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Subcutaneous Administration of Amifostine During Fractionated Radiotherapy: A Randomized Phase II Study

From the Department of Radiotherapy/Oncology and Medical Oncology, University Hospital of Iraklion, and Tumour and Angiogenesis Research Group, Iraklion, and Schering Plough SA, Agiou Dimitriou, Alimos, Greece.

Address reprint requests to Michael I. Koukourakis, MD, Tumour and Angiogenesis Research Group, 18, Dimokratias Avenue, Iraklion 71306, Crete, Greece; email targ{at}her.forthnet.gr

PURPOSE: Amifostine (WR-2721) is an impotant cytoprotective agent. Although intravenous administration is the standard route, pharmacokinetic studies have shown acceptable plasma levels of the active metabolite of amifostine (WR-1605) after subcutaneous administration. The subcutaneous route, due to its simplicity, presents multiple advantages over the intravenous route when amifostine is used during fractionated radiotherapy.

PATIENTS AND METHODS: Sixty patients with thoracic, 40 with head and neck, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled onto a randomized phase II trial to assess the feasibility, tolerance, and cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine 500 mg, diluted in 2.5 mL of normal saline, was injected subcutaneously 20 minutes before each radiotherapy fraction.

RESULTS: The subcutaneous amifostine regimen was well tolerated by 85% of patients. In approximately 5% of patients, amifostine therapy was interrupted due to cumulative asthenia, and in 10%, due to a fever/rash reaction. Hypotension was never noted, whereas nausea was frequent. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (P < .04). The delays in radiotherapy because of grade 3 mucositis were significanly longer in the group of patients treated with radiotherapy alone (P < .04). Amifostine significantly reduced the incidence of acute perineal skin and bladder toxicity (P < .0006).

CONCLUSION: Subcutaneous administration of amifostine is well tolerated, effectively reduces radiotherapy’s early toxicity, and prevents delays in radiotherapy. The subcutaneous route is much simpler and saves time compared with the intravenous route of administration and can be safely and effectively applied in the daily, busy radiotherapy practice.

This study was designed, analyzed, interpreted, and financially supported by the Tumour and Angiogenesis Research Group, Crete, Greece. Schering-Plough SA and U.S. Bioscience provided financial support.

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