR-2721, and the HIF1α protein levels were determined by Western blot analysis. In vivo experiments with Wistar rats were performed in order to assess immunohistochemically changes in the intracellular accumulation of HIF1α induced by Amifostine (200 mg/kg). Results By 30 min following Amifostine administration, the hemoglobin oxygen saturation and pO_2 levels had increased in the peripheral blood while glucose levels had reduced, providing evidence that normal tissue metabolism switches to glycolytic pathways. Incubation of cell lines with Amifostine resulted in HIF1α induction. In Wistar rats administration of Amifostine resulted in increased HIF1α accumulation in normal tissues. Conclusions Since it is doubtful whether dephosphorylation of Amifostine to the active metabolite WR-1065 occurs within tumoral tissues (an acidic environment that lacks vascular alkaline phosphatase activity), intracellular hypoxia and upregulation of HIF1α represents an additional, normal tissue-specific, Amifostine cytoprotective pathway.
Caroline M. Spencer - One of the best experts on this subject based on the ideXlab platform.
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Amifostine
Drugs, 2001Co-Authors: Christine R. Culy, Caroline M. SpencerAbstract:Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response. This selective protection is due to the greater conversion and uptake of the active metabolite, WR-1065, in normal versus neoplastic tissues. In a pivotal phase III trial, 242 patients with advanced ovarian cancer were randomised to receive treatment with cisplatin 100 mg/m^2 and cyclophosphamide 1000 mg/m^2 every 3 weeks with or without pretreatment with intravenous Amifostine 910 mg/m^2. Over 6 cycles of therapy, Amifostine significantly reduced haematological, renal and neurological toxicities; treatment delays, treatment discontinuation and days in hospital related to these adverse events were also significantly reduced in patients receiving Amifostine versus patients receiving chemotherapy alone. In another randomised phase III trial in 303 patients with head and neck cancer undergoing irradiation therapy (total dose 50 to 70Gy), pretreatment with intravenous Amifostine 200 mg/m^2 significantly reduced the incidence of acute and late grade ≥2 xerostomia. However, mucositis was not significantly reduced in Amifostine recipients compared with patients receiving radiotherapy alone, although this has been shown in smaller randomised trials. Amifostine (340 mg/m^2) also provided significant protection against pneumonitis and oesophagitis in patients with lung cancer receiving thoracic irradiation in a preliminary report from a phase III trial (n = 144). Other studies have demonstrated protective effects of Amifostine in other tumour types and other chemotherapy, radiation and radiochemotherapy regimens; however, evidence is still limited in these indications. No evidence of tumour protection by Amifostine has been demonstrated in any clinical trials. Amifostine has also been shown to stimulate haematopoietic stem cells and has been investigated as a therapy for patients with myelodysplastic syndrome in number of small preliminary studies. At the recommended dose and schedule, Amifostine is generally well tolerated. Adverse effects are usually reversible and manageable and those most frequently experienced include nausea and vomiting, transient hypotension and somnolence and sneezing. Conclusion: The results of phase III trials have confirmed the safety and efficacy of Amifostine as a cytoprotectant to ameliorate cisplatin-induced cumulative renal toxicity, for which it is the only agent proven to be effective, and neutropenia in patients with advanced ovarian cancer, and to reduce xerostomia in patients with head and neck cancer receiving irradiation therapy. Depending on the outcome of numerous ongoing clinical trials, Amifostine may eventually find broader clinical applications, both as a cytoprotectant and as a potential therapy in myelodysplastic syndrome. Overview of Pharmacodynamic Properties Amifostine is a prodrug which is converted by the membrane-bound enzyme alkaline phosphatase to the active metabolite WR-1065. WR-1065 is preferentially taken up into normal rather than neoplastic cells because of the higher alkaline phosphatase activity, better vascularisation and higher pH of normal tissue. Once inside the cell, WR-1065 protects against chemotherapy and radiotherapy damage by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen and directly binding and inactivating cytotoxic drugs, thereby either avoiding or repairing DNA damage. In preclinical studies, Amifostine protected a broad range of normal tissues and organs from a variety of cytotoxic therapies including alkylating agents, platinum agents, anthracyclines, taxanes and irradiation. In most of these studies, Amifostine did not reduce, and in specific instances actually enhanced, the cytotoxic effect of irradiation or chemotherapy on tumours. The best protective results were obtained when Amifostine was given 5 to 30 minutes before cytotoxic therapy. Recent investigations have shown that Amifostine, in addition to its protective effects, may also exert a trophic effect on normal human haematopoietic progenitor cells. In 1 study, pretreatment with Amifostine enhanced the formation of haematopoietic colonies by up to 7-fold in bone marrow taken from 6 healthy donors. Similar stimulatory effects have been observed in the bone marrow of patients with myelodysplastic syndrome. Preclinical studies show that Amifostine may protect against chemotherapyor radiotherapy-induced secondary tumours. In mice, pretreatment with Amifostine (400 mg/kg intraperitoneally) was shown to reduce the formation of secondary tumours following treatment with gamma irradiation of the hind limbs. Preclinical studies have demonstrated that Amifostine/WR-1065 can protect cells from the mutagenic effects of cisplatin, cyclophosphamide, bleomycin, chlormethine and irradiation at the hypoxanthineguanine phosphoribosyl transferase locus. The antimutagenic effect of Amifostine is observed at doses as low as 50 mg/kg in some animal models and can be seen when Amifostine is administered either 30 minutes before or up to 3 hours after cytotoxic exposure. Overview of Pharmacokinetic Properties Following intravenous administration, Amifostine is rapidly cleared from the plasma with a distribution half-life (t½_α) of ≈0.8 minutes. The rapid clearance of Amifostine is largely due to the fast conversion of Amifostine to its active metabolite, WR-1065. This metabolite is also rapidly removed from the plasma (t½_α of ≈11 minutes), probably because of rapid uptake into cells and conversion into disulphide metabolites. Animal studies show that maximum tissue concentrations of WR-1065 occur rapidly, within 5 to 15 minutes after Amifostine injection. Uptake of WR-1065 is greatest in kidney, salivary gland, intestinal mucosa, liver and lung tissue and is considerably lower in the brain and skeletal muscle. Only small amounts of Amifostine and its metabolites are excreted in the urine. In 10 patients receiving a 15-minute infusion of Amifostine 740 mg/m^2, the average percentage of the total administered Amifostine dose in the urine was 1.05, 1.38 and 4.2% for Amifostine, WR-1065 and WR-33278, respectively. Some clinical and preclinical data suggest that Amifostine exhibits nonlinear kinetics consistent with saturable metabolism. However, this remains to be determined. Therapeutic Use Amifostine has undergone clinical evaluation as a cytoprotectant in patients receiving cytotoxic chemotherapy and/or irradiation therapy. In addition to this role, recent studies have investigated the ability of Amifostine to stimulate haematopoietic stem cells in patients with myelodysplastic syndrome and as an adjunct therapy in patients undergoing autologous bone marrow transplant. In most clinical trials, Amifostine was administered as a short intravenous infusion of 740 or 910 mg/m^2 before chemotherapy and ≤500 mg/m^2 before irradiation therapy. There was no evidence of any tumour protection by Amifostine in any comparative trials. Doses of Amifostine used in patients with myelodysplastic syndrome vary since an optimal schedule and dose have not yet been determined. Chemoprotectant. Amifostine has been investigated in combination with a variety of different chemotherapy regimens in patients with a diverse range of solid and non-solid malignancies. The main focus of clinical investigation has been the efficacy of Amifostine in protecting normal tissues from toxicities associated with platinum agents and cyclophosphamide. More recently, investigations into the use of Amifostine in regimens containing other agents have been initiated. In the largest study, a randomised phase III trial in 242 patients with advanced ovarian cancer, treatment with intravenous Amifostine 910 mg/m^2 before a regimen of cisplatin (100 mg/m^2) and cyclophosphamide (1000 mg/m^2) provided significant haematological, renal and neurological protection without affecting tumour response and patient survival. Over 6 cycles of therapy, the incidence of severe neutropenic episodes causing fever or requiring antibiotic therapy was significantly reduced in patients receiving Amifostine versus patients receiving chemotherapy alone (10 vs 21%) which resulted in significantly fewer days in hospital (89 vs 226 days). By cycle 6, the percentage of patients requiring treatment delays or treatment discontinuation due to elevated serum creatinine levels was significantly lower in Amifostine recipients (10 vs 36%), as was the percentage of patients whose creatinine clearance was reduced by ≥40% from baseline (13 vs 30%). The severity and incidence of peripheral neurotoxicity were also significantly reduced in Amifostine recipients versus patients receiving cisplatin-based chemotherapy alone. In other smaller comparative trials, Amifostine was shown to protect against carboplatin- and mitomycin-induced thrombocytopenia and topotecan-induced neutropenia. However, Amifostine did not seem to provide significant protection against the haematological or neurological toxicities of paclitaxel in 1 randomised trial. More data are necessary before the role of Amifostine in combination with these various regimens can be determined. The haematological protective effects of Amifostine have been compared with those of the stimulatory effects of granulocyte colony-stimulating factor (G-CSF) in patients with non-small cell lung cancer (NSCLC) receiving carboplatin therapy. In this phase III trial, 45 patients were randomised to receive carboplatin [administered to achieve an area under the concentration-time curve (AUC) equal to 9] with either Amifostine (n = 24; 740 mg/m^2 given before and 2 hours after carboplatin) or G-CSF (n = 21; 263 μg/day for 13 days after carboplatin therapy). The results show that, while the 2 agents have comparable effects on neutropenia, Amifostine is statistically superior to G-CSF in reducing thrombocytopenia and expediting platelet recovery. In Patients Undergoing Bone Marrow Transplantation. In these patients, Amifostine may reduce the nonhaematological adverse effects (e.g. mucositis) of high dose myeloablative carboplatin- or melphalan-based therapy and protect normal haematopoietic cells during ex vivo purging of autologous bone marrow. However, only limited data exist. Radioprotectant. The radioprotective effects of Amifostine have been analysed in patients receiving pelvic, thoracic, and head and neck irradiation in a number of comparative and noncomparative trials. Differences in the doses and regimens of Amifostine and irradiation used, and different tumour types and efficacy parameters, make direct comparisons difficult. In a randomised phase III study involving 303 patients with head and neck cancer receiving irradiation therapy (total dose 50 to 70Gy), pretreatment with Amifostine 200 mg/m^2 significantly reduced both acute and late xerostomia compared with irradiation alone. Amifostine did not reduce mucositis in this trial; however, Amifostine has protected against mucositis in other, smaller comparative trials. The protective effects of Amifostine during thoracic irradiation were described in a preliminary report from a randomised phase III trial in 144 patients with lung cancer. In patients receiving pretreatment with Amifostine 340 mg/m^2 (n = 73), irradiation-induced oesophagitis and pneumonitis were significantly reduced compared with the control group (n = 71). Subcutaneous Amifostine (500mg) also provided significant protection in a subgroup of 55 patients receiving thoracic irradiation therapy for a variety of thoracic tumours in another randomised trial. The protective effect of Amifostine in patients receiving pelvic irradiation has also been examined, although results are variable. Amifostine was shown to protect against late, but not early, mucosal toxicities in 1 randomised trial involving 71 patients with rectal adenocarcinoma. In another randomised trial involving a group of 36 patients with various pelvic tumours, Amifostine was shown to protect against acute mucosal irradiation injury. Radiochemotherapy Protectant. At this stage, there are only limited comparative data available from investigations of the role of Amifostine as a cytoprotectant in patients receiving combined modality therapy. In 1 randomised trial, Amifostine was shown to provide significant protection against oesophagitis and pneumonitis in patients with NSCLC receiving chemotherapy with paclitaxel (60 mg/m^2) or carboplatin (AUC = 2) in addition to thoracic irradiation therapy (2Gy daily for 5 days/week). However, in another larger randomised study in patients with NSCLC, Amifostine did not provide significant haematological, renal or auditory protection against a regimen of cisplatin, ifosfamide and mitomycin combined with thoracic irradiation therapy. Amifostine has also been evaluated in patients with head and neck cancer receiving combined irradiation and carboplatin therapy in 2 randomised trials. In both studies, Amifostine pretreatment significantly reduced the incidence of severe mucositis and late xerostomia; Amifostine also significantly reduced acute xerostomia and haematological toxicity in 1 study. Therapeutic Potential in Myelodysplastic Syndrome. Investigations into the therapeutic potential of Amifostine in patients with myelodysplastic syndrome are limited and only a few reports have been published in full. Because of the preliminary nature of these mainly noncomparative trials, a number of different Amifostine regimens have been investigated in an effort to establish an optimal dosage and administration schedule. Response rates also vary widely, with uni- or multilineage haematological responses reported in 0 to 83% of patients. The best results have been observed in patients receiving a treatment schedule of 3 times weekly Amifostine 200 mg/m^2 for 3 weeks followed by a 2-week break. The efficacy of this schedule has recently been shown in a randomised, double-blind, placebo-controlled study. Although these results have not been published in full, the response rate was 37% in patients receiving Amifostine and 11% in patients receiving placebo. Amifostine has also been investigated in combination with other agents such as G-CSF, topotecan, pentoxifylline and dexamethasone with some success. It is not yet known if the haematological effects of Amifostine are sustained with prolonged treatment. In all the trials conducted to date, the haematopoietic effects of Amifostine were transient, with cytopenias typically returning to baseline a few weeks after Amifostine therapy was withdrawn. Tolerability At the recommended dose and schedule, Amifostine is generally well tolerated. Adverse effects were usually reversible and manageable and those most frequently experienced include nausea and vomiting on the day of therapy and transient reductions in systolic blood pressure during infusion. Other adverse effects such as sneezing, somnolence, dizziness, flushing, hiccups and chills are generally episodic and do not require interruption of therapy. Most authors report asymptomatic decreases in systolic blood pressure of between 20 and 50mm Hg with spontaneous normalisation of blood pressure usually occurring within 5 to 10 minutes after the infusion is stopped. In 2 large randomised trials, hypotension was reported in 61.5 and 15% of patients receiving intravenous Amifostine 910 and 200 mg/m^2 in addition to chemo- and radiotherapy, respectively. This adverse event rarely necessitates therapy withdrawal and blood pressure reductions observed to date have not been associated with central nervous system, cardiovascular or renal consequences. Nausea and vomiting are usually mild to moderate in intensity and sudden in onset, occurring during or just after Amifostine infusion and usually resolving spontaneously in less than an hour. These adverse effects can be reduced by administration of antiemetic agents such as dexamethasone and serotonin 5-HT_3 receptor antagonists. In 2 large randomised trials, the incidence of nausea and vomiting was significantly higher in patients receiving Amifostine in addition to chemotherapy or irradiation therapy than in patients receiving chemotherapy or irradiation therapy alone; however, in patients receiving chemotherapy, the incidence of severe (grade 3 or 4) nausea and vomiting was similar between patients treated with or without Amifostine. Transient decreases in serum calcium levels are occasionally observed in patients receiving Amifostine therapy. However, clinically relevant hypocalcaemia is rare, occurring in
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Amifostine an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome
Drugs, 2001Co-Authors: Christine R. Culy, Caroline M. SpencerAbstract:UNLABELLED Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response. This selective protection is due to the greater conversion and uptake of the active metabolite, WR- 1065, in normal versus neoplastic tissues. In a pivotal phase III trial, 242 patients with advanced ovarian cancer were randomised to receive treatment with cisplatin 100 mg/m2 and cyclophosphamide 1000 mg/m2 every 3 weeks with or without pretreatment with intravenous Amifostine 910 mg/m2. Over 6 cycles of therapy, Amifostine significantly reduced haematological, renal and neurological toxicities: treatment delays, treatment discontinuation and days in hospital related to these adverse events were also significantly reduced in patients receiving Amifostine versus patients receiving chemotherapy alone. In another randomised phase III trial in 303 patients with head and neck cancer undergoing irradiation therapy (total dose 50 to 70Gy), pretreatment with intravenous Amifostine 200 mg/m2 significantly reduced the incidence of acute and late grade > or =2 xerostomia. However, mucositis was not significantly reduced in Amifostine recipients compared with patients receiving radiotherapy alone, although this has been shown in smaller randomised trials. Amifostine (340 mg/m2) also provided significant protection against pneumonitis and oesophagitis in patients with lung cancer receiving thoracic irradiation in a preliminary report from a phase III trial (n = 144). Other studies have demonstrated protective effects of Amifostine in other tumour types and other chemotherapy, radiation and radiochemotherapy regimens; however, evidence is still limited in these indications. No evidence of tumour protection by Amifostine has been demonstrated in any clinical trials. Amifostine has also been shown to stimulate haematopoietic stem cells and has been investigated as a therapy for patients with myelodysplastic syndrome in number of small preliminary studies. At the recommended dose and schedule, Amifostine is generally well tolerated. Adverse effects are usually reversible and manageable and those most frequently experienced include nausea and vomiting, transient hypotension and somnolence and sneezing. CONCLUSION The results of phase III trials have confirmed the safety and efficacy of Amifostine as a cytoprotectant to ameliorate cisplatin-induced cumulative renal toxicity, for which it is the only agent proven to be effective, and neutropenia in patients with advanced ovarian cancer, and to reduce xerostomia in patients with head and neck cancer receiving irradiation therapy. Depending on the outcome of numerous ongoing clinical trials, Amifostine may eventually find broader clinical applications, both as a cytoprotectant and as a potential therapy in myelodysplastic syndrome.
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Amifostine a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential as a radioprotector and cytotoxic chemoprotector
Drugs, 1996Co-Authors: Caroline M. Spencer, Karen L GoaAbstract:Amifostine (WR-2721) was originally developed as a radioprotective agent. In animals, it protects normal tissues from the damaging effects of irradiation and, as shown in more recent studies, of several cytotoxic agents. Protection of tumours is generally reduced compared with that of normal tissues in animals, suggesting that Amifostine may increase the therapeutic window of cytotoxic therapies. Clinical data concerning Amifostine suggest that cytotoxic chemotherapy-induced haematological toxicity and cisplatin-induced neurotoxicity, nephrotoxicity and ototoxicity are decreased upon administration of Amifostine prior to cytotoxic drugs. Similarly, Amifostine reduces damage to normal tissues caused by radiotherapy. Available data show that this protection is achieved without adversely affecting tumour response or patient survival. In 1 large trial, the reduction in cyclophosphamide- and cisplatin-related toxicities manifested as a decrease in the incidence and severity of neutropenia-related fever and sepsis and in the number of patients with ovarian cancer who discontinue therapy before completion of treatment, thus improving the tolerability of this antineoplastic regimen. In addition, the incidences of cisplatin-induced nephro- and neurotoxicity were reduced. Increased doses of cytotoxic therapy have also been administered when Amifostine was given prior to therapy, which may increase tumour response. The predominant adverse effect associated with Amifostine are hypotension, nausea and vomiting, somnolence and sneezing. Thus, Amifostine is likely to be a useful adjuvant to the treatment of patients with malignancy, particularly those receiving cyclophosphamide plus cisplatin. discontinued therapy before completion of treatment, thus improving the tolerability of this antineoplastic regimen. In addition, the incidences of cisplatin-induced.
Walter J Curran - One of the best experts on this subject based on the ideXlab platform.
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a phase ii trial of subcutaneous Amifostine and radiation therapy in patients with head and neck cancer
Seminars in Radiation Oncology, 2002Co-Authors: Pramila Rani Anne, Walter J CurranAbstract: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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a phase ii trial of subcutaneous Amifostine and radiation therapy in patients with head and neck cancer
International Journal of Radiation Oncology Biology Physics, 2001Co-Authors: Pramila Rani Anne, David M Brizel, Mitchell Machtay, David I Rosenthal, William H Morrison, David H Irwin, P Chougule, Noel C Estopinal, Anthony M Berson, Walter J CurranAbstract:Purpose: Intravenous Amifostine 200 mg/m{sup 2} reduces xerostomia in head-and-neck cancer patients. This Phase II study evaluated subcutaneous (s.c.) Amifostine in a similar patient population. Patients and Methods: Patients received Amifostine 500 mg, administered as two 250-mg s.c. injections 60 min before once-daily radiation for head-and-neck cancer (50-70 Gy in 5-7 weeks). The primary endpoint was the incidence of {>=}Grade 2 acute xerostomia. Results: Fifty-four patients received s.c. Amifostine and radiotherapy. The incidence of {>=}Grade 2 acute xerostomia was 56% (95% CI, 43-69%) and the incidence of {>=}Grade 2 late xerostomia at 1 year was 45% (95% CI, 29-61%). The incidence of acute xerostomia was lower than reported previously with no Amifostine in a controlled study; rates of acute xerostomia were similar between s.c. and i.v. Amifostine in the two studies. The rate of late xerostomia with s.c. Amifostine was intermediate between rates for i.v. Amifostine and no Amifostine, and not statistically significantly different from either historical control. Grades 1-2 nausea and emesis were the most common Amifostine-related adverse events. Grade 3 Amifostine-related adverse events reported by >1 patient included: dehydration (11%); rash (6%); and weight decrease, mucositis, dyspnea, and allergic reaction (each 4%). Seven patients (13%) had serious cutaneousmore » adverse events outside the injection site. One-year rates of locoregional control, progression-free survival, and overall survival were 78%, 75%, and 85%, respectively. Conclusions: Subcutaneous Amifostine provides a well-tolerated yet simpler alternative to i.v. Amifostine for reducing acute xerostomia in head-and-neck cancer patients.« less
Wolfgang Oster - One of the best experts on this subject based on the ideXlab platform.
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phase iii randomized trial of Amifostine as a radioprotector in head and neck cancer
Journal of Clinical Oncology, 2000Co-Authors: David M Brizel, Todd H Wasserman, Michael Henke, Vratislav Strnad, Volkar Rudat, Alain Monnier, F Eschwege, Jay Zhang, Lesley Russell, Wolfgang OsterAbstract:PURPOSE: Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether Amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients. PATIENTS AND METHODS: Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade ≥ 2 acute xerostomia, grade ≥ 3 acute mucositis, and grade ≥ 2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m2 intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional c...
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Chemoprotective and radioprotective effects of Amifostine: an update of clinical trials.
International journal of hematology, 2000Co-Authors: Robert L. Capizzi, Wolfgang OsterAbstract: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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randomized study of a short course of weekly cisplatin with or without Amifostine in advanced head and neck cancer
Annals of Oncology, 1999Co-Authors: A S T Planting, Wolfgang Oster, G Catimel, P H M De Mulder, A De Graeff, F Hoppener, I Verweij, J.b. VermorkenAbstract:Summary Background Cisplatin is one of the most active cytotoxic agents available for the treatment of patients with head and neck cancer. In a previous phase II study with weekly administration of cisplatin, a response rate of 51% was achieved. However, only in a minority of the patients the planned high dose intensity of 80 mg/m2/week could be reached because of toxicity, mainly thrombocytopenia and ototoxicity. Amifostine is a cytoprotective drug that can diminish the toxicity of alkylating agents and platinum compounds. Therefore the effect of Amifostine on toxicity and activity of weekly cisplatin was investigated in a randomized study. Patients and methods Patients with locally advanced, recurrent or metastatic head and neck cancer were eligible. Patients were randomized to weekly cisplatin 70 mg/m2 for six cycles preceded by Amifostine 740 mg/m2, or cisplatin only. Cisplatin was administered in hypertonic saline (3% NaCl) as a one-hour infusion; Amifostine was administered as a 15-minute infusion directly before the administration of cisplatin. Results Seventy-four patients were entered in the study. The median number of cisplatin administrations was 6 (range 2–6), equal in both arms. In both treatment arms the median dose intensity of cisplatin achieved was the planned 70 mg/m2/week. In the cisplatin only arm 6 out of 206 cycles were complicated by thrombocytopenia grade 3 or 4 versus 1 of 184 cycles in the Amifostine arm (P = 0.035). Hypomagnesaemia grade 2 + 3 was significantly less observed in the Amifostine arm (P = 0.04). Neurotoxicity analyzed by serial vibration perception thresholds (VPT) showed a diminished incidence of subclinical neurotoxicity in the Amifostine arm (P = 0.03). No protective effect on renal and ototoxicity could be shown. Hypotension was the main side effect of Amifostine but only of relevance in one patient. The antitumor activity of cisplatin was preserved as 63% of the evaluable patients in the Amifostine arm responded compared to 50% of the evaluable patients in the cisplatin alone arm. Conclusion Our study indicated that in combination with weekly administered cisplatin Amifostine reduced the risk of thrombocytopenia, hypomagnesemia as well as subclinical neurotoxicity, but did not result in a higher dose intensity of cisplatin. Addition of Amifostine did not compromise the antitumor effect of cisplatin.
Christine R. Culy - One of the best experts on this subject based on the ideXlab platform.
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Amifostine
Drugs, 2001Co-Authors: Christine R. Culy, Caroline M. SpencerAbstract:Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response. This selective protection is due to the greater conversion and uptake of the active metabolite, WR-1065, in normal versus neoplastic tissues. In a pivotal phase III trial, 242 patients with advanced ovarian cancer were randomised to receive treatment with cisplatin 100 mg/m^2 and cyclophosphamide 1000 mg/m^2 every 3 weeks with or without pretreatment with intravenous Amifostine 910 mg/m^2. Over 6 cycles of therapy, Amifostine significantly reduced haematological, renal and neurological toxicities; treatment delays, treatment discontinuation and days in hospital related to these adverse events were also significantly reduced in patients receiving Amifostine versus patients receiving chemotherapy alone. In another randomised phase III trial in 303 patients with head and neck cancer undergoing irradiation therapy (total dose 50 to 70Gy), pretreatment with intravenous Amifostine 200 mg/m^2 significantly reduced the incidence of acute and late grade ≥2 xerostomia. However, mucositis was not significantly reduced in Amifostine recipients compared with patients receiving radiotherapy alone, although this has been shown in smaller randomised trials. Amifostine (340 mg/m^2) also provided significant protection against pneumonitis and oesophagitis in patients with lung cancer receiving thoracic irradiation in a preliminary report from a phase III trial (n = 144). Other studies have demonstrated protective effects of Amifostine in other tumour types and other chemotherapy, radiation and radiochemotherapy regimens; however, evidence is still limited in these indications. No evidence of tumour protection by Amifostine has been demonstrated in any clinical trials. Amifostine has also been shown to stimulate haematopoietic stem cells and has been investigated as a therapy for patients with myelodysplastic syndrome in number of small preliminary studies. At the recommended dose and schedule, Amifostine is generally well tolerated. Adverse effects are usually reversible and manageable and those most frequently experienced include nausea and vomiting, transient hypotension and somnolence and sneezing. Conclusion: The results of phase III trials have confirmed the safety and efficacy of Amifostine as a cytoprotectant to ameliorate cisplatin-induced cumulative renal toxicity, for which it is the only agent proven to be effective, and neutropenia in patients with advanced ovarian cancer, and to reduce xerostomia in patients with head and neck cancer receiving irradiation therapy. Depending on the outcome of numerous ongoing clinical trials, Amifostine may eventually find broader clinical applications, both as a cytoprotectant and as a potential therapy in myelodysplastic syndrome. Overview of Pharmacodynamic Properties Amifostine is a prodrug which is converted by the membrane-bound enzyme alkaline phosphatase to the active metabolite WR-1065. WR-1065 is preferentially taken up into normal rather than neoplastic cells because of the higher alkaline phosphatase activity, better vascularisation and higher pH of normal tissue. Once inside the cell, WR-1065 protects against chemotherapy and radiotherapy damage by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen and directly binding and inactivating cytotoxic drugs, thereby either avoiding or repairing DNA damage. In preclinical studies, Amifostine protected a broad range of normal tissues and organs from a variety of cytotoxic therapies including alkylating agents, platinum agents, anthracyclines, taxanes and irradiation. In most of these studies, Amifostine did not reduce, and in specific instances actually enhanced, the cytotoxic effect of irradiation or chemotherapy on tumours. The best protective results were obtained when Amifostine was given 5 to 30 minutes before cytotoxic therapy. Recent investigations have shown that Amifostine, in addition to its protective effects, may also exert a trophic effect on normal human haematopoietic progenitor cells. In 1 study, pretreatment with Amifostine enhanced the formation of haematopoietic colonies by up to 7-fold in bone marrow taken from 6 healthy donors. Similar stimulatory effects have been observed in the bone marrow of patients with myelodysplastic syndrome. Preclinical studies show that Amifostine may protect against chemotherapyor radiotherapy-induced secondary tumours. In mice, pretreatment with Amifostine (400 mg/kg intraperitoneally) was shown to reduce the formation of secondary tumours following treatment with gamma irradiation of the hind limbs. Preclinical studies have demonstrated that Amifostine/WR-1065 can protect cells from the mutagenic effects of cisplatin, cyclophosphamide, bleomycin, chlormethine and irradiation at the hypoxanthineguanine phosphoribosyl transferase locus. The antimutagenic effect of Amifostine is observed at doses as low as 50 mg/kg in some animal models and can be seen when Amifostine is administered either 30 minutes before or up to 3 hours after cytotoxic exposure. Overview of Pharmacokinetic Properties Following intravenous administration, Amifostine is rapidly cleared from the plasma with a distribution half-life (t½_α) of ≈0.8 minutes. The rapid clearance of Amifostine is largely due to the fast conversion of Amifostine to its active metabolite, WR-1065. This metabolite is also rapidly removed from the plasma (t½_α of ≈11 minutes), probably because of rapid uptake into cells and conversion into disulphide metabolites. Animal studies show that maximum tissue concentrations of WR-1065 occur rapidly, within 5 to 15 minutes after Amifostine injection. Uptake of WR-1065 is greatest in kidney, salivary gland, intestinal mucosa, liver and lung tissue and is considerably lower in the brain and skeletal muscle. Only small amounts of Amifostine and its metabolites are excreted in the urine. In 10 patients receiving a 15-minute infusion of Amifostine 740 mg/m^2, the average percentage of the total administered Amifostine dose in the urine was 1.05, 1.38 and 4.2% for Amifostine, WR-1065 and WR-33278, respectively. Some clinical and preclinical data suggest that Amifostine exhibits nonlinear kinetics consistent with saturable metabolism. However, this remains to be determined. Therapeutic Use Amifostine has undergone clinical evaluation as a cytoprotectant in patients receiving cytotoxic chemotherapy and/or irradiation therapy. In addition to this role, recent studies have investigated the ability of Amifostine to stimulate haematopoietic stem cells in patients with myelodysplastic syndrome and as an adjunct therapy in patients undergoing autologous bone marrow transplant. In most clinical trials, Amifostine was administered as a short intravenous infusion of 740 or 910 mg/m^2 before chemotherapy and ≤500 mg/m^2 before irradiation therapy. There was no evidence of any tumour protection by Amifostine in any comparative trials. Doses of Amifostine used in patients with myelodysplastic syndrome vary since an optimal schedule and dose have not yet been determined. Chemoprotectant. Amifostine has been investigated in combination with a variety of different chemotherapy regimens in patients with a diverse range of solid and non-solid malignancies. The main focus of clinical investigation has been the efficacy of Amifostine in protecting normal tissues from toxicities associated with platinum agents and cyclophosphamide. More recently, investigations into the use of Amifostine in regimens containing other agents have been initiated. In the largest study, a randomised phase III trial in 242 patients with advanced ovarian cancer, treatment with intravenous Amifostine 910 mg/m^2 before a regimen of cisplatin (100 mg/m^2) and cyclophosphamide (1000 mg/m^2) provided significant haematological, renal and neurological protection without affecting tumour response and patient survival. Over 6 cycles of therapy, the incidence of severe neutropenic episodes causing fever or requiring antibiotic therapy was significantly reduced in patients receiving Amifostine versus patients receiving chemotherapy alone (10 vs 21%) which resulted in significantly fewer days in hospital (89 vs 226 days). By cycle 6, the percentage of patients requiring treatment delays or treatment discontinuation due to elevated serum creatinine levels was significantly lower in Amifostine recipients (10 vs 36%), as was the percentage of patients whose creatinine clearance was reduced by ≥40% from baseline (13 vs 30%). The severity and incidence of peripheral neurotoxicity were also significantly reduced in Amifostine recipients versus patients receiving cisplatin-based chemotherapy alone. In other smaller comparative trials, Amifostine was shown to protect against carboplatin- and mitomycin-induced thrombocytopenia and topotecan-induced neutropenia. However, Amifostine did not seem to provide significant protection against the haematological or neurological toxicities of paclitaxel in 1 randomised trial. More data are necessary before the role of Amifostine in combination with these various regimens can be determined. The haematological protective effects of Amifostine have been compared with those of the stimulatory effects of granulocyte colony-stimulating factor (G-CSF) in patients with non-small cell lung cancer (NSCLC) receiving carboplatin therapy. In this phase III trial, 45 patients were randomised to receive carboplatin [administered to achieve an area under the concentration-time curve (AUC) equal to 9] with either Amifostine (n = 24; 740 mg/m^2 given before and 2 hours after carboplatin) or G-CSF (n = 21; 263 μg/day for 13 days after carboplatin therapy). The results show that, while the 2 agents have comparable effects on neutropenia, Amifostine is statistically superior to G-CSF in reducing thrombocytopenia and expediting platelet recovery. In Patients Undergoing Bone Marrow Transplantation. In these patients, Amifostine may reduce the nonhaematological adverse effects (e.g. mucositis) of high dose myeloablative carboplatin- or melphalan-based therapy and protect normal haematopoietic cells during ex vivo purging of autologous bone marrow. However, only limited data exist. Radioprotectant. The radioprotective effects of Amifostine have been analysed in patients receiving pelvic, thoracic, and head and neck irradiation in a number of comparative and noncomparative trials. Differences in the doses and regimens of Amifostine and irradiation used, and different tumour types and efficacy parameters, make direct comparisons difficult. In a randomised phase III study involving 303 patients with head and neck cancer receiving irradiation therapy (total dose 50 to 70Gy), pretreatment with Amifostine 200 mg/m^2 significantly reduced both acute and late xerostomia compared with irradiation alone. Amifostine did not reduce mucositis in this trial; however, Amifostine has protected against mucositis in other, smaller comparative trials. The protective effects of Amifostine during thoracic irradiation were described in a preliminary report from a randomised phase III trial in 144 patients with lung cancer. In patients receiving pretreatment with Amifostine 340 mg/m^2 (n = 73), irradiation-induced oesophagitis and pneumonitis were significantly reduced compared with the control group (n = 71). Subcutaneous Amifostine (500mg) also provided significant protection in a subgroup of 55 patients receiving thoracic irradiation therapy for a variety of thoracic tumours in another randomised trial. The protective effect of Amifostine in patients receiving pelvic irradiation has also been examined, although results are variable. Amifostine was shown to protect against late, but not early, mucosal toxicities in 1 randomised trial involving 71 patients with rectal adenocarcinoma. In another randomised trial involving a group of 36 patients with various pelvic tumours, Amifostine was shown to protect against acute mucosal irradiation injury. Radiochemotherapy Protectant. At this stage, there are only limited comparative data available from investigations of the role of Amifostine as a cytoprotectant in patients receiving combined modality therapy. In 1 randomised trial, Amifostine was shown to provide significant protection against oesophagitis and pneumonitis in patients with NSCLC receiving chemotherapy with paclitaxel (60 mg/m^2) or carboplatin (AUC = 2) in addition to thoracic irradiation therapy (2Gy daily for 5 days/week). However, in another larger randomised study in patients with NSCLC, Amifostine did not provide significant haematological, renal or auditory protection against a regimen of cisplatin, ifosfamide and mitomycin combined with thoracic irradiation therapy. Amifostine has also been evaluated in patients with head and neck cancer receiving combined irradiation and carboplatin therapy in 2 randomised trials. In both studies, Amifostine pretreatment significantly reduced the incidence of severe mucositis and late xerostomia; Amifostine also significantly reduced acute xerostomia and haematological toxicity in 1 study. Therapeutic Potential in Myelodysplastic Syndrome. Investigations into the therapeutic potential of Amifostine in patients with myelodysplastic syndrome are limited and only a few reports have been published in full. Because of the preliminary nature of these mainly noncomparative trials, a number of different Amifostine regimens have been investigated in an effort to establish an optimal dosage and administration schedule. Response rates also vary widely, with uni- or multilineage haematological responses reported in 0 to 83% of patients. The best results have been observed in patients receiving a treatment schedule of 3 times weekly Amifostine 200 mg/m^2 for 3 weeks followed by a 2-week break. The efficacy of this schedule has recently been shown in a randomised, double-blind, placebo-controlled study. Although these results have not been published in full, the response rate was 37% in patients receiving Amifostine and 11% in patients receiving placebo. Amifostine has also been investigated in combination with other agents such as G-CSF, topotecan, pentoxifylline and dexamethasone with some success. It is not yet known if the haematological effects of Amifostine are sustained with prolonged treatment. In all the trials conducted to date, the haematopoietic effects of Amifostine were transient, with cytopenias typically returning to baseline a few weeks after Amifostine therapy was withdrawn. Tolerability At the recommended dose and schedule, Amifostine is generally well tolerated. Adverse effects were usually reversible and manageable and those most frequently experienced include nausea and vomiting on the day of therapy and transient reductions in systolic blood pressure during infusion. Other adverse effects such as sneezing, somnolence, dizziness, flushing, hiccups and chills are generally episodic and do not require interruption of therapy. Most authors report asymptomatic decreases in systolic blood pressure of between 20 and 50mm Hg with spontaneous normalisation of blood pressure usually occurring within 5 to 10 minutes after the infusion is stopped. In 2 large randomised trials, hypotension was reported in 61.5 and 15% of patients receiving intravenous Amifostine 910 and 200 mg/m^2 in addition to chemo- and radiotherapy, respectively. This adverse event rarely necessitates therapy withdrawal and blood pressure reductions observed to date have not been associated with central nervous system, cardiovascular or renal consequences. Nausea and vomiting are usually mild to moderate in intensity and sudden in onset, occurring during or just after Amifostine infusion and usually resolving spontaneously in less than an hour. These adverse effects can be reduced by administration of antiemetic agents such as dexamethasone and serotonin 5-HT_3 receptor antagonists. In 2 large randomised trials, the incidence of nausea and vomiting was significantly higher in patients receiving Amifostine in addition to chemotherapy or irradiation therapy than in patients receiving chemotherapy or irradiation therapy alone; however, in patients receiving chemotherapy, the incidence of severe (grade 3 or 4) nausea and vomiting was similar between patients treated with or without Amifostine. Transient decreases in serum calcium levels are occasionally observed in patients receiving Amifostine therapy. However, clinically relevant hypocalcaemia is rare, occurring in
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Amifostine an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome
Drugs, 2001Co-Authors: Christine R. Culy, Caroline M. SpencerAbstract:UNLABELLED Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response. This selective protection is due to the greater conversion and uptake of the active metabolite, WR- 1065, in normal versus neoplastic tissues. In a pivotal phase III trial, 242 patients with advanced ovarian cancer were randomised to receive treatment with cisplatin 100 mg/m2 and cyclophosphamide 1000 mg/m2 every 3 weeks with or without pretreatment with intravenous Amifostine 910 mg/m2. Over 6 cycles of therapy, Amifostine significantly reduced haematological, renal and neurological toxicities: treatment delays, treatment discontinuation and days in hospital related to these adverse events were also significantly reduced in patients receiving Amifostine versus patients receiving chemotherapy alone. In another randomised phase III trial in 303 patients with head and neck cancer undergoing irradiation therapy (total dose 50 to 70Gy), pretreatment with intravenous Amifostine 200 mg/m2 significantly reduced the incidence of acute and late grade > or =2 xerostomia. However, mucositis was not significantly reduced in Amifostine recipients compared with patients receiving radiotherapy alone, although this has been shown in smaller randomised trials. Amifostine (340 mg/m2) also provided significant protection against pneumonitis and oesophagitis in patients with lung cancer receiving thoracic irradiation in a preliminary report from a phase III trial (n = 144). Other studies have demonstrated protective effects of Amifostine in other tumour types and other chemotherapy, radiation and radiochemotherapy regimens; however, evidence is still limited in these indications. No evidence of tumour protection by Amifostine has been demonstrated in any clinical trials. Amifostine has also been shown to stimulate haematopoietic stem cells and has been investigated as a therapy for patients with myelodysplastic syndrome in number of small preliminary studies. At the recommended dose and schedule, Amifostine is generally well tolerated. Adverse effects are usually reversible and manageable and those most frequently experienced include nausea and vomiting, transient hypotension and somnolence and sneezing. CONCLUSION The results of phase III trials have confirmed the safety and efficacy of Amifostine as a cytoprotectant to ameliorate cisplatin-induced cumulative renal toxicity, for which it is the only agent proven to be effective, and neutropenia in patients with advanced ovarian cancer, and to reduce xerostomia in patients with head and neck cancer receiving irradiation therapy. Depending on the outcome of numerous ongoing clinical trials, Amifostine may eventually find broader clinical applications, both as a cytoprotectant and as a potential therapy in myelodysplastic syndrome.
