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Five Year-Survival with High-Dose Melatonin and Other Antitumor Pineal Hormones in Advanced Cancer Patients Eligible for the Only Palliative Therapy

Paolo Lissoni, Franco Rovelli, Fernando Brivio, Giusy Messina, Arianna Lissoni, Sonja Pensato and Giuseppe Di Fede

Cancer progression has appeared at least in part to be due to a deficiency of the mechanisms responsible for the natural antitumor immune response. Moreover, more recent studies have demonstrated that cancer-related immunosuppression does not depend only of alterations of immune cells themselves, but also on an altered neuroendocrine regulation of the antitumor immune response, which is mainly inhibited by the mu-opioid agonists, such as beta-endorphin, and stimulated by the pineal gland through at least three immunostimulating molecules, able to exert a direct antiproliferative anticancer activity without any important biological toxicity, consisting of the indole hormones melatonin (MLT) and the 5-methoxytryptamine (5-MTT), and of the beta-carboline pinealine (PNL). Finally, cancer progression has been shown to be constantly associated with a progressive decline in the endocrine function of the pineal gland, which could be involved in cancer dissemination itself. Then, the simple endocrine oncostatic pineal replacement therapy could counteract cancer growth and enhance the survival time, as suggested by preliminary clinical studies. On the basis, a pineal endocrine regimen was proposed in a group of untreatable advanced solid tumor patients, for whom no other effective standard anticancer therapy was available. The study included 212 patients, suffering from the most common tumor histotypes and eligible for the only best supportive care and with life expectancy less than 1 year. All pineal indoles were given orally at the time corresponding to that of their maximal circadian secretion, every day without interruption until disease progression. MLT was given at pharmacological doses (100 mg/day in the night period), while 5-MTT during the light period and PNL at the onset of the evening were administered at mild-pharmacological doses (5-MTT: 10 mg/day; PNL: 1 mg/day). A disease control (DC) was achieved in 111/212 (52%) patients, with an objective tumor regression in 16/212 (8%), irrespectively of tumor histotype. A 1-year and 5-year percentages of survival were achieved in 46% and 11%, respectively, and there were significantly higher in patients with DC than in the progressed ones. Finally, the evidence of normal pretreatment values of lymphocyte-to-monocyte ratio (LMR) and/or their normalization on therapy have appeared to be associated with most favorable clinical results. No biological toxicity occurred on pineal endocrine oncostatic treatment. This study shows that an endocrine substitutive therapy with the most known antitumor pineal hormones may represent a new non-toxic inexpensive anticancer therapy, which can improve the survival and control cancer growth also in patients for whom no other effective therapy is available, at least to improve their life. By concluding according to their results the palliative therapy of untreatable cancer patients for whom no other standard therapy available could be associated with a concomitant therapy with natural anticancer agents, namely the same pineal hormone.