Oncology Encyclopedia: Amifostine

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Definition

Amifostine, also known as the brand name Ethyol and as ethiofos or WR2721, is a medicine that helps protect certain tissues of the body from damage caused by chemotherapy or radiation therapy.

Purpose

Amifostine is a protectant agent that is used in combination with the chemotherapy drug cisplatin or in combination with radiation therapy. Amifostine is approved by the Food and Drug Administration (FDA) to prevent kidney damage caused by repeat doses of the chemotherapy agent cisplatin in patients who have a diagnosis of ovarian cancer or non-small cell lung cancer. It is also FDA approved for patients with head and neck cancer who are receiving radiation therapy after surgery. In this group of patients, amifostine helps decrease radiation damage to the salivary glands, which can cause dry mouth.

Description

Amifostine has been on the market since the mid-1990s. A clear colorless solution, it is administered into a vein before chemotherapy and has been shown to decrease kidney damage by greater than 50% in advanced ovarian cancer patients who have received multiple cycles of cisplatin. It is also used before radiation therapy to prevent damage to the salivary gland known as the parotid gland.

When cisplatin is given to patients, it becomes broken down into toxic substances that destroy cancer cells and normal cells. When amifostine is administered into the body, it is broken down by an enzyme that occurs in large quantities in normal cells but not in cancerous cells. It then is converted into a substance called free thiol, which combines with the poisonous cisplatin byproducts in the normal cells and makes them nontoxic.

In patients who receive radiation to the mouth area, including the salivary glands, the radiation causes the release of substances called free oxygen species, which damage cells of the mouth. An enzyme in cells of the mouth breaks down amifostine into a substance called free thiol. The free thiol blocks the free oxygen substances from damaging the salivary cells and decreases the amount of dry mouth patients suffer from when they receive radiation to the head and neck area.

Recommended Dosage

Before dosing amifostine in chemotherapy or radiation therapy patients, intravenous fluids need to be given to keep the body well flushed with fluid and to maintain a normal blood pressure. All patients will receive amifostine lying down, sometimes with the head of the body lower than the feet. Patients should also receive medication to help prevent the nausea and vomiting that occurs due to amifostine.

Amifostine dosages can be determined using a mathematical calculation that measures a person's body surface area (BSA). This number is dependent upon a patient's height and weight. The larger the person, the greater the body surface area. Body surface area is measured in units known as square meter (m2). To determine the actual dose a patient is to receive, the body surface area is calculated and then multiplied by the drug dosage in milligrams per squared meter (mg/m2).

The recommended dosage of amifostine for protection of the kidney is 910mg/m2 administered as a 15-minute infusion into a vein. This is to begin 30 minutes before chemotherapy administration. If a patient has difficulty with this dose, the dosage can be lowered to 740 mg/m2.

The recommended dosage of amifostine for radiation therapy patients is 200 mg/m2 administered once a day into a vein over a three-minute time period 15 to 30 minutes before the patient receives radiation treatment.

Precautions

Amifostine can cause a decrease in blood pressure when it is administered. During the 24 hours before receiving amifostine, patients need to drink a lot of liquids. When amifostine is being administered, medical personnel will be monitoring the patient's blood pressure. If the blood pressure drops significantly, the infusion of amifostine will be stopped until blood pressure returns to normal. The doctor will decide if the patient should receive any additional amifostine. Patients who have low blood pressure to begin with or patients who are not drinking a lot of fluids—referred to as being dehydrated—should not receive amifostine.

Patients with a known previous allergic reaction to aminothiol drugs should not receive amifostine.

Patients who may be pregnant, thinking of becoming pregnant, or who have a history of heart problems or strokes should tell their doctor before receiving amifostine.

Side Effects

The most common side effect from receiving amifostine is a lowering of blood pressure, which occurs in approximately 62% of patients treated at a dose of 910mg/m2. This lowering of blood pressure occurs within the first 15 minutes of administering the drug. Blood pressure is monitored throughout the infusion of amifostine. If the blood pressure drops to certain level then the drug is stopped and restarted only when blood pressure returns to normal.

Nausea and vomiting are common side effects. They occur rapidly and can be severe. Usually, patients are given medicines before receiving amifostine that can help prevent or decrease these side effects. Other side effects include sneezing, hiccups, a warm feeling and redness of the face, sleepiness and dizziness, metallic taste, fever, rash, and chills.

Rare side effects of amifostine are: a lowering of calcium levels in the blood, seizures, allergic reactions which include symptoms of fever, shaking chills, itching, low blood pressure, shortness of breath, and rashes. There have been rare reports of throat swelling, chest tightness, and heart stopping.

All side effects a patient experiences should be reported to their doctor.

Interactions

Amifostine causes a decrease in blood pressure and should be used with caution in patients who take blood pressure lowering medicines or other medications that may lower blood pressure. If patients are taking blood pressure medications, they may be asked to stop taking these medications for 24 hours before receiving amifostine.

Patients should tell their doctors if they have a known allergic reaction to amifostine or any other medications or substances, such as foods and preservatives. Before taking any new medications, including nonprescription medications, vitamins, and herbal medications, patients should notify their doctors.

—Nancy J. Beaulieu, RPh., BCOP

Brand names: Ethyol®

Chemical formula:

Español:
Amifostina, Solución para inyección

Amifostine Solution for injection

What is this medicine?

AMIFOSTINE is a protective medicine. It is used to prevent or lessen the kidney damage that can be caused by cisplatin chemotherapy. It is also used to prevent some side effects caused by radiation therapy to the head or neck.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•dehydrated
•heart disease
•history of stroke or TIAs
•irregular heartbeat
•low blood pressure
•low levels of calcium in the blood
•taking medicine for high blood pressure
•an unusual or allergic reaction to amifostine, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

This medicine is for infusion into a vein. It is given by a health care professional in a hospital or clinic setting.

Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

•medicines for blood pressure

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Your condition will be monitored carefully while you are receiving this medicine. Visit your doctor as directed.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•breathing problems
•chest pain or tightness
•fast, irregular heartbeat
•feeling faint or lightheaded, falls
•fever, chills
•low blood pressure
•nausea, vomiting
•redness, blistering, peeling or loosening of the skin, including inside the mouth
•seizures
•trouble passing urine or change in the amount of urine

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•flushing
•hiccups
•sneezing
•tired

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

This drug is given in a hospital or clinic and will not be stored at home.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

Ethyol(amifostine)

放射線治療與化學治療不論對正常細胞或癌細胞都無選擇性，因此在癌細胞被消滅的同時，正常細胞亦遭受池魚之殃，病人常見治療後有口腔潰瘍、食慾不振、腹瀉、落髮及白血球、血小板下降等副作用，甚至引發其他可致命的併發症。副作用往往也限制了治療劑量的給予，影響了療效；部份副作用可以靠改變給藥方法予以減輕，如分散或長時間給藥，或以局部給藥方式，像腹膜內或動脈化療，讓高濃度的藥物只局限於病灶所在，不致引發全身性的副作用；或待藥物作用時間過後，馬上給予某種拮抗藥物（解毒劑），減除抗癌藥部份細胞殺傷力。然而上述方法，並無選擇性，只能稍減對正常細胞的毒性，相對地癌細胞的療效也被打折扣，另外的解決之道即是迅速治療發生的副作用，儘量降低傷害的程度，如白血球生成素及強效止吐劑的注射，但此種作法，亦只可部份減輕已形成的副作用，並無預防的功效。因此抗癌治療的毒性一向為病患所詬病，醫師對抗癌治療可說是既愛又恨，療效與零副作用猶同魚與熊掌，不可兼得。又腫瘤形成後，癌細胞不斷滋生，經由淋巴管及血管蔓延各處，族群越來越複雜，最後生出有抗藥性的細胞群，此時腫瘤即到達無法根治的地步，任何治療皆告無效；故抗癌治療藥物的毒性與放射線治療無法有效控制腫瘤滋生蔓延，是目前治癌無法奏全功的絆腳石。

當病患接受頭頸部放射線照射治療劑量在50格雷以上時，將會發生不可逆之嚴重副作用乾口症和口腔黏膜發炎，這也是要達到治療鱗狀上皮細胞癌最低之有效劑量 。
當乾口症（Xerostomia）發生時將會影響到：
(1).臨床醫師使用放射線照射治療無法完成預定之療程不僅未能達到療效也造成醫療資源之浪費。

(2).病患由於唾液腺遭受到破壞，無法正常分泌唾液，造成說話、飲食之不便，長期生活品質將會大受影響。

部份腫瘤對化學治療有明顯的劑量反應關係，因此可以施行高劑量化療以增加療效，於此同時，亦增加了器官的毒性，自體造血幹細胞移植雖可輔助高劑量化療之進行，但費用高昂，且對化療的非血液細胞副作用於事無補。

為令癌症病患免除或減少副作用，並能完成放射線治療與化學治療之療程，增加療效，Amifostine( Ethyol ,WR-2721)的臨床使用，使抗癌治療邁入新境界。前述正常細胞與癌細胞有幾近相同的代謝機轉，因此對化學或放射治療會產生同樣的傷害反應，這些傷害部份由於自由基所致，故若能使用抗氧化物消除細胞內自由基，即能降低細胞毒性；美國食品藥物管理局（FDA）於1999年核准Amifostine上市，衛生署也於2001年八月底核准Amifostine上市，使用於減少末期卵巢癌或非小細胞肺癌病患接受cisplatin高劑量給藥所引起的累積性腎毒性，以及用於減低因接受包含耳下腺（腮腺）在內之局部放射線治療的頭頸癌病患引起的中度至嚴重度乾口症。Amifostine能使癌症之病患免於放射線治療與化學治療時所引發之嚴重副作用。

Amifostine ，源自二次大戰後之冷戰時期，一九五O年美國軍方為減少核子戰爭士兵之傷亡，從一千四百多種化學物質研究發展出來的一種抗輻射細胞保護劑，此藥物必須經由正常細胞常有的一種鹼性磷酸酵素作用之後，才能轉換成有保護細胞作用的代謝物WR-1065，使細胞不受輻射及化學藥物的傷害，由於癌細胞之鹼性磷酸酵素含量較正常細胞低得多，癌細胞內的血流狀況及較酸環境亦不利鹼性磷酸酵素作用，實驗証明Amifostine注射後，正常細胞內的濃度會比癌細胞高出十倍，因此Amifostine對正常細胞有選擇性的保護作用，但必須於化療或放射治療前15--30分鐘給予。超過半數患者使用Amifostine時會有輕微嘔吐及低血壓現象。

另外化療及電療對正常細胞有致癌及突變效應，Amifostine 的保護作用是否可減少癌症病患日後發生續發癌的機會，則有待長期評估。不過現在已進行之多項試驗証明，Amifostine可提高化療及電療的有效治療劑量，增加反應率，並觀察到Amifostine可以配合其他生長因子，細胞素共同使用，有加成保護造血幹細胞效果。

Amifostine注射後，於正常細胞內的濃度較癌細胞高十倍，包括腎臟、肺臟、肝臟、皮膚、骨髓、腸道及脾臟等，但卻無法存於腦組織、橫紋肌及腫瘤細胞，因此Amifostine對正常細胞有選擇性的保護作用，目前有眾多的人體臨床試驗正進行中，以進一步了解其對各種化療藥物療效的影響與臨床運用，包括常用的化療藥物所引起之腎毒性、耳毒性、神經毒性與骨髓毒性等：

1. 腎毒性與神經毒性： cisplatin, vincristine, paclitaxel及oxaliplatin皆有腎毒性或神經毒性：分別試用於皮膚黑色素瘤、頭頸癌、肺癌、卵巢癌病患
Cisplatin普遍會引起腎臟及神經毒性，尤其在糖尿病或年老患者，對Cisplatin毒性更為敏感，當Amifostine 以740-910 mg /m2的劑量伴隨Cisplatin給予，其10% 的腎毒性發生率，較對照組的36% 顯然低得多。Carboplatin 與Paclitaxel聯合治療目前被認為是卵巢癌的最佳療法，但副作用大，Amifostine 可明顯舒緩治療期間的腎、神經毒性及血小板下降的程度，減少併發症的發生。Oxaliplatin 所引起之神經毒性也有明顯減低之現象。

骨髓毒性：証據顯示Amifostine可減少化療病患紅血球輸血量。此外，使用carboplatin的化療患者，加用Amifostine可減輕血小板下降程度(p<0.001)及減少血小板輸注量(p=0.0l7)。Amifostine亦於卵巢癌進行隨機分配第三相臨床研究結果顯示，使用組較對照組有較輕微的白血球下降程度，較短的使用抗生素天數，及較短的住院日數，顯然使用Amifostine可減輕所產生之化療骨髓毒性。

目前巳有研究評估Amifostine對(MDS) myelodysplasic syndrome的治療效果，研究發現Amifostine 具有刺激骨髓造血之作用，且Amifostine有誘發myelodysplastic 細胞凋零、衰敗之作用。多項實驗證實Amifostine配合其他生長因子，細胞素共同使用，有加成保護造血幹細胞之效果，使用Amifostine 對於MDS之病患建議劑量為200--300mg/m2 ,每週三次 ，連續使用四週-六週，這也是Amifostine有別於保護劑的角色，使用於治療作用，最有潛力之發展方向。

當使用於減輕化療骨髓毒性及供固體癌自體骨髓移植時，可以減輕對幹細胞的傷害，以求縮短此類病患血球恢復期及減低血球減少所導致的併發症。

2. 放射治療毒性：頭頸癌放射治療後引起的乾口症(100％ vs 12% ,P<0.001)及口腔黏膜炎(86％ vs. 0%，P<0.001)，Amifostine可有效降低其發生率，因此有利放射治療反應率的提高，縱使同時併行放射及化學治療的病患亦有減輕毒性的療效，多項多中心隨機雙盲實驗皆有令人滿意之結果。

3. 至於直腸癌及子宮癌放射治療引起的骨盆腔器官毒性如直腸炎，膀胱炎等及胸腔放射治療的食道，肺臟傷害，Amifostine的臨床試驗亦在進行中。
另外化療及電療對正常細胞有突變效應（mutagenic），經由放射化學治療所可能引起的續發性惡性腫瘤，Amifostine除保護作用外，低劑量之Amifostine亦有明顯之抗突變效果，可減少日後發生續發癌的機會。如在暴露於放射線之後三小時內使用Amifostine，便可達到抗突變之效果，並可以運用於與大量放射線有關之工作者，例如於清除核子反應爐內廢棄物之工作人員或發生核電廠意外時，暴露於放射線中之工作人員，使用Amifostine可減少致癌之危險。

由於肺癌、口腔癌、鼻咽癌、卵巢癌等癌症之好發年齡在40至50歲之壯年期，易對社會、經濟、勞動力及家庭造成重大衝擊。所以一個能有效減少病患接受化學治療與放射線治療副作用傷害，同時對於其抗腫瘤療效果沒有影響之藥物是非常重要的。

結論
Amifostine使選擇性的抗癌治療成為可行，除可增加化學治療及放射治療效果外，與其他細胞素的聯合療法更有美好的遠景。因此利用Amifostine保護正常細胞，使之免受抗癌治療的傷害，避免副作用的發生，實在是腫瘤科醫生與病患之福音。