Use of melatonin in oncologic practice

Melatonin, a pineal gland hormone, has powerful antioxidant, immunomodulatory and detoxifying effects. Research in recent decades has shown that melatonin has numerous oncostatic properties. Melatonin is involved in cell cycle modulation, apoptosis induction, cell differentiation stimulation, and metastasis inhibition. The hormone has been shown to have inhibitory effects on telomerase activity, linoleic acid transport, a precursor of the mitogenic metabolite 1,3-hydroxyoctadecadienoic acid, and tumor growth factor production. The inhibitory effect of melatonin on tumor angiogenesis is mediated by suppression of vascular endothelial growth factor expression, the most active angiogenic factor. Suppression of MLT initiation and growth of hormone-dependent tumors is believed to be mediated by decreased expression of estrogen receptors and aromatase activity. Increased activity of natural killers, which improves immunological surveillance, and stimulation of cytokine production (IL-2, IL-6, IL-12, IFN-γ) are also apparently involved in the oncostatic effect of the hormone. Clinical trials indicate a limitation of side effects of antitumor treatment and an improvement in survival when using melatonin in cancer patients. The aim of this review was to analyze the experience of using melatonin in cancer patients who received radiation, chemotherapy, or palliative and supportive treatment.

Melatonin and radiotherapy

It is well known that most human tumors are poorly oxygenated due to limitations of perfusion and blood diffusion into the tumor, significant structural and functional abnormalities of intratumor microcirculation, and the development of anemia in cancer patients. Anemia can develop as a result of the oncological process, as well as under the influence of chemo- and radiation therapy. The importance of preventing anemia in cancer patients during radiation therapy is noted. Anemia, which entails hypoxia, leads to a decrease in overall and relapse-free survival and a limitation of locoregional control in various tumors, since it can contribute to a decrease in the sensitivity of tumor cells to radio- and chemotherapy. Melatonin can have a beneficial effect in patients with anemia. The normalizing effect of low doses of melatonin on the level of erythrocytes was noted in healthy individuals, with the most pronounced increase in the number of erythrocytes found in those examined with the lowest initial content. In addition, melatonin exhibits an antiserotonergic effect, which is expressed in limiting the inhibition of blood flow by serotonin. This can lead to an increase in blood flow and restoration of compromised microcirculation in the tumor microenvironment. Improved blood flow to the tumor under the action of melatonin should help overcome radioresistance and increase radiation-induced death of tumor cells.

Clinical experience with melatonin in radiotherapy is very limited, and the results obtained are ambiguous. In our study, melatonin at a dose of 9 mg daily (3 mg at 14:00 and 6 mg 30 min before sleep) prevented the radiation-induced decrease in the number of red blood cells, the fall in the hemoglobin level, and the decrease in the absolute number of lymphocytes in patients with stage II-III endometrial cancer receiving a standard course of radiotherapy. In patients with rectal cancer and cervical cancer who were exposed to pelvic irradiation at a total dose of 50.4 Gy, the use of melatonin alone or melatonin in combination with another pineal hormone, 5-methoxytryptamine, did not significantly limit the development of lymphopenia.

The effect of melatonin on the effectiveness of radiation therapy has also been assessed. In a study by P. Lissoni et al., which included 30 patients with glioblastoma multiforme, the best results were in patients who received radiotherapy (60 Gy) in combination with melatonin (20 mg/day) compared to those who received radiotherapy alone. One-year survival with melatonin use reached 6/14, while in the control group this figure was 1/16 (p < 0.05). P. Lissoni's studies stimulated the conduct of phase II clinical trials RTOG, the purpose of which was to compare the results of total fractional brain irradiation at a total dose of 30 Gy (retrospective control) and irradiation with concomitant melatonin intake in patients with solid tumors metastasizing to the brain. Patients were randomized to receive melatonin (20 mg/day) in the morning or evening. In none of the groups did the survival rates differ significantly from the retrospective control. The average survival in the groups receiving melatonin in the morning and evening was 3.4 and 2.8 months, respectively, while in the control this figure was 4.1 months. The authors suggested that the discrepancy between their results and the data of P. Lissoni may be due to differences in the biological properties of the melatonin used, individual differences in the absorption of the drug with low bioavailability, as well as the non-optimal nature of the selected dose, which justifies the need to study the dose-effect relationship with oral administration of melatonin.

Melatonin and Chemotherapy

Chemotherapy, causing immunosuppressive and cytotoxic effects, has a negative impact on the physiological antitumor defense mechanisms of patients, causes damage to certain healthy organs and tissues, and worsens the quality of life of patients. Clinical studies have shown that melatonin prevents or weakens the development of chemotherapy-induced thrombocytopenia, myelosuppression, neuropathy, cachexia, cardiotoxicity, stomatitis, and asthenia].

Melatonin administration also improves tumor response and increases survival in patients receiving chemotherapy. A positive effect of concomitant administration of melatonin (20 mg/day before bedtime) and the cytostatic drug irinotecan (CPT-11) was observed in a study of 30 patients with metastatic colorectal carcinoma with disease progression after treatment with 5-fluorouracil (5-FU). No patients achieved a complete tumor response, while partial responses were observed in 2/16 patients receiving CPT-11 alone and in 5/14 patients receiving CPT-11 and melatonin. Disease stabilization was observed in 5/16 patients receiving CPT-11 alone and in 7/14 patients receiving additional melatonin. Thus, disease control in patients whose therapy included melatonin was significantly higher than that observed with treatment with CPT-11 alone (12/14 vs. 7/16, p < 0.05)].

An early study by P. Lissoni noted that in patients with advanced non-small cell lung cancer (NSCLC) who took melatonin (20 mg daily in the evening), cisplatin and etoposide, the one-year survival rate was significantly higher compared to this indicator in patients who received only chemotherapy. A later study found that 6% of patients with this disease who received similar treatment achieved 5-year survival, while in the group of patients who received only chemotherapy, survival did not exceed 2 years.

A randomized study by P. Lissoni demonstrated the positive effect of concomitant melatonin (20 mg daily) on the efficacy of several chemotherapeutic combinations in 250 patients with advanced solid tumors with poor clinical status. The one-year survival rate and objective tumor regression were significantly higher in patients receiving chemotherapy and melatonin compared to those receiving chemotherapy alone.

A recent study of 150 patients with metastatic NSCLC showed that the tumor response rate was significantly higher in patients treated with cisplatin and gemcitabine in combination with melatonin (20 mg/day in the evening) compared with patients who received chemotherapy alone (21/50 vs. 24/100, p < 0.001). The authors noted that patients with spiritual faith had a higher objective tumor regression rate than other patients who received chemotherapy and concomitant melatonin treatment (6/8 vs. 15/42, p < 0.01).

A randomized trial of 370 patients with metastatic NSCLC and gastrointestinal tumors evaluated the effects of melatonin (20 mg/day orally in the evening) on the efficacy and toxicity of several chemotherapeutic combinations. NSCLC patients received cisplatin and etoposide or cisplatin and gemcitabine. Colorectal cancer patients received oxaliplatin and 5-FU, or CPT-11, or 5-FU and folate (FA). Gastric cancer patients received cisplatin, epirubicin, 5-FU and FA, or 5-FU and FA. Overall tumor regression and 2-year survival were significantly higher in patients concomitantly treated with melatonin than in patients receiving the chemotherapeutic combinations alone.

Improved treatment outcomes with melatonin were observed in a study involving 100 patients with unresectable advanced primary hepatocellular carcinoma. Patients underwent transcatheter arterial chemoembolization (TACE) alone or in combination with melatonin. The 0.5, 1, and 2-year survival rates in the TACE group were 82, 54, and 26%, respectively, while in the TACE and melatonin group these rates increased to 100, 68, and 40%, respectively. Melatonin was associated with increased tumor resectability. Two-stage resection was performed in 14% (7/50) of patients after TACE in combination with melatonin and only 4% (2/50) after TACE. In patients treated with TACE and melatonin, an increase in IL-2 levels was observed, indicating the contribution of the immunostimulatory function of melatonin to the increased therapeutic response in this group of patients.

Increased tumor response was also observed in patients with metastatic melanoma with disease progression after receiving dacarbazine and interferon-a. Melatonin was used in combination with low doses of IL-2 and cisplatin. Objective tumor response was observed in 31% (4/13) of patients. Disease stabilization was noted in 5 patients.

Thus, the use of melatonin helps to reduce toxicity and increase the effectiveness of chemotherapeutic regimens in patients with various nosological forms of oncological diseases.

Melatonin in palliative care

Patients with advanced cancer are characterized by multisymptoms. The most common symptoms are pain, fatigue, weakness, anorexia, dry mouth, constipation and weight loss of more than 10%. Melatonin, exhibiting such biological activities as anticachectic, antiasthenic, thrombopoietic, can be useful in the palliative treatment of cancer patients.

A study of 1440 patients with advanced solid tumors showed that the incidence of cachexia, asthenia, thrombocytopenia, and lymphocytopenia was significantly lower in patients receiving melatonin (20 mg/day orally at night) and supportive care than in those receiving supportive care alone.

It is believed that the beneficial effect of melatonin in cachexia may be mediated by its effect on the levels of proinflammatory cytokines involved in the development of cachexia. A study of 100 patients with advanced solid tumors showed that weight loss of more than 10% was significantly less frequent in patients receiving maintenance therapy in combination with melatonin compared with those receiving maintenance therapy alone. At the same time, the level of tumor necrosis factor was significantly lower (p < 0.05) in patients receiving melatonin.

Melatonin, even in the absence of antitumor efficacy, is thought to have significant benefit in improving sleep in cancer patients. Breast cancer patients who received melatonin for 4 months after completion of antitumor treatment showed improvements in sleep quality and duration compared to those receiving placebo.

In patients with advanced cancer who had failed to respond to previous standard anticancer treatment or for whom this treatment was contraindicated, melatonin treatment also had a beneficial effect on tumor response and survival, as demonstrated by the results of randomized, controlled trials.

In a study of 63 patients with metastatic NSCLC that had progressed on first-line chemotherapy (cisplatin), treatment with melatonin (10 mg/day orally at 7:00 p.m.) resulted in disease stabilization and increased one-year survival compared with maintenance therapy alone. Improvement in overall health was also noted in the melatonin-treated group.

In patients with unresectable brain metastases from solid tumors, melatonin (20 mg/day at 8:00 p.m.) increased one-year, relapse-free, and overall survival compared with patients receiving maintenance therapy with steroids and anticonvulsants.

Positive results have been obtained in the treatment of patients with advanced melanoma with melatonin. In a small study of 30 melanoma patients who had undergone surgery for metastases to regional lymph nodes, daily melatonin (20 mg/day orally in the evening) resulted in increased relapse-free survival compared with controls.

Patients with refractory metastatic tumors, in whom the use of melatonin led to disease control, had a statistically significant decrease in the number of immunosuppressive T-regulatory cells, normalization of the cortisol rhythm, and a decrease in the secretion of vascular endothelial growth factor.

An increase in the treatment efficacy of patients with advanced cancer was observed when using melatonin in combination with IL-2. In such patients, melatonin potentiated the immunostimulatory properties of IL-2, increasing the number of T lymphocytes, NK cells, CD25+ cells and eosinophils. Melatonin significantly increased IL-2-induced lymphocytosis in patients with metastatic solid tumors. It is also reported that melatonin is able to counteract the negative effect of morphine on the clinical efficacy of IL-2. In patients with advanced renal cell carcinoma chronically receiving morphine, the use of melatonin increased the antitumor efficacy of IL-2 immunotherapy, significantly increasing the 3-year survival of patients. Information is also provided on the limitation of melatonin side effects caused by the use of IL-2. In patients with metastatic renal cell carcinoma who received thirty-three 5-day courses of IL-2 at a dose of 3 million IU/m2 daily and MLT (10 mg/day orally at 8:00 p.m.), there was a decrease in the frequency of episodes of severe hypotension and depressive symptoms compared with patients receiving IL-2 alone. In patients with advanced solid tumors with persistent thrombocytopenia who received IL-2 together with melatonin, normalization of platelet counts was observed in 70% of cases. With IL-2 alone, a decrease in platelet count was observed associated with destruction of peripheral platelets due to activation of the macrophage system by IL-2.

In patients with locally advanced or widespread solid tumors (excluding melanoma and renal cell carcinoma), comparison of IL-2 (3 million IU/day at 8:00 p.m., 6 days/week for 4 weeks) and IL-2 plus melatonin (40 mg daily at 8:00 p.m., starting 7 days before IL-2 injections) revealed a higher objective tumor regression in patients treated with IL-2 and melatonin than in those receiving IL-2 alone (11/41 vs. 1/39, p < 0.001). This group of patients also had a higher one-year survival rate (19/41 vs. 6/39, p < 0.05).

An increase in one-year survival with IL-2 therapy (3 million IU/day, 6 days/week for 4 weeks) and melatonin (40 mg/day) compared with the survival of patients receiving only maintenance therapy was noted in patients with metastatic colorectal cancer that progressed after treatment with 5-FU and FC (9/25 versus 3/25, p < 0.05).

A comparison of the results of therapy including IL-2 (3 million IU/day for 4 weeks) and melatonin (40 mg/day) and maintenance therapy was performed in 100 patients with solid tumors for whom standard antitumor treatment was contraindicated. Partial tumor regression was observed in 9/52 (17%) patients receiving immunotherapy and in none of the patients receiving maintenance therapy. Those treated with IL-2 and melatonin also had higher rates of one-year survival (21/52 vs. 5/48, p < 0.005) and improved overall condition (22/52 vs. 8/48, p < 0.01).

Improved tumor response and increased 3-year survival were demonstrated in a large-scale study that included 846 patients with metastatic solid tumors (NSCLC or gastrointestinal tumors) randomized to receive maintenance therapy alone, maintenance therapy and melatonin (20 mg/day, orally in the evening), or melatonin and IL-2 (3 million IU/day subcutaneously, 5 days/week for 4 weeks). The best results were seen in the group receiving melatonin and IL-2 along with maintenance therapy.

Results from small non-randomized studies have also shown the efficacy of melatonin in combination with IL-2 in patients with solid, hematological, and endocrine malignancies.

The beneficial effects of melatonin in cancer patients who received chemo-, radio-, supportive or palliative therapy are confirmed by the results of meta-analyses.

Thus, a meta-analysis of 21 clinical trials of the effectiveness of melatonin treatment for patients with solid tumors showed a reduction in the relative risk (RR) of one-year mortality by an average of 37%. An improvement in the effect was noted in relation to complete and partial tumor responses, as well as disease stabilization. The RRs were 2.33 (95% confidence interval (CI) = 1.29-4.20), 1.90 (1.43-2.51), and 1.51 (1.08-2.12), respectively. Analysis of the results of treatment in which the use of melatonin was combined with chemotherapy showed a decrease in one-year mortality (RR = 0.60; 95% CI = 0.54-0.67) and an increase in the number of complete and partial responses and disease stabilization. The pooled ORs were 2.53 (1.36–4.71), 1.70 (1.37–2.12), and 1.15 (1.00–1.33), respectively.

Summarizing the presented positive results of the use of melatonin alone and in combination with IL-2 in the practice of treating cancer patients, it is necessary to note the importance of further studies of neuroendocrine and immune disorders involved in the control of neoplastic growth, for the development of new combination strategies using such a polyfunctional compound as melatonin, as well as other pineal hormones, the biological activity of which has been studied much less.

PhD in Medicine P. P. Sorochan, I. S. Gromakova, PhD in Medicine N. E. Prokhach, PhD in Biology I. A. Gromakova, M. O. Ivanenko. Use of Melatonin in Oncology Practice // International Medical Journal - No. 3 - 2012