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Efficacy of Melatonin in Alleviating Radiotherapy-Induced Fatigue, Anxiety, and Depression in Breast Cancer Patients: A Randomized, Triple-Blind, Placebo-Controlled Trial

Published on Friday, 05 September 2025

Abstract

Background: This trial evaluated the efficacy of melatonin versus placebo in alleviating radiotherapy-induced fatigue, anxiety, and depression in breast cancer patients.

Methods and materials: This randomized, triple-blind, parallel-group, single-center clinical trial was conducted in the radiation oncology department of Namazi Hospital in Shiraz, Iran. Eligible breast cancer patients scheduled for adjuvant radiotherapy were randomly assigned to receive either 20 mg oral melatonin daily or a placebo. All participants underwent conventional radiotherapy (50 Gy total, delivered as 2 Gy per day). Patients in the melatonin group received the intervention starting on the first day of radiotherapy and continuing until treatment completion. Assessments were performed at baseline and 1 week after the intervention using the Multidimensional Fatigue Inventory and Beck's Depression and Anxiety checklists. Data were analyzed using SPSS version 22 with a significance level set at P < .05.

Results: Both groups (n = 50 each) had comparable baseline characteristics. Baseline MFI fatigue (P = .06), Beck Anxiety Inventory (P = .5), and Beck Depression Inventory (P = .9) scores showed no significant differences between groups. Post-intervention, the melatonin group had significantly lower scores than the placebo group (Mann-Whitney U test, P < .001 for all): MFI fatigue (median: 42.5 vs 55), Beck Anxiety Inventory (median: 28.5 vs 38), and Beck Depression Inventory (median: 29 vs 38). In the placebo group, changes were minimal: MFI fatigue scores were nearly unchanged (median: 56 vs 55), with no significant differences in Beck Anxiety Inventory (median: 38 vs 38, P = .08) or Beck Depression Inventory scores (median: 38 vs 38, P = .3). Within the melatonin group, the Friedman test showed significant reductions from baseline to post-intervention in MFI fatigue (median: 61-42.5), Beck Anxiety Inventory (median: 38-28.5), and Beck Depression Inventory scores (median: 38.5-29; P < .001 for all).

Conclusion: Melatonin administration during radiotherapy significantly alleviated fatigue, anxiety, and depression in breast cancer patients.

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About this publication.

The Di Bella's Method: Use of Melatonin, Estrogen therapy (Anastrozole 1 mg tab per day), pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea, Somatostatin/Octreotide analogues and/or derivatives with Cabergoline and/or Bromocriptine (together with others chemical compounds) in Breast Cancer:

- A retrospective observational clinical study of triple negative breast cancer cases treated with Di Bella Method: A preliminary data;

- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;

- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day and more orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);