Clinical Status and Optimal Use of Amifostine Review

Historically, the notion of patients deriving potentially significant benefit from cytotoxic therapy was disparaged because of the presumption that cytotoxic therapies could not distinguish between normal and neoplastic tissues. However, the degree and duration of cytotoxic damage to normal and neoplastic tissue differ sufficiently to allow for clinically meaningful benefits in the palliation and cure of cancer. Whether the goal of therapy is palliation or cure determines the degree of risk and cost that the patient and health care system are willing to accept, since virtually all cytotoxic therapies have a narrow therapeutic index. This toxicity to normal organs not only limits the use and achievement of the full therapeutic potential of cytotoxic agents but also claims a cost in terms of patient morbidity and mortality. Oncologists attempt to mitigate the toxic effects of chemotherapeutic agents by adjusting the dose and frequency of treatment. A major drawback to this strategy is insufficient control of the tumor. A growing area for new drug development is the evolving field of supportive care agents intended to avert or minimize treatment-limiting toxicities to normal organs. Historically, the oldest approach of this type was the use of rescue agents, such as leucovorin “rescue” following high-dose methotrexate. [1] This approach has been useful for the treatment of pharmacologic sanctuaries, such as the central nervous system (CNS),[2] as well as tumors that are relatively resistant to standard doses of methotrexate, such as osteosarcoma. Likewise, the use of marrow-stimulatory cytokines following moderately toxic doses of drugs has been useful. An alternate approach to rescue techniques is the use of cytoprotective agents, or cytoprotectors. These drugs selectively protect normal tissues from the cytotoxic effects of drugs and/or radiation while preserving their antitumor effects. The ideal cytoprotector should be easily administered and should have a broad spectrum of activity; not only should it be able to protect multiple tissues, but also it should protect these tissues from diverse cytotoxic treatments. The agent also should have a reasonable safety profile. By improving patient tolerability to the therapy, the cytoprotector may provide multiple benefits: It may improve patient quality of life; allow for dose-inten-sification and, thus, improved response and/or cure rates; and decrease costs associated with other supportive care measures needed to treat treatment complications. To date, three cytoprotectors have been approved by international regulatory agencies. Mesna (Mesnex) is approved for the protection of the bladder from the toxicity associated with ifosfamide (Ifex) and high-dose cyclophosphamide (Cytoxan, Neosar). [3] Dexrazoxane (Zinecard) is used to protect the heart from the cardiomyopathy associated with the cumulative cardiotoxic effects of doxorubicin. [4] Both of these agents are drugor drug class–specific and their protective effect is limited to specific organs—the urinary bladder for mesna and the heart for dexrazoxane. Amifostine (WR-2721 [Ethyol]) is the first broad-spectrum cytoprotective agent to be approved by international regulatory agencies. In this context, broad spectrum refers to cytoprotection against a broad array of cytotoxic therapies, ie, multiple drug classes as well as radiation, in multiple organ systems. Laboratory and clinical studies have shown that amifostine protects cells in virtually all organ systems except the CNS, which is a target for both acute and cumulative (or delayed) cytotoxic damage. Because of poor tissue distribution pharmacokinetics in the CNS, this organ