Randomized Phase II Trial of High-Dose Melatonin and Radiation Therapy for RPA Class 2 Patients With Brain Metastases (RTOG 0119)

Abstract

Backround-RTOG 0119 was a Phase II randomized trial for RTOG RPA Class 2 patients with brain metastases to determine if high-dose melatonin improves survival over historical controls, and to determine if the time of day melatonin was given affects its toxicity or efficacy.Methods-RTOG RPA class 2 patients with brain metastases were randomized to 20 mg of melatonin given either in the morning (8-9 am) or evening (8-9 pm). All patients received radiation therapy (30 Gy in 10 fractions) in the afternoon. Melatonin was continued until neurological deterioration or death. The primary endpoint was overall survival time. Neurological deterioration as reflected by the Mini-Mental Status Exam was also measured.Results-Neither of the randomized groups had survival distributions that differed significantly from the historic control of patients treated with whole brain radiotherapy The median survivals of Corresponding Author: Lawrence Berk, MD, PhD, Radiation Oncology, Moffitt Cancer Center at Tampa General Hospital, 2 Columbia Dr., Tampa, FL 39606, E-mail: Berklb@moffitt.usf.edu. No conflicts of interest All patients gave IRB approved informed consent prior to enrolling on this trial.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access IntroductionMelatonin, an indoleamine molecule (N-acetyl, 5-methoxytryptamine) plays an important role in a number of processes including circadian rhythm regulation, sleep disorders, seasonal reproduction, retinal physiology, immune function, intermediary metabolism (1,2) and carcinogenesis. (3) It is also a highly efficient and potent free radical scavenger/antioxidant molecule and physiological blood levels of correlate with the total antioxidant capacity of the serum. (4) Oral ingestion of microgram amounts of melatonin results in near physiological nocturnal blood levels of melatonin. (5,6) The oral bioavailability of milligram doses of oral melatonin from nutritional supplements is about 15% (7) and results in supra-physiological melatonin levels.Numerous studies have demonstrated that physiological and pharmacological blood concentrations of melatonin inhibit tumorigenesis in a variety of in vivo and in vitro experimental models of neoplasia. (6,8,9) A preliminary study demonstrated that pretreatment of rats bearing hepatomas, for two weeks prior to a single dose of radiation administered just prior to lights off, with a non-tumor inhibiting dose of melatonin also given just before lights off, had a marked radiosensitizing effect. Pretreatment of tumor-bearing rats with AM doses of melatonin were ineffective. (10) The gre...

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Treatment of Radiation Injury

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