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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 ≥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.
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 (t½α) 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 (t½α 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/m2, 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.
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/m2 before chemotherapy and ≤500 mg/m2 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/m2 before a regimen of cisplatin (100 mg/m2) and cyclophosphamide (1000 mg/m2) 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/m2 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/m2 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/m2 (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/m2) 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/m2 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.
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/m2 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-HT3 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 <1% of patients. These effects can usually be mitigated with oral calcium and vitamin D supplements.
Allergic reactions, ranging from mild skin rashes to anaphylaxis, have rarely been reported with amifostine treatment.
Trials assessing the use of amifostine in young or elderly populations or in patients with myelodysplastic syndrome are limited at this stage but the drug appears to be well tolerated in these populations.
Pharmacoeconomic Aspects of Amifostine
The pharmacoeconomic aspects of using amifostine as a cytoprotectant in patients with ovarian cancer have been analysed in a US and a Canadian study.
The US study used a cost-utility analysis conducted from the perspective of the payer. Using the results from a large phase III, randomised clinical study, this trial analysed the impact of incorporating amifostine into a regimen of cyclophosphamide and cisplatin. The cost of amifostine therapy (6 cycles of 910 mg/m2) was estimated at 36 161 US dollars ($US) per quality-adjusted life-year saved (1997 costs), which falls within the range considered to be cost effective.
The Canadian study used willingness-to-pay methodology to estimate the amount that the Canadian tax-paying public would spend to make amifostine available to Canadians with ovarian cancer. From the responses obtained from 50 tax payers, the results indicated that tax payers would be willing to pay an average of 3476 Canadian dollars ($Can) [$US2451] (1997 costs) for amifostine as an income tax increase over their lifetime. When this amount was subtracted from the overall cost of amifostine ($Can3826; $US2697), the net cost of amifostine was $Can350 ($US247) per patient. If the dosage of amifostine is reduced from 910 to 740 mg/m2, the cost of amifostine is further reduced, resulting in a net benefit of $Can597 per patient.
The results of both these trials suggest that amifostine therapy should be in the range of affordable technologies in both the US and Canada.
In a preliminary report of an economic analysis in patients receiving amifostine in addition to cisplatin and irradiation therapy for head and neck cancer, amifostine appeared to provide cost savings due to the reduction in the adverse events of this regimen.
However, more detailed pharmacoeconomic analyses are necessary before the economic implications of incorporating amifostine into cancer treatment regimens can be confirmed.
Dosage and Administration
Amifostine is currently indicated to reduce the cumulative renal toxicity associated with cisplatin therapy in patients with advanced ovarian cancer or NSCLC, and to reduce acute and late xerostomia in patients with head and neck cancer receiving fractionated irradiation therapy where the irradiation port includes a substantial portion of the parotid glands. Amifostine is also approved for use in Europe to reduce the neutropenia-related risk of infection associated with combination therapy with cyclophosphamide and cisplatin in patients with advanced ovarian cancer.
The dosage of amifostine varies according to the accompanying treatment regimen. In patients receiving amifostine in addition to cisplatin, the recommended starting dose is 910 mg/m2 administered as a 15-minute intravenous infusion once daily, approximately 30 minutes before chemotherapy. When amifostine is given prior to radiotherapy, a dose of 200 mg/m2 is administered once daily as a 3-minute intravenous infusion 15 to 30 minutes before initiating standard fractionated irradiation therapy (1.8 to 2.0Gy).
Monitoring of blood pressure is necessary during infusion of amifostine, and infusion should be interrupted if there is a significant drop in systolic pressure (of ≥20mm Hg). The infusion may be restarted if blood pressure returns to baseline within 5 minutes and the patient remains asymptomatic. Amifostine 740 mg/m2 should be used for subsequent treatment cycles if the full dosage cannot be administered.
Amifostine therapy requires coadministration of an antiemetic and, if necessary, calcium supplementation. The efficacy and tolerability of amifostine has not been established in children or elderly patients, and the drug should be used with care in patients who have pre-existing cardiovascular or cerebrovascular disease or a history of stroke or transient ischaemic attacks.
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