The Role of Amifostine as a Radioprotector

The article by Drs. Wasserman and Brizel concludes that protection of normal tissue from side effects due to radiotherapy will permit dose escalation and improve therapeutic efficacy and treatment outcomes. Although this concept is sound in principle, its generalized clinical application hinges critically on two controversial issues associated with the use of all putative radioprotective agents: (1) the extent of a reduction in normal tissue side effects afforded in a variety of dose-limiting normal tissues, and (2) the potential for tumor protection. Modulation of Radiation Response Although a great deal of effort has been expended on various approaches to sensitizing tumors to radiotherapy, attempts to protect normal tissue from ionizing radiation damage have focused primarily on sulfhydryl-containing compounds.[1] A lead agent initially developed at the Walter Reed Army Institute of Research (WR-2721) and subsequently known as amifostine (Ethyol) protects against sparsely ionizing radiation predominantly by scavenging free radicals.[1,2] The extent of this radioprotection is strongly dependent on oxygen concentration, because the active metabolite of amifostine and oxygen compete for free radicals.[2] Indeed, in a series of elegant preclinical studies, Denekamp et al[3] clearly demonstrated that amifostine protection in vivo is maximal at intermediate levels of oxygen. While the effective scavenging of free radicals offers an attractive model for the protective action of agents like amifostine, this explanation is likely to be an oversimplification, with other complex factors undoubtedly being involved.[1,4] Protection of Normal Tissues Preclinical investigations have shown that, in general, amifostine offers good protection to the hematopoietic system and salivary glands (protection factors near 3), intermediate protection to organs such as the kidneys and lungs (protection factors 1-2), and no protection to the central nervous system.[1,4] In addition to this intertissue variability, the extent of amifostine protection within normal tissues varies. The nature of the variability is uncertain, but factors such as differences in tissue oxygen tensions as well as amifostine distribution and pharmacodynamics may be involved.[2,5] As discussed by Drs. Wasserman and Brizel, the use of amifostine may reduce the side effects of radiotherapy alone or in combination with chemotherapy in a number of clinical settings. In the largest study to date—a phase III randomized trial in head and neck cancer—Brizel et al[6] reported that patients who received amifostine had reductions in both acute xerostomia of grade 2 or greater (78% vs 51%, P < .0001) and chronic xerostomia of grade 2 or greater (57% vs 34%, P < .002). Median saliva production was also greater in patients treated with amifostine. However, no reduction in radiation-induced mucositis was seen. Long-term xerostomia is associated with difficulty in maintaining a normal diet and an increased risk of dental caries. Amifostine is clearly an option that may reduce the likelihood and severity of xerostomia and, thereby, improve quality of life. Another alternative is to reduce the treatment volume with conformal radiation therapy approaches. Intensity-modulated radiation therapy and three-dimensional radiation therapy techniques may not only reduce the incidence of acute and chronic xerostomia, but may also reduce the likelihood of other acute and late adverse events. Therapeutic Index The question of selectivity lies at the heart of the matter when discussing the use of radioprotectors in cancer treatment. In the early 1980s, this issue sparked a firestorm of scientific debate.[7,8] Almost 20 years later, concerns that amifostine may protect tumors from the effects of radiation have not been unequivocally alleviated. While some preclinical data—particularly those obtained from trials using large single-drug doses—may be brought to question, results reported in studies in which