Clarification on the Potential of Subcutaneous Ethyol as a Radioprotective Agent
Authors: Karen D. Godette, Charles R. Thomas, Michael I. Koukourakis
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.5.1582 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11230504 Clarification on the Potential of Subcutaneous Ethyol as a Radioprotective Agent Karen D. GodettexKaren D. GodetteSearch for articles by this author , Charles R. Thomas JrxCharles R. Thomas JrSearch for articles by this author Michael I. KoukourakisxMichael I. KoukourakisSearch for articles by this author Show More Winthrop Cancer Center, Emory University School of Medicine, Atlanta, GAUniversity of Texas Health Science Center at San Antonio, San Antonio Cancer Institute, San Antonio, TXUniversity of Thessalia, Larisa, Greece https://doi.org/10.1200/JCO.2001.19.5.1582 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01032001In Reply:We thank Drs Thomas and Godette, as well as the Editor-in-Chief of the Journal of Clinical Oncology, for giving us the opportunity to clarify some points related to the subcutaneous administration of amifostine.1The dose of 500 mg of amifostine powder, contained in one vial of the commercially available drug for intravenous administration, can be well dissolved in 2 mL of normal saline, giving a transparent homogeneous solution within 1 minute. In 2.5 mL of normal saline, the drug is rapidly dissolved in seconds. If the volume of the normal saline is decreased to less than 2 mL, the drug can no longer be dissolved.Although the pharmacokinetics of amifostine after intravenous administration have been well studied,2 the pharmacokinetics of the subcutaneous administration of the drug are quite unclear. The only data available were reported in an abstract presented at the 1997 annual meeting of the American Society of Clinical Oncology.3 Shaw et al examined the blood levels of WR-2721 and of the active metabolite WR-1065 in 12 males with myelodysplastic syndrome. Subcutaneous administration of 500 mg of amifostine resulted in area under the curve values that could be obtained after the intravenous administration of 250 to 300 mg of amifostine. WR-1065 area under the curve values from both routes of administration were found not to be statistically different. Unfortunately, this study has not been published, nor have other related studies, and I think it would be an excellent opportunity for the Editor-in-Chief of the Journal to kindly invite Dr Shaw’s comments on the pharmacokinetics of subcutaneous amifostine. I do believe, however, that plasma pharmacokinetics, although of value, should not be used to create isoeffect formulas between intravenous and subcutaneous administration of the drug. What is important for cytoprotection is the final amount of the thiol and of disulphide groups accumulated intracellularly at the time of irradiation (20 minutes after administration). Experimental or phase I studies using this end point are not available. If the subcutaneous route is meant to find a place in clinical practice, the pharmaceutical companies responsible for the drug should support the conduct of such studies.Concerning the incidence of hypotension, none of the more than 200 patients treated up to now in my department with radiotherapy or chemoradiotherapy supported with subcutaneous administration of amifostine experienced higher than grade 1 hypotension. In fact, there is no need for blood pressure measurement if amifostine is given subcutaneously at a dose of 500 mg. My limited experience with subcutaneous administration of 1,000 mg of amifostine during hypofractionated radiotherapy also shows that clinical hypotension never occurs even at this high dose level. Our standard practice is to measure blood pressure before and after subcutaneous administration of amifostine, once every week. We also keep in mind that, although of limited clinical relevance, amifostine may increase the incidence of orthostatic hypotension. The radiographers responsible for the treatment of these patients are informed of this potential event, and patients are kept in a siting position for 1 minute after the end of their daily radiotherapy before they are allowed to exit the treatment room.Some of our patients treated with subcutaneous amifostine are being treated with medication for hypertension. We recommend that all patients continue their standard antihypertension therapy during their radiotherapy/amifostine treatment. Our experience shows no evidence that the hypotension expected due to amifostine (given either subcutaneously or intravenously at doses of 500 to 1,000 mg) is aggravated by the concomitant intake of standard antihypertensive medication. Although patients with severe cardiovascular diseases were excluded from the phase II study reported, six patients treated up to now also had a history of cardiac infarction (1 to 8 years before radiotherapy), and five suffered from chronic obstructive pulmonary disease. All patients received the regimen without any cardiovascular or pulmonary complications related to amifostine administration.Subcutaneous administration of amifostine does indeed simplify the administration of this important drug during radiotherapy. A pharmacoeconomic study is ongoing to assess the cost benefit from such an approach versus the intravenous route. Pure phase III trials that recruit patients with homogeneous tumoral entities and uniform radiotherapy schemes are required to confirm our preliminary encouraging findings. The role of subcutaneous administration of amifostine in the feasibility of aggressive chemoradiotherapy combinations with novel drugs4 or in the application of altered fractionation schemes5 is also a field of research that may reveal another important role of amifostine as an agent that enhances the efficacy of radiotherapy by allowing the application of highly effective schemes, still impossible to apply without cytoprotection.1. Koukourakis MI, Kyrias G, Kakolyris S, et al: Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized phase II study. J Clin Oncol 18:: 2226,2000-2233, Link, Google Scholar2. Shaw L, Turrisi A, Glover DJ, et al: Human pharmacokinetics of WR-2721. Int J Radiat Oncol Biol Phys 12:: 1501,1986-1504, Crossref, Medline, Google Scholar3. Shaw L, Brown W, Schein P, et al: A phase I study comparing bioavailability of intravenous and subcutaneous administration of amifostine (Ethyol). Proc Am Soc Clin Oncol 16:: 250A,,1997 (abstr 883) Google Scholar4. Koukourakis MI: Subcutaneous injection of Ethyol: An alternative route of administration, in Abstract Book of a Satellite Symposium: Advances in Radiation Oncology. Presented at the 19th Annual Meeting of the European Society for Therapeutic Radiology and Oncology, Istanbul, Turkey, 2000 (abstr) Google Scholar5. Bourhis J, De Crevoisier R, Abdulkarim B, et al: A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 46:: 1105,2000-1108, Crossref, Medline, Google Scholar