The use of melatonin in cancer practice

Melatonin, a hormone of the pineal gland, has powerful antioxidant, immunomodulating and detoxifying effects. Studies of recent decades indicate that melatonin is inherent in numerous oncostatic properties. Melatonin is involved in modulation of the cell cycle, induction of apoptosis, stimulation of cell differentiation, suppression of metastasis. The inhibitory effects of the hormone on telomerase activity, the transport of linoleic acid, the precursor of the mitogenic metabolite of 1,3-hydroxyoctadecadienoic acid, the production of tumor growth factors have been noted. The inhibitory effect of melatonin on tumor angiogenesis is mediated by the suppression of endothelial vascular growth factor expression, the most active angiogenic factor. Suppression of MLT initiation and growth of hormone-dependent tumors is believed to be mediated by a decrease in the expression of estrogen receptors and aromatase activity. Increasing the activity of natural killers, which improves immunological surveillance, and stimulation of cytokine production (IL-2, IL-6, IL-12, IF-y) is also evidently involved in the oncostatic action of the hormone. Clinical trials suggest limiting the side effects of antitumor treatment and improving survival with melatonin in cancer patients. The purpose of this review was to analyze the experience of using melatonin in cancer patients who received radiation, chemotherapeutic or palliative and supportive treatment.

Melatonin and radiotherapy

It is well known that most human tumors are poorly oxygenated due to the limitations of perfusion and diffusion of blood in the tumor, significant structural and functional anomalies of intracelastic microcirculation, and the development of anemia in cancer patients. Anemia can develop both as a result of the oncological process, and under the influence of chemo- and radiation therapy. They note the importance of preventing anemia in cancer patients during radiation therapy. Anemia, which leads to hypoxia, leads to a reduction in overall and disease-free survival and the restriction of locoregional control in different tumors, since it can contribute to reducing the sensitivity of tumor cells to radio and chemotherapy. Melatonin can have a beneficial effect in patients with anemia. 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 red blood cells found in the surveyed with the lowest initial content. In addition, melatonin shows an antiserotonergic effect, which is expressed in limiting the inhibition of blood flow by serotonin. This can lead to increased blood flow and recovery of compromised microcirculation in the tumor microenvironment. Improving the blood flow to the tumor with the action of melatonin should help to overcome the radioresistance and increase the radiation-induced death of tumor cells.

The experience of clinical use of melatonin in radiotherapy is very limited, and the results are ambiguous. In our study, the use of melatonin 9 mg daily (3 mg at 14:00 and 6 mg 30 minutes before sleep) prevented the radiation-induced decrease in the number of red blood cells, a drop in hemoglobin level, and a decrease in the absolute number of lymphocytes in patients with uterine cancer of stage II-III who received a standard course of radiotherapy. In patients with rectal cancer and cervical cancer who underwent irradiation of the pelvic region in 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 radiotherapy has also been evaluated. In a study by P. Lissoni et al., Which included 30 patients with a multiform glioblastoma, the best results were in patients receiving radiotherapy (60 Gy) in combination with melatonin (20 mg / day), compared with those receiving radiotherapy alone. The annual survival rate with melatonin was 6/14, while in the control group this was 1/16 (p <0.05). The research of P. Lissoni stimulated the clinical trials of the second phase of 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 administration 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, survival rates were significantly different from retrospective control. The average survival rate in the groups receiving melatonin in the morning and in the evening was 3.4 and 2.8 months, respectively, while in the control this indicator was 4.1 months. The authors suggested that the discrepancy between their results and P. Lissoni's data may be due to differences in the biological properties of the melatonin used, the individual differences in absorption of the drug having low bioavailability, and the nonoptimality of the chosen dose, which justifies the need for investigating the dose-effect relationship in the oral administration of melatonin.

Melatonin and chemotherapy

Chemotherapy, causing immunosupressive and cytotoxic effect, has a negative effect on the physiological antitumor protective mechanisms of patients, causes damage to certain healthy organs and tissues, 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, asthenia].

The use of melatonin also contributes to improving the tumor response and improving survival in patients receiving chemotherapy. A positive effect of simultaneous administration of melatonin (20 mg / day before sleep) and a cytotoxic drug irinotecan (CPT-11) was noted in a study that included 30 patients with metastatic colorectal carcinoma with progression of the disease after treatment with 5-fluorouracil (5-FU). A complete tumor response was not observed in any of the patients, while a partial response was noted in 2/16 patients receiving only CPT-11, and in 5/14 patients receiving CPT-11 and melatonin. Stabilization of the disease was noted in 5/16 patients receiving only CPT-11, and in 7/14 patients receiving additional melatonin. Thus, the control of the disease in patients in which melatonin was included was significantly higher than that observed in the treatment of only CPT-11 (12/14 versus 7/16, p <0.05)].

In an early study by P. Lissoni, it was 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 annual survival was significantly higher than that in patients who received only chemotherapy. A later study found that 6% of patients in this nosology who received similar treatment achieved a 5-year survival rate, whereas in the chemotherapy-only group, the survival did not exceed 2 years.

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

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

In a randomized trial involving 370 patients with metastatic NSCLC and gastrointestinal tumors, the effect of melatonin (20 mg / day, per os, daily in the evening) on the efficacy and toxicity of several chemotherapeutic combinations was evaluated. Patients with NSCLC received cisplatin and etoposide or cisplatin and gemcitabine. Patients with colorectal cancer received oxaliplatin and 5-FU, or CPT-11, or 5-FU and folate (FC). Patients with stomach cancer received cisplatin, epirubicin, 5-FU and FC or 5-FU and FC. The total regression of tumors and the magnitude of 2-year survival in patients with concomitant treatment with melatonin was significantly higher than in patients who received only combinations of chemotherapeutic drugs.

Improvement of treatment results with melatonin was noted in a study that included 100 patients with inoperable primary primary hepatocellular carcinoma. Patients were given only transcatheter arterial chemoembolization (TACHE) or combined it with melatonin. Values of 0.5; 1 and 2-year survival rates in the TACHE-treated group were 82%, 54%, and 26%, respectively, whereas in the TAC and melatonin group, these rates increased to 100%, 68%, and 40%, respectively. In the case of melatonin, increased resectability of the tumor was noted. Two-stage resection was performed by 14% (7/50) of patients after TACHE in combination with melatonin and only 4% (2/50) after TACEC. In patients treated with TACHE and melatonin, an increase in the level of IL-2 was noted, indicating the contribution of the immune-stimulating function of melatonin to an increase in the therapeutic response in this group of patients.

An increase in the tumor response was also noted in patients with metastatic melanoma with progression of the disease after taking dacarbazine and interferon-a. Melatonin was used in combination with low doses of IL-2 and cisplatin. An objective tumor response was observed in 31% (4/13) patients. Stabilization of the disease 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 cancer.

Melatonin for palliative treatment

Patients with advanced cancer are characterized by multisymptomatic symptoms. The most common symptoms are pain, fatigue, weakness, anorexia, dry mouth, constipation and weight loss of more than 10%. Melatonin, showing such biological activities as anti-cancer, anti-asthenic, thrombopoietic, may be useful in the palliative treatment of cancer patients.

A study of 1440 patients with common 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 supporting treatment than those receiving only maintenance treatment .

It is believed that the positive effect of melatonin in cachexia can be mediated by its effect on the levels of pro-inflammatory cytokines involved in the development of cachexia. In a study involving 100 patients with common solid tumors, it was shown that a loss of more than 10% of weight was noted significantly less in patients receiving maintenance therapy in combination with melatonin, compared with those receiving only maintenance therapy. The content of tumor necrosis factor was significantly lower (p <0.05) in patients receiving melatonin.

It is believed that melatonin, even in the absence of antitumor efficacy, can be of significant benefit, improving the sleep of cancer patients. In patients with breast cancer who received melatonin for 4 months after the end of the antitumor treatment, improvement in the quality and duration of sleep was noted compared with those receiving placebo.

In patients with advanced cancer who did not respond to the previous standard antitumor treatment, or those who were not suitable for this treatment, melatonin also had a beneficial effect on tumor response and survival, as indicated by the results of randomized, controlled trials.

In a study that included 63 patients with metastatic NSCLC progressing with first-line chemotherapy (cisplatin), treatment with melatonin (10 mg / day orally at 19:00) resulted in stabilization of the disease and an increase in annual survival compared to maintenance therapy. There was also an improvement in the general condition in the group of patients receiving melatonin.

In patients with unresectable metastases of solid tumors in the brain, the use of melatonin (20 mg / day at 20:00) increased the annual, disease-free and overall survival in comparison with the rates of patients receiving maintenance therapy with steroids and anticonvulsant drugs.

Positive results were obtained with treatment with melatonin in patients with advanced melanoma. In a small study involving 30 melanoma patients operated on for metastases in regional lymph nodes, the daily use of melatonin (20 mg / day orally in the evening) resulted in an increase in disease-free survival in comparison with the control.

Patients with untreatable metastatic tumors, in which melatonin application led to disease control, had a statistically significant decrease in the number of immunosuppressive T-regulatory cells, normalization of the rhythm of cortisol, a decrease in the secretion of endothelial growth factor of the vessels.

An increase in the effectiveness of treatment of patients with advanced cancer was observed with melatonin in combination with IL-2. In such patients, melatonin potentiated the immunostimulating properties of IL-2, increasing the number of T-lymphocytes, NK cells, CB25 + 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 effectiveness 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 given on the limitation of melatonin side effects caused by the use of IL-2. In patients with metastatic renal cancer who received thirty-three 5-day IL-2 courses at a dose of 3 million IU / m2 daily and MLT (10 mg / day orally at 20:00), a reduction in the incidence of episodes of severe hypotension and symptoms of depression was noted with patients receiving only IL-2. Patients with common solid tumors with persistent thrombocytopenia who received IL-2 together with melatonin in 70% of cases observed a normalization of the number of platelets. In the treatment of IL-2 alone, a decrease in the number of platelets associated with the destruction of peripheral platelets due to activation of the macrophage system IL-2 was noted.

In patients with locally advanced or common solid tumors (with the exception of melanoma and kidney cancer), a comparison of the results of treatment with IL-2 (3 million IU / day at 20:00, 6 days / week for 4 weeks) and IL-2 in combination with melatonin (40 mg daily at 20:00, starting 7 days prior to injection of IL-2) revealed a higher objective regression of the tumor in patients treated with IL-2 and melatonin compared to those receiving IL-2 alone (11/41 versus 1 / 39, p <0.001). In the same group of patients, a higher annual survival was noted (19/41 versus 6/39, p <0.05).

The increase in the annual survival rate for 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, progressed after treatment with 5-FU and PK (9/25 versus 3/25, p <0.05).

Comparison of the results of therapy including IL-2 (3 million IU / day for 4 weeks) and melatonin (40 mg / day) and maintenance therapy were performed in 100 patients with solid tumors, which were contraindicated for standard antitumor therapy. Partial tumor regression was observed in 9/52 (17%) of patients receiving immunotherapy, and not in one patient receiving supportive treatment. IL-2 treated with melatonin also showed higher rates of 1-year survival (21/52 vs. 5/48, p <0.005) and improvement in general condition (22/52 vs 8/48, p <0.01).

Improvement of tumor response and increase in 3-year survival was established in a large-scale study involving 846 patients with metastatic solid tumors (NSCLC or gastrointestinal tumors) randomized to receive only maintenance therapy, maintenance therapy and melatonin (20 mg / day, orally in evening time) or melatonin and IL-2 (3 million IU / day subcutaneously, 5 days / week for 4 weeks). The best results were noted in the group receiving along with maintenance therapy melatonin and IL-2.

The results of small non-randomized studies also showed the effectiveness of melatonin in combination with IL-2 in patients with solid, hematological and endocrine malignancies.

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

Thus, a meta-analysis of 21 clinical trials of the effectiveness of treatment of melatonin in patients with solid tumors showed a reduction in the relative risk (RR) of annual mortality by an average of 37%. Improvement of the effect was noted with regard to complete and partial tumor responses, as well as stabilization of the disease. The ORs 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 combined with chemotherapy, showed a reduction in annual mortality (RR = 0.60, 95% CI = 0.54-0.67) and an increase in the number of complete and partial responses and stabilization of the disease. The generalized PRs were 2.53 (1.36-4.71), 1.70 (1.37-2.12) and 1.15 (1.00-1.33), respectively.

Summarizing the given positive results of using both melatonin and in combination with IL-2 in the practice of cancer treatment, it is necessary to note the importance of further studies of neuroendocrine and immune disorders involved in the control of neoplastic growth, to develop new combined strategies using such a multifunctional compound as melatonin, and also other pineal hormones, the biological activity of which has been studied much less.

Cand. Honey. P. P. Sorochan, I. S. Gromakova, Cand. Honey. N.E. Prokhach, Cand. Biol. Sciences IA Gromakova, MO O. Ivanenko. Application of melatonin in oncology practice // International Medical Journal - №3 - 2012