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Amifostine is an cytoprotective agent that is FDA approved for the treatment of reducing the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and also to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Common adverse reactions include hypotension, nausea and/or vomiting, flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups, sneezing, and decrease in serum calcium concentrations.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
To reduce the cumulative renal toxicity
- Amifostine for Injection is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.
For Reduction of Cumulative Renal Toxicity with chemotherapy
- The recommended starting dose of Amifostine for Injection is 910 mg/m2 administered once daily as a 15-minute i.v. infusion, starting 30 minutes prior to chemotherapy.
- The 15-minute infusion is better tolerated than more extended infusions. Further reductions in infusion times for chemotherapy regimens have not been systematically investigated.
- Patients should be adequately hydrated prior to Amifostine for Injection infusion and kept in a supine position during the infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.
- The infusion of Amifostine for Injection should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
- If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted so that the full dose of Amifostine for Injection may be administered. If the full dose of amifostine cannot be administered, the dose of amifostine for subsequent chemotherapy cycles should be 740 mg/m2.
- It is recommended that antiemetic medication, including dexamethasone 20 mg i.v. and a serotonin 5HT3 receptor antagonist, be administered prior to and in conjunction with Amifostine for Injection. Additional antiemetics may be required based on the chemotherapy drugs administered.
Reduce the incidence of Xerostomia
- Amifostine for Injection is indicated to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands .
- For the approved indications, the clinical data do not suggest that the effectiveness of cisplatin based chemotherapy regimens or radiation therapy is altered by Amifostine for Injection. There are at present only limited data on the effects of amifostine on the efficacy of chemotherapy or radiotherapy in other settings.
- Amifostine should not be administered to patients in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the context of a clinical study.
For Reduction of Moderate to Severe Xerostomia from Radiation of the Head and Neck
- The recommended dose of Amifostine for Injection is 200 mg/m2 administered once daily as a 3-minute i.v. infusion, starting 15-30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy).
- Patients should be adequately hydrated prior to Amifostine for Injection infusion. Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
- It is recommended that antiemetic medication be administered prior to and in conjunction with Amifostine for Injection. Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting.
- Amifostine for Injection is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use vial contains 500 mg of amifostine on the anhydrous basis.
- Prior to intravenous injection, Amifostine for Injection is reconstituted with 9.7 mL of sterile 0.9% Sodium Chloride Injection, USP. The reconstituted solution (500 mg amifostine/10 mL) is chemically stable for up to 5 hours at room temperature (approximately 25°C) or up to 24 hours under refrigeration (2°C to 8°C).
- Amifostine for Injection prepared in polyvinylchloride (PVC) bags at concentrations ranging from 5 mg/mL to 40 mg/mL is chemically stable for up to 5 hours when stored at room temperature (approximately 25°C) or up to 24 hours when stored under refrigeration (2°C to 8°C).
CAUTION: Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if cloudiness or precipitate is observed.
- The compatibility of Amifostine for Injection with solutions other than 0.9% Sodium Chloride for Injection, or Sodium Chloride solutions with other additives, has not been examined. The use of other solutions is not recommended.
Off-Label Use and Dosage (Adult)
There is limited information regarding Off-Label Guideline-Supported Use of Amifostine in adult patients.
Adverse effect of radiation therapy, Radioiodine - Disturbance of salivary secretion
- Amifostine (500 mg/m(2))
Antineoplastic adverse reaction - Myelosuppression
- 2 doses of amifostine 910 mg/m(2)
Antineoplastic adverse reaction - Nephrotoxicity
- Amifostine (910 mg/m(2), days 1-3)
- Intravenous amifostine 100 mg, 200 mg, or 400 mg/m(2) 3 times per week or 740 mg/m(2) weekly for 3 consecutive weeks
Myelosuppression - Radiation-induced disorder
- Higher doses of amifostine (750 to 900 mg/m(2)
Non-small cell lung cancer; Adjunct
- Amifostine 740 or 910 mg/m(2)
- Amifostine 500 mg IV before each radiotherapy session
Radiation respiratory disease
- 340 mg/m(2) over 10 minutes daily 
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness in pediatric patients have not been established.
Off-Label Use and Dosage (Pediatric)
The safety and effectiveness in pediatric patients have not been established.
The safety and effectiveness in pediatric patients have not been established.
- Amifostine for Injection is contraindicated in patients with known hypersensitivity to aminothiol compounds.
Effectiveness of the Cytotoxic Regimen
- Limited data are currently available regarding the preservation of antitumor efficacy when Amifostine for Injection is administered prior to cisplatin therapy in settings other than advanced ovarian cancer. Although some animal data suggest interference is possible, in most tumor models the antitumor effects of chemotherapy are not altered by amifostine. Amifostine should not be used in patients receiving chemotherapy for other malignancies in which chemotherapy can produce a significant survival benefit or cure (e.g., certain malignancies of germ cell origin), except in the context of a clinical study.
Effectiveness of Radiotherapy
- Amifostine for Injection should not be administered in patients receiving definitive radiotherapy, except in the context of a clinical trial, since there are at present insufficient data to exclude a tumor-protective effect in this setting. Amifostine was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of amifostine on the incidence of xerostomia and on toxicity in the setting of combined chemotherapy and radiotherapy and in the setting of accelerated and hyperfractionated therapy have not been systematically studied.
- Patients who are hypotensive or in a state of dehydration should not receive Amifostine for Injection. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. Patients receiving amifostine at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding amifostine treatment, should not receive amifostine.
- Prior to Amifostine for Injection infusion patients should be adequately hydrated. During amifostine infusion patients should be kept in a supine position. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. It is important that the duration of the 910 mg/m2 infusion not exceed 15 minutes, as administration of amifostine as a longer infusion is associated with a higher incidence of side effects. For infusion durations less than 5 minutes, blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated. If hypotension occurs, patients should be placed in the Trendelenburg position and be given an infusion of normal saline using a separate i.v. line. During and after amifostine infusion, care should be taken to monitor the blood pressure of patients whose antihypertensive medication has been interrupted since hypertension may be exacerbated by discontinuation of antihypertensive medication and other causes such as i.v. hydration.
- Guidelines for interrupting and restarting Amifostine for Injection infusion if a decrease in systolic blood pressure should occur are provided . Hypotension may occur during or shortly after amifostine infusion, despite adequate hydration and positioning of the patient . Hypotension has been reported to be associated with dyspnea, apnea, hypoxia, and in rare cases seizures, unconsciousness, respiratory arrest and renal failure.
- Serious cutaneous reactions have been associated with Amifostine for Injection administration. Serious cutaneous reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis. These reactions have been reported more frequently when amifostine is used as a radioprotectant . Some of these reactions have been fatal or have required hospitalization and/or discontinuance of therapy. Patients should be carefully monitored prior to, during and after amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration .
- Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with Amifostine for Injection administration.
Nausea and Vomiting
- Antiemetic medication should be administered prior to and in conjunction with Amifostine for Injection . When amifostine is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored.
- Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of Amifostine for Injection. If necessary, calcium supplements can be administered.
- Patients should be adequately hydrated prior to the Amifostine for Injection infusion and blood pressure should be monitored .
- The safety of Amifostine for Injection administration has not been established in elderly patients, or in patients with preexisting cardiovascular or cerebrovascular conditions such as ischemic heart disease, arrhythmias, congestive heart failure, or history of stroke or transient ischemic attacks. *Amifostine should be used with particular care in these and other patients in whom the common amifostine adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences.
- Prior to chemotherapy, Amifostine for Injection should be administered as a 15-minute infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.
- Prior to radiation therapy, Amifostine for Injection should be administered as a 3-minute infusion . Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
- Cutaneous reactions may require permanent discontinuation of Amifostine for Injection or urgent dermatologic consultation and biopsy.
- Cutaneous evaluation of the patient prior to each Amifostine for Injection administration should be performed with particular attention paid to the development of the following:
- Any rash involving the lips or involving mucosa not known to be due to another etiology (e.g., radiation mucositis, herpes simplex, etc.)
- Erythematous, edematous, or bullous lesions on the palms of the hands or soles of the feet and/or other cutaneous reactions on the trunk (front, back, abdomen)
- Cutaneous reactions with associated fever or other constitutional symptoms.
- Cutaneous reactions must be clearly differentiated from radiation-induced dermatitis and from cutaneous reactions related to an alternate etiology. Amifostine for Injection should be permanently discontinued for serious or severe cutaneous reactions or for cutaneous reactions associated with fever or other constitutional symptoms not known to be due to another etiology. Amifostine should be withheld and dermatologic consultation and biopsy considered for cutaneous reactions or mucosal lesions of unknown etiology appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms of the hand or soles of the feet. *Reinitiation of amifostine should be at the physician’s discretion based on medical judgment and appropriate dermatologic evaluation.
- In case of severe acute allergic reactions Amifostine for Injection should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis.
Clinical Trials Experience
- In the randomized study of patients with ovarian cancer given Amifostine for Injection at a dose of 910 mg/m2 prior to chemotherapy, transient hypotension was observed in 62% of patients treated. The mean time of onset was 14 minutes into the 15-minute period of amifostine infusion, and the mean duration was 6 minutes. In some cases, the infusion had to be prematurely terminated due to a more pronounced drop in systolic blood pressure. In general, the blood pressure returned to normal within 5-15 minutes. Fewer than 3% of patients discontinued amifostine due to blood pressure reductions. In the randomized study of patients with head and neck cancer given amifostine at a dose of 200 mg/m2 prior to radiotherapy, hypotension was observed in 15% of patients treated. (see TABLE 6)
- In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued Amifostine for Injection due to adverse events. All but one of these patients continued to receive radiation treatment until completion.
- Hypotension that requires interruption of the Amifostine for Injection infusion should be treated with fluid infusion and postural management of the patient (supine or Trendelenburg position). If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted, so that the full dose of amifostine can be administered. Short term, reversible loss of consciousness has been reported rarely.
- Nausea and/or vomiting occur frequently after Amifostine for Injection infusion and may be severe. In the ovarian cancer randomized study, the incidence of severe nausea/vomiting on day 1 of cyclophosphamide-cisplatin chemotherapy was 10% in patients who did not receive amifostine, and 19% in patients who did receive amifostine. In the randomized study of patients with head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received amifostine and 1% in patients who did not receive amifostine.
- Decrease in serum calcium concentrations is a known pharmacological effect of Amifostine for Injection. At the recommended doses, clinically significant hypocalcemia was reported in 1% of patients in the randomized head and neck cancer study .
- Other effects, which have been described during, or following Amifostine for Injection infusion are flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups and sneezing. These effects have not generally precluded the completion of therapy.
Clinical Trials and Pharmacovigilance Reports
- Allergic reactions characterized by one or more of the following manifestations have been observed during or after Amifostine for Injection administration: hypotension, fever, chills/rigors, dyspnea, hypoxia, chest tightness, cutaneous eruptions, pruritus, urticaria and laryngeal edema. Cutaneous eruptions have been commonly reported during clinical trials and were generally non-serious. Serious, sometimes fatal skin reactions including erythema multiforme, and in rare cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have also occurred. *The reported incidence of serious skin reactions associated with amifostine is higher in patients receiving amifostine as a radioprotectant than in patients receiving amifostine as a chemoprotectant. Rare anaphylactoid reactions and cardiac arrest have also been reported.
- Hypotension, usually brief systolic and diastolic, has been associated with one or more of the following adverse events: apnea, dyspnea, hypoxia, tachycardia, bradycardia, extrasystoles, chest pain, myocardial ischemia and convulsion. Rare cases of renal failure, myocardial infarction, respiratory and cardiac arrest have been observed during or after hypotension.
- Rare cases of arrhythmias such as atrial fibrillation/flutter and supraventricular tachycardia have been reported. These are sometimes associated with hypotension or allergic reactions.
- Transient hypertension and exacerbations of preexisting hypertension have been observed rarely after Amifostine for Injection administration.
- Seizures and syncope have been reported rarely.
There is limited information regarding Amifostine Postmarketing Experience in the drug label.
- Special consideration should be given to the administration of Amifostine for Injection in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension.
Use in Specific Populations
- Amifostine has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. Amifostine for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amifostine in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Amifostine during labor and delivery.
- No information is available on the excretion of amifostine or its metabolites into human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, it is recommended that breast feeding be discontinued if the mother is treated with Amifostine for Injection.
- The safety and effectiveness in pediatric patients have not been established.
- The clinical studies did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.
There is no FDA guidance on the use of Amifostine with respect to specific gender populations.
There is no FDA guidance on the use of Amifostine with respect to specific racial populations.
There is no FDA guidance on the use of Amifostine in patients with renal impairment.
There is no FDA guidance on the use of Amifostine in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amifostine in women of reproductive potentials and males.
There is no FDA guidance one the use of Amifostine in patients who are immunocompromised.
Administration and Monitoring
- Patients should be carefully monitored prior to, during and after amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration
- Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of Amifostine for Injection
- Patients should be adequately hydrated prior to the Amifostine for Injection infusion and blood pressure should be monitored
There is limited information regarding IV Compatibility of Amifostine in the drug label.
- In clinical trials, the maximum single dose of Amifostine for Injection was 1300 mg/m2. No information is available on single doses higher than this in adults. In the setting of a clinical trial, pediatric patients have received single amifostine doses of up to 2700 mg/m2. At the higher doses, anxiety and reversible urinary retention occurred.
- Administration of Amifostine for Injection at 2 and 4 hours after the initial dose has not led to increased nausea and vomiting or hypotension. The most likely symptom of overdosage is hypotension, which should be managed by infusion of normal saline and other supportive measures, as clinically indicated.
Mechanism of Action
- Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. The ability of amifostine to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to either cisplatin or radiation.
- Amifostine for Injection is an organic thiophosphate cytoprotective agent known chemically as 2-[(3-aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) and has the following structural formula:
- Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is C5H15N2O3PS and it has a molecular weight of 214.22.
- Amifostine for Injection is the trihydrate form of amifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis.
There is limited information regarding Pharmacodynamics of Amifostine in the drug label.
- Clinical pharmacokinetic studies show that amifostine is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of amifostine remains in the plasma 6 minutes after drug administration. Amifostine is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m2 of amifostine, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5-8 minutes after intravenous infusion of amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on amifostine pharmacokinetics.
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long term animal studies have been performed to evaluate the carcinogenic potential of amifostine. Amifostine was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium strain and at the TK locus in the mouse L5178Y cell assay. The metabolite was negative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes.
chemotherapy for Ovarian Cancer
- A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without Amifostine for Injection pretreatment at 910 mg/m2, in two successive cohorts of 121 patients with advanced ovarian cancer. *In both cohorts, after multiple cycles of chemotherapy, pretreatment with amifostine significantly reduced the cumulative renal toxicity associated with cisplatin as assessed by the proportion of patients who had ≥40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum creatinine (>1.5 mg/dL), or severe hypomagnesemia. Subgroup analyses suggested that the effect of amifostine was present in patients who had received nephrotoxic antibiotics, or who had preexisting diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as well as in patients who lacked these risks. Selected analyses of the effects of amifostine in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below.
- In the randomized ovarian cancer study, Amifostine for Injection had no detectable effect on the antitumor efficacy of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically confirmed complete remission rates), time to progression, and survival duration were all similar in the amifostine and control study groups. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study.
Radiotherapy for Head and Neck Cancer
- A randomized controlled trial of standard fractionated radiation (1.8 Gy - 2.0 Gy/day for 5 days/week for 5-7 weeks) with or without Amifostine for Injection, administered at 200 mg/m2 as a 3 minute i.v. infusion 15-30 minutes prior to each fraction of radiation, was conducted in 315 patients with head and neck cancer. Patients were required to have at least 75% of both parotid glands in the radiation field. The incidence of Grade 2 or higher acute (90 days or less from start of radiation) and late xerostomia (9-12 months following radiation) as assessed by RTOG Acute and Late Morbidity Scoring Criteria, was significantly reduced in patients receiving amifostine (TABLE 4).
- At one year following radiation, whole saliva collection following radiation showed that more patients given Amifostine for Injection produced >0.1 gm of saliva (72% vs. 49%). In addition, the median saliva production at one year was higher in those patients who received amifostine (0.26 gm vs. 0.1 gm). Stimulated saliva collections did not show a difference between treatment arms. These improvements in saliva production were supported by the patients' subjective responses to a questionnaire regarding oral dryness.
- In the randomized head and neck cancer study, locoregional control, disease-free survival and overall survival were all comparable in the two treatment groups after one year of follow-up (see TABLE 5).
- Amifostine for Injection is supplied as a sterile lyophilized powder in 10 mL single-use vials (NDC 55390-308-03). Each single-use vial contains 500 mg of amifostine on the anhydrous basis. The vials are available packaged as follows:
- 3 pack - 3 vials per carton (NDC 55390-308-03)
- Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) [See USP].
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Patient Counseling Information
There is limited information regarding Patient Counseling Information of Amifostine in the drug label.
Precautions with Alcohol
- Alcohol-Amifostine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
- Ethyol ®
Look-Alike Drug Names
- A® — B®
The contents of this FDA label are provided by the National Library of Medicine.
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- Schiller JH, Storer B, Berlin J, Wittenkeller J, Larson M, Pharo L; et al. (1996). "Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival.". J Clin Oncol. 14 (6): 1913–21. PMID 8656260.
- Kouvaris J, Kouloulias V, Malas E, Antypas C, Kokakis J, Michopoulos S; et al. (2003). "Amifostine as radioprotective agent for the rectal mucosa during irradiation of pelvic tumors. A phase II randomized study using various toxicity scales and rectosigmoidoscopy.". Strahlenther Onkol. 179 (3): 167–74. PMID 12627259. doi:10.1007/s00066-003-0970-y.
- Antonadou D, Coliarakis N, Synodinou M, Athanassiou H, Kouveli A, Verigos C; et al. (2001). "Randomized phase III trial of radiation treatment +/- amifostine in patients with advanced-stage lung cancer.". Int J Radiat Oncol Biol Phys. 51 (4): 915–22. PMID 11704311.