Amifostine in the treatment of head and neck cancer: intravenous administration, subcutaneous administration, or none of the above.

Radiotherapy (RT) exerts most of its effect through ionization of water, which results in the formation of highly reactive free radicals that can damage the DNA. Oxygen binds to short-lived free radical sites in the DNA and fixes the damage, whereas molecules such as sulfhydryl compounds compete with oxygen and reduce free radical activity to exert a protective effect. However, sulfhydryl compounds such as cysteine do not have a preference for protecting normal cells as compared with tumor cells. Amifostine was formed by the addition of a phosphate group to the sulfhydryl compound, resulting in a prodrug activated by membrane-bound alkaline phosphatase, which dephosphorylates the prodrug to its active sulfhydryl molecule. The cellular concentration of alkaline phosphatase is low in tumors, given that the pH of tumors is often lower than that of normal tissues, and this provides a selective mechanism for normal tissue protection in preference to protection of the tumor. Other mechanisms for preferential protection of the normal tissues include increased uptake of the compound by certain organs such as the salivary glands and kidneys. The primary adverse effects of combined chemotherapy and RT for the treatment of head and neck cancer include acute mucositis and dermatitis and late xerostomia and dysphagia. Multiple protecting agents have been developed to ameliorate these effects, although amifostine has the longest track record and largest body of controlled studies that assess its effectiveness. Notably, the landmark study by Brizel et al of patients who were administered postoperative RT demonstrated reduced xerostomia in the amifostine arm. This study gained the drug approval by the US Food and Drug Administration, which was followed by an intensive marketing effort by the drug manufacturer. The main barriers to the widespread use of amifostine have been the logistics of its use and its toxicity. Because of rapid clearance from the blood and tissue, the drug needs to be delivered shortly before RT, preferably before each RT fraction. Intravenous bolus drug administration, used as a standard, causes high rates of adverse effects, including hypotension and nausea, which require close observation. These adverse effects may occur in addition to similar adverse effects that result from concurrent chemotherapy, which is frequently administered to patients with head and neck cancer, and cause a substantial drop in patient compliance. In recent years, the subcutaneous (SC) route of amifostine administration has been promoted as a way to simplify logistics, reduce toxicity, and improve drug bioavailability. In this issue of Journal of Clinical Oncology, Bardet et al report the results of a controlled study of patients with head and neck cancer who received conventional radiotherapy without concurrent chemotherapy and who were randomly assigned to receive amifostine intravenously, 200 mg/m daily before each RT fraction, or subcutaneously, 500 mg before each fraction. The authors reported no difference in compliance; 70% of the patients in each arm received the full amifostine dose, and the remainder discontinued amifostine treatment because of toxicity or logistic issues. No significant difference in xerostomia, the study’s primary end point, was observed between the two arms when all time points were considered, or in other end points relating to RT toxicity, or in tumor control rates. The primary difference between the arms was the nature of amifostine toxicity: higher rates of grade 1 to 2 hypotension were observed in the group that received amifostine intravenously, and higher rates of skin rash and pain at injection sites were observed in the group that received SC amifostine, but no differences were observed in the rates of nausea/vomiting. Given that no overall difference in compliance was found, the authors recommended that the intravenous route should remain the standard mode of amifostine administration. Is this recommendation reasonable? One could argue that if efficacy and patient compliance are equal, the preferred administration route should be the one that offers the most convenience and demands the least personnel, time, and resources. The impression of previous investigators was that SC administration was simpler, did not require blood pressure monitoring throughout the infusion period or the presence of a specialized nurse, resolved logistic problems that had previously limited the number of patients who could be treated daily with amifostine, and was likely to reduce the costs of administering the drug. It is unlikely, therefore, that the study by Bardet et al will change practice patterns, which in recent years have tended to favor the SC route. A more important question related to amifostine is whether we should use it at all in the treatment of advanced head and neck cancer. If controlled studies do show that it substantially reduces acute and late sequelae of therapy without protecting the cancer cells, its use may not only improve patients’ well-being but may also, by improving the tolerance to therapy, reduce treatment breaks, as suggested in one JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 2 JANUARY 1