Treatment of Human Metastatic Malignant Melanoma with High Dose Oral Melatonin

Abstract

Cutaneous malignant melanoma (MM) is the most rapidly increasing cancer in Caucasians throughout the world(1,2). The cause of the current epidemic is increasing exposure to ultraviolet light in the form of sunshine that has occurred over the past 50 years from changes in clothing habits and lifestyle (3,4). Most MM develop in pre-existing nevi, primarily in sun exposed sites, in fair skinned, blue eyed, brown haired, upper middle class Caucasians who work indoors but spend large amounts of time outdoors in leisure time activities (5,6). Unlike cancers beginning in the epithelial skin, which usually remain localized, MM spreads rapidly from the primary site to other parts of the body via the blood and lymphatic systems. Early surgical excision may be curative but once the disease has spread beyond regional lymph nodes no form of therapy has been shown to be of consistent and long lasting benefit. Based on current figures 20 to 30% of all persons currently diagnosed with MM will develop metastatic disease, and most if not all, will die as a direct consequence. Numerous forms of therapy have, or are, being tried including chemo and immunotherapy, vaccines and recently gene therapy (7,8,9). All have some limited effect but most patients eventually develop brain metastases and no therapy has been shown to significantly prolong life when this occurs (10). With this background we have begun to seek new and novel agents for the treatment of metastatic MM. Melatonin has been previously examined as a possible anti-neoplastic agent by a number of investigators, including ourselves (11,12,13). In-vitro melatonin has been shown to suppress the growth of cancer cells, including MM (12). Likewise in animal models of MM, administration of melatonin has been shown to delay disease progression and death (13). Melatonin, both alone and with other agents, has been used to treat a variety of human cancers with variable results, but generally low response rates (11,14). We previously reported on a phase 1, dose escalation trial of oral melatonin in patients with metastatic cutaneous and ocular MM(11). In this initial trial there was little toxicity, even at very high daily doses of oral melatonin, and occasional patients appeared to have minor responses with partial regression of metastatic disease. No dose response curve was noted in this study. Patients receiving very high doses (700mg per M2) were no more likely to respond than those receiving much lower doses. We therefore elected to carry out a further study using a fixed dose of oral melatonin (200mg orally per day) in a larger group of patients with metastatic MM to determine more precisely the possible therapeutic benefit and toxicity. The results of this study are reported here.