The article by Drs. Wasserman and
Brizel provides a good overview of the use of 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
(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
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.
1. Hensley ML, Schuchter LM, Lindley C, et al: American
Society of Clinical Oncology clinical practice guidelines for the use of
chemotherapy and radiotherapy protectants. J Clin Oncol 17:3333-3355, 1999.
2. Brizel DM, Wasserman TH, Henke M, et al: Phase III
randomized trial of amifostine as a radioprotector in head and neck cancer. J
Clin Oncol 18:3339-3345, 2000.
3. Kemp G, Rose P, Lurain J, et al: Amifostine pretreatment
for protection against cyclophosphamide-induced and cisplatin-induced
toxicities: Results of a randomized control trial in patients with advanced
ovarian cancer. J Clin Oncol 14:2101-2112, 1996.
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cancer. Ann Oncol 9:505-509, 1998.
5. Erratum. J Clin Oncol 18:4110-4111, 2000.
6. Vikram B, Brizel DM: Letter to the editor and response. J
Clin Oncol 19:1233-1234, 2001.
7. Koukourakis MI, Kyrias G, Kakolyris S, et al: Subcutaneous
administration of amifostine during fractionated radiotherapy: A randomized
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(simultaneous modulated accelerated radiation therapy) boost: A new accelerated
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modulated radiotherapy. Int J Radiat Oncol Biol Phys 45:21-32, 1999.
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J Radiat Oncol Biol Phys 49:907-916, 2001.
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