The article by Drs. Wasserman and Brizel provides a good overview of the use of amifostine(Drug information on amifostine) as a radioprotector. As a broad class of agents, radioprotectors are used with two goals in mind. If local control of the tumor is adequate, a radioprotector can decrease toxicity, thereby allowing the patient to complete therapy with fewer acute and late complications. If local control of the tumor is poor, a radioprotector can protect normal tissue while allowing the radiation dose and, hopefully, tumor control to be increased. In the latter situation, equivalent acute toxicity would be an acceptable trade-off for enhanced local control. To date, most clinical trials of radioprotectors have focused on the former use.
Tumor Protection vs Control
A concern about the use of chemical radioprotectors is that they may protect the tumor in addition to normal tissue, leading to a decrease in local control. To achieve a therapeutic gain with a radioprotector, there must be a differential effect in tumor vs normal tissue. Membrane-bound alkaline phosphatase converts amifostine (Ethyol) to its active form, and normal tissue contains higher levels of this enzyme compared to tumor tissue. In addition, tumor tissue tends to be acidic (which decreases the activity of alkaline phosphatase) and is hypovascularized (which decreases the delivery of amifostine). These mechanisms result in greater accumulation of the active form of amifostine (and thus, more protection) in normal tissue compared to tumor.
Clinically, there is no evidence that the use of amifostine results in tumor protection,[2,3] although the reported trials may not have had sufficient power to detect a small decrease in tumor control secondary to the protective effects of amifostine. In some studies, survival actually increased in the amifostine arm, although the difference was not statistically significant.[2,4] It is possible that the slight gain in control was secondary to a decrease in treatment interruptions in the amifostine arm.
Use in Head and Neck Cancer
In development for over 40 years, amifostine received Food and Drug Administration (FDA) approval for use as a protectant against cisplatin(Drug information on cisplatin) (Platinol)-induced renal toxicity in ovarian and non-small-cell lung carcinoma and against radiation-induced xerostomia in the postoperative treatment of head and neck carcinomas, where the radiation port includes a substantial portion of the parotid gland. In the drug insert, the warning section advises caution regarding the use of amifostine in other tumor systems, in the definitive treatment of head and neck carcinoma, in chemoradiation regimens, and in hyperfractionation regimens.
For head and neck carcinomas, should the use of amifostine be limited to the postoperative setting? In the study by Brizel et al, 102 of 303 patients were treated with definitive radiation, and although survival and local control were not reported in this subgroup of patients, there was no difference in these parameters based on the use of amifostine for the group as a whole. In a small, phase II randomized study by Buntzel et al, 13 of 39 patients were treated definitively with chemoradiotherapy, and no reduction in disease control was reported.