A Randomized, Controlled, Parallel-Group, Trial on the Long-term Effects of Melatonin on Fatigue Associated With Breast Cancer and Its Adjuvant Treatments

Abstract

Objective:

Cancer related fatigue is a distressing condition and correlated with decrease in quality of life of patients with malignant conditions. In continuation of our previous research, we assessed long term anti-fatigue effects of melatonin in patients with the breast cancer.

Material and methods:

In this clinical trial, 92 breast cancer patients were randomly assigned to receive either melatonin (18 mg/day) or placebo from 1 week before the adjuvant treatments until 2 years after their completion. The levels of fatigue were assessed before and after intervention using Brief Fatigue Inventory (BFI) and were compared at a significance level of P ≤ .05.

Results:

The BFI scores were similar between the 2 groups at the baseline (placebo group: 5.56 ± 1.59 and melatonin group: 5.72 ± 1.68, P = .67). After the intervention, not only the mean fatigue score was significantly lower in melatonin group (2.93 ± 1.04 vs 1.99 ± 1.02, P < .001, P ≤ .05), but also a greater reduction in fatigue score in intervention group was evident over time (P ≤ .001).

Conclusion:

Long-term usage of melatonin even after completion of adjuvant therapies in women with breast cancer decreased the levels of fatigue associated with the malignant condition and its treatments.

The trial registry name and URL, and registration number:

Iranian Registry of Clinical Trials, https://en.irct.ir/trial/62267, IRCT20180426039421N3

Introduction

Breast cancer is the most prevalent female malignancy and the leading cause of cancer-related death among them. ¹ With the implementation of screening programs, raising breast cancer awareness among women, and ongoing advances in breast cancer treatments, the patients’ survival rates have improved significantly. ¹ Therefore, dealing with other aspects of suffering from breast cancer and ameliorating treatment-related side effects directly affecting patients’ quality of life (QoL) have attracted attention. Among these, cancer-related fatigue (CRF) has pronounced effects. With variety of consequences on physical and mental health, CRF can substantially reduce the quality of life in cancer survivors. ² It occurs in patients with cancer as a multidimensional scenario due to disease symptoms or as a result of cancer treatment. ² On the other hand, it’s crucial to evaluate the CRF in light of the timeline of the disease, from the first signs and symptoms through the latter phases of treatment and finally survival. A study by Ancoli-Israel et al ³ showed that the breast cancer patients who experienced exhaustion, insufficient sleep, and sadness prior to chemotherapy, would sense more fatigue and had worse quality of life during the treatment than patients who did not experience these symptoms as much. The intensity of the patient’s pain before cancer therapy, as well as feelings of anxiety, sadness, and sleep disruption, could also be predictive of post-treatment fatigue. ⁴ According to the findings of the Donovan et al ⁵ study, prediction exhaustion in women with early-stage breast cancer varied depending on the type and sequence of treatment. Women with early-stage breast cancer who received chemotherapy as their first form of treatment felt more fatigue during the active treatment than those who received radiation. Additionally, comparing the effects of radiotherapy, it was found that those who had radiotherapy as their initial treatment option had higher levels of CRF than those who received radiotherapy following chemotherapy, which can be explained by changing their mental background. ⁵ The above is also supported by Andrykowski et al ⁶ who found that the women getting adjuvant chemotherapy had a twofold increased risk of developing CRF during treatment than those treated with radiotherapy. The last issue to be covered regarding the disease timeline is the possibility of CRF becoming a chronic condition. According to Jones et al ⁷ significant clinical levels of CRF impacting the quality of life were found in around one-third of disease-free cancer survivors (including breast, prostate, or colorectal cancer) up to 6 years after their last treatment.

Despite the great prevalence, severity, and discomfort associated with CRF, the pathogenic process is unknown and appears to be complicated, including the combination of psychological and physical components. Based on some hypotheses, it may be caused by either a muscle’s inability to respond to central impulses, originating from the muscular tissue or the neuromuscular junction, or by a progressive impairment of central nervous system signaling. The release of cytokines (such as TNF-α), anemia, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, circadian rhythm problems, unbalanced serotonin levels, and a problem with the vagal afferent nerve are some other theories.^8-10

As aforementioned, dysregulation of circadian rhythm, mainly controlled by melatonin, is one of the main predisposing factors of CRF that have frequently been reported in cancer patients. A meta-analysis by He et al ¹¹ revealed that circadian disturbance has been related to an elevated risk of female breast cancer. The National Toxicology Program (NTP) systematic review also, demonstrated that the persistent night work (regular or long-term night shifts, especially in early adulthood) is linked to breast cancer in women and also related with biological consequences that are known as essential hallmarks of carcinogens, according to mechanistic investigations in humans and nonhumans. ¹²

Melatonin (N-acetyl-5 methoxytryptamine), an indole amine, is distributed from various sources in human body. The pineal gland is primarily responsible for producing it in reaction to darkness. Melatonin is also synthesized by the bone marrow, digestive system, lymphocytes, skin, and retina. The biological clock that regulates melatonin’s 24-hour production and secretion, known as the suprachiasmatic nucleus, is located in the hypothalamus. Melatonin production, unlike other circadian rhythm biomarkers, is unaffected by environmental influences other than light, making it significant for diagnosing circadian dysregulation. Melatonin levels rise at night, then begin to decline in the morning and continue to reduce throughout the day. When melatonin levels are high, target organs are stimulated to enter correct homeostatic metabolic rhythms, which help the body protect itself against a variety of illnesses.^13,14

In addition to its involvement in the circadian cycle, melatonin is being studied for its potential in cancer prevention and treatment. ¹⁴ According to a systematic review and meta-analysis of 14 studies by Chuffa et al that investigated the microRNA networks controlled by melatonin in cancers, melatonin modified the expression of miRNA-associated genes in breast cancer, which are related to cellular proliferation, differentiation, apoptosis, senescence, p53 signaling system, and autophagy. Melatonin increased the expression of genes involved in immunological responses and apoptotic processes, whereas it decreased the expression of genes involved in cellular aggressiveness/metastasis (eg, mitosis, telomerase activity, and angiogenesis). ¹⁵

In our previous research, “A randomized, controlled, parallel-group trial on the effects of melatonin on fatigue associated with breast cancer and its adjuvant treatments,” we discovered that concurrent administration of melatonin throughout chemo-/radiotherapy of breast cancer patients reduced the levels of cancer-related fatigue. ¹⁶ In the present study, we have reported the 2-year follow-up of breast cancer patients with adjuvant administration of melatonin.

Methods and Materials

Study Patients

Female patients whose diagnoses of invasive breast carcinoma were confirmed pathologically at Be’sat Hospital and Mahdieh Diagnostic and Treatment Center of Hamadan, Iran, were enrolled in this double-blinded randomized placebo-controlled clinical trial between 2019 and 2020. The last date of follow up was June, 2022. Stage I to III breast cancer patients [according to The American Joint Committee on Cancer (AJCC) staging system, eighth Edition] in whom adjuvant chemotherapy and radiotherapy based on the National Comprehensive Cancer Network (NCCN) Guidelines were indicated, were selected consecutively. All patients with prior history of any malignancies except cutaneous basal cell carcinoma, previous history of receiving chemotherapy, presence of distant metastasis at presentation, and neoadjuvant chemotherapy were excluded. Exclusion criteria were poorly controlled hypercalcemia, lactation, pregnancy, usage of warfarin, methylphenidate, and sleeping pills. Moreover, occurrence of any grade ≥2 toxicities based on the Common Terminology Criteria for Adverse Events (CTC-AE) v 5.0 during the intervention led to exclusion of patients from the study. Occurrences of these toxicities are accompanied with prolongation and/or discontinuation of adjuvant treatments (either radiotherapy or chemotherapy). To maintain the homogeneity of adjuvant treatments across the groups, patients who experienced these grade ≥2 toxicities were excluded.

The study protocol was approved by the Research Ethics Committee of the Medical School of Hamadan University of Medical Sciences (IR.UMSHA.REC.1400.813) and registered on the Iranian Registry of Clinical Trials (IRCT20180426039421N3). A signed informed consent form prior to the enrollment was provided by all of the patients.

Trial Design and Definition of Primary Endpoints

The study was designed as a randomized, controlled, parallel-group, trial. A stratified permuted block randomization method with block sizes of 4 generated by computer to assign patients in each group. In sealed envelopes, the numbers that were dedicated to each group were put by a person who was outside of the research team. The envelopes would be opened at the time of assignment. Both groups were matched based on type of surgery, hormone receptor expression, or type of adjuvant systemic therapy during the randomization. In this double-blinded and placebo-controlled trial, the physicians, nurses, outcome assessor, and patients did not have any access to the study group assignment.

Level of fatigue was the primary endpoint in this trial. The Persian version of the brief fatigue inventory (BFI) was used to assess the cancer related fatigue. The BFI is a validated tool, ¹⁷ and although the tool is not officially validated in Persian, a study by Khatiban et al ¹⁸ showed that the tool was a reliable measure in Persian with Cronbach’s alpha of .92. On a single page, fatigue and its interruption are measured by BFI through 9 items, utilizing a 0 to 10 scale. First, in 3 separate questions, participants are asked to describe their level of fatigue within the last 24 hours, using “no fatigue” and “fatigue as severe as you can imagine.” The next 6 items describe the extent to which their lives have been impacted by fatigue over the past 24 hours. These factors include general activity, mood, walking ability, regular work, interpersonal relationships, and life satisfaction. Briefly, the scores in BFI are as follows: No fatigue  = 0, mild fatigue  = 0 to 3, average fatigue  = 4 to 6, severe fatigue  = 7 to 9, and very severe fatigue  = 10. In our previous research, melatonin was prescribed during the chemotherapy and radiotherapy and CRF was assessed before and 4 weeks after intervention. ¹⁶ In the current study, we have reported the long-term outcomes of melatonin administration in breast cancer patients.

Treatment Schedule

The adjuvant chemotherapy and then adjuvant radiotherapy were used in all patients in both groups within 4 weeks from the surgery (breast conserving surgery [BCS] or modified radical mastectomy [MRM]). The intervention group received 18 mg oral melatonin daily (18 mg once a day) from 1 week prior to adjuvant treatment until 2 years after completion of adjuvant radiotherapy every night (1 hour before the bedtime). The placebo group received a similar cellulose-made drug with similar instructions and duration. Melatonin tablets were provided by RAZAK Laboratory, Tehran, Iran, and similar tablets were produced at the School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

Chemotherapy regimen in patients with stage II and III was consisted of the dose-dense AC-T [including doxorubicin (A), cyclophosphamide (C), and paclitaxel (T)] every 2 weeks with granulocyte colony-stimulating factor (G-CSF) for 8 cycles [AC × 4 and T × 4]. Trastuzumab was added within and after the prescription of paclitaxel, if indicated (Her2/neu positive patients). In patients with hormone positive stage I breast cancer, the CMF chemotherapy regimen was prescribed [cyclophosphamide, methotrexate, fluorouracil]. The radiotherapy protocol in both groups was conventional radiotherapy of chest wall/whole breast with regional node irradiation if necessary.

Data Registration, Quality Assurance and Follow-Up

Patient were visited before each course of chemotherapy and then weekly during radiation. After the completion of adjuvant treatments, patients were followed up every 3 months. All visits were done by the corresponding oncologist who asked patients about the use of melatonin/placebo drug to evaluate their adherence to the treatment. Collectively, the study lasted 125 weeks (1 week before the start of adjuvant treatment, 16 weeks for during chemotherapy, 5 weeks for radiotherapy, and 103 weeks for follow-up). The BFI was evaluated in 3 periods including 1 week before the commencement of adjuvant treatment and at 4 weeks after treatment completion and finally 2 years later by 1 of investigators (Z.K.A.) who was blinded to the groups.

Statistical Methods

Sample size was calculated based on results of our pilot study using $\frac{{\left(Z_{1-\alpha /2}+Z_{1-\beta }\right)}^2\left(S_1^2+S_2^2\right)}{{\left(U_1-U_2\right)}^2}$ considering α = .05, power of 80%, µ₁ = 4.31, µ₂ = 6.91, S1 = 3.8, and S2 = 3.6 and estimated a minimum of n = 34. To overcome the possible high drop-out rate due to the long follow-up period, at least 100 patents were enrolled in each group. Statistical Package for the Social Sciences (SPSS) software version 16 was used for data analysis. To compare the means of 2 groups, the Student’s t-test was used. In order to compare categorical variables, the Chi-square test was used. The level of significance was considered P less than .05.

Results

Out of 208 eligible patients, 102 patients were enrolled in the intervention group (oral melatonin) and 106 were enrolled in control group (oral placebo). In the intervention group, 6 patients were excluded due to severe nausea and vomiting and 5 due to distant metastases/recurrence. In the control group, 6 patients were excluded due to failure to follow up and 8 patients due to distant metastases/recurrence (Figure 1).

Figure 1.

Screening, randomization, and analysis.

All patients in both groups had Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1. Characteristics of the patients at baseline are shown in Table 1. Table 2a shows the mean and standard deviation of fatigue scores over time across groups. As seen the mean Fatigue score diminishes in both groups. Results of repeated measurement Analysis of Variance also were reported in Table 2b. According to the results the time effect was statistically significant (P < .001). Also, the interaction between time and group was significant indicating different trends over time across groups. There was no statistically significant difference between severity and mean score of fatigue in the patients before the intervention. However, after intervention, the mean fatigue score and severity of fatigue were significantly lower in the intervention group (P < .05). As it is shown in Figure 2, both groups show a decreasing fatigue score over time. A greater decrease in the intervention group is evident, so that the mean difference at 1 year after intervention was statistically significant (Table 2a). The adherence rate was high in our study and all patients received the intended intervention.

Table 1.

Characteristics of the Patients at Baseline.

Variable	Placebo (n = 92)	Intervention (n = 91)	P-value
Comorbidities
DM	46	60	.029
HTN	28	26	.782
Hypothyroidism	12	16	.394
Treatment related data
Type of surgery
MRM	32	21	.081
BCS	60	70
Type of CT
DOX-based	85	81	.431
Other	7	10
Type of RT
Conventional	92	91	1.000
Hypofractionated	0	0
Tamoxifen
Yes	78	72	.319
No	14	19
Tumor related data
TNM staging
Stage I	5	7	.821
Stage II	19	19
Stage III	68	65
Molecular subtypes
Luminal A	50	38	.367
Luminal B	27	34
HER2 enriched	9	13
Triple negative	6	6

Abbreviations: BCS, breast conserving surgery; DM, diabetes mellitus; DOX, doxorubicin; ER, estrogen receptor; Her2, human epidermal growth factor receptor 2; HTN, Hypertension; MRM, modified radical mastectomy; PR, progesterone receptor.

Table 2.

(a) Mean Fatigue Score Over Time by Groups (Placebo and Melatonin) and (b) Results of Repeated Measurement Analysis of Variance.

(a)	Before intervention		1 mo after intervention		2 y after intervention
Group	Mean ± SD	n	Mean	n	Mean	n
Placebo	5.56 ± 1.59	106	4.80 ± 1.02	92	2.93 ± 1.04	92
Intervention	5.72 ± 1.68	102	3.97 ± 1.29	91	1.99 ± 1.02	91
Independent samples t-test	t = 0.427		t = −2.79		t = −3.58
P-value	.671		.007		.001
(b)
Source of variation	F		P-value
Group	3.02		.087
Time	204.15		<.001
Group by time	9.157		.001

Figure 2.

Marginal estimated means of fatigue over time.

Table 3a shows the number of patients with severe fatigue over time across groups. As seen, the number of patients with severe fatigue diminishes in intervention group, so that the there was a significant difference between 2 groups in terms of having severe fatigue both in 1 month and 2 years after intervention. Results of repeated measurement Analysis of Variance also were reported in Table 2b. According to the results, the time effect was statistically significant (P < .001). Also, the interaction between time and group was significant indicating different trends over time across groups. Moreover, the results of Cochran’s Q Test statistics showed that these proportions in both groups change over time.

Table 3.

(a) The Number of Patients With Severe Fatigue Over Time by Groups (Placebo and Melatonin) and (b) Results of Generalized Estimating Equation.

(a)	Before intervention		1 mo after intervention		2 y after intervention
Group	Count (%)	n	Count (%)	n	Count (%)	n
Placebo	20 (18.9)	106	29 (31.5)	92	13 (14.1)	92
Intervention	29 (28.4)	102	16 (38)	91	6 (6.6)	91
Chi-square statistics	2.64		4.79		2.79
P-value	.104		.029		.096
(b)
Group	Cochran’s Q Test statistics		P-value
Placebo	10.941		.004
Intervention	27.30		<.001

Figure 3 shows the mean of severity score over time by groups. Both groups show a decreasing severity score over time. A greater decrease in the intervention group is evident, so that the mean difference at 1 year after intervention was statistically significant (Table 4a). Figure 4 shows the mean of interference score over time by groups. According to the results the mean difference between 2 groups before and 1 month after intervention was not significant (P > .05). However, the mean difference of interference score between 2 groups was significant (P = .001) (Table 5).

Figure 3.

Marginal estimated means of severity over time.

Table 4.

(a) Mean Severity Score Over Time by Groups (Placebo and Melatonin) and b) Results of Repeated Measurement Analysis of Variance.

(a)	Before intervention		1 mo after intervention		2 y after intervention
Group	Mean ± SD	n	Mean	n	Mean	n
Placebo	5.32 ± 1.65		4.76 ± 1.27		2.94 ± 1.03
Intervention	5.53 ± 1.74		3.66 ± 1.20		1.97 ± 1.08
Independent samples t-test	t = 0.319		t = −3.698		t = −3.701
P-value	.751		<.001		<.001
(b)
Source of variation	F		P-value
Group	4.578		.037
Time	180.957		<.001
Group by time	10.746		<.001

Figure 4.

Marginal estimated means of interference over time.

Table 5.

(a) Mean Interference Score Over Time by Groups (Placebo and Melatonin); (b) Results of Repeated Measurement Analysis of Variance.

(a)	Before intervention		1 mo after intervention		2 y after intervention
Group	Mean ± SD	n	Mean	n	Mean	n
Placebo	5.63 ± 1.80		4.78 ± 1.30		2.93 ± 1.07
Intervention	5.84 ± 1.77		4.23 ± 1.87		2.02 ± 1.01
Independent samples t-test	t = 0.532		t = −1.456		t = −3.447
P-value	.596		.150		.001
(b)
Source of variation	F		P-value
Group	4.578		.236
Time	153.808		<.001
Group by time	5.628		.005

Discussion

Cancer-related fatigue (CRF) is defined by the National Comprehensive Cancer Network (NCCN) as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” in its most comprehensive and widely-used definition. ¹⁹ Cancer survivors indicate that tiredness remains distressing symptom months or even years after treatment has been completed and that persistent CRF impacts their quality of life (QOL) since patients cannot fully engage in responsibilities and activities.^20,21 Also, it is mentioned that most hurting complication of cancer and its treatment is exhaustion, even more than pain, nausea, and vomiting, which are routinely treated with therapeutic agents. ²²

Aside from the use of pharmacologic treatments in the treatment of CRF, the management of CRF is challenging, and the results of various studies conflict. The findings of meta-analysis by Mustian et al comprising 113 independent trials with 11 525 participants, demonstrated that exercise, psychological therapy, and the combination of these 2, both during and after cancer treatment, decreased CRF. Contrarily, pharmaceutical therapies do not considerably have effects on it. ²³

In our earlier research, we discovered that administration of melatonin in breast cancer patients receiving adjuvant chemotherapy and radiotherapy significantly decreased their level of fatigue. ¹⁶ Subsequently, we showed the efficacy of melatonin in the management of fatigue in breast cancer patients. ²⁴ In the current study, the BFI score was similar before the intervention in both groups. After the intervention (18 mg/day of oral melatonin), not only both the mean fatigue score and severity of fatigue were significantly lower in melatonin group (P ≤ .05), but a greater decrease in fatigue score in the intervention group is evident over time (P ≤ .001). There is possibility that a decrease in CRF is associated with an increase in QOL as well as a decrease in the distress caused by symptoms, including pain, poor appetite, feeling drowsy, bowel problems, xerostomia, nausea, vomiting, losing weight, and feeling dizzy. ²⁵ More research is needed into this potential association. According to Palmer et al ²⁶ double-blinded, randomized, and placebo-controlled trial evaluating the administration of 20 mg of melatonin before to and throughout the initial round of adjuvant chemotherapy for breast cancer suggested that melatonin provided neuroprotective effects that could offset the adverse effects of adjuvant chemotherapy on mental function, quality of sleep, and depression. In contrast to previous findings, no evidence of melatonin’s therapeutic effect was found in the Hansen et al ²⁷ study, which examined the impact of a lower dose of melatonin (6 mg oral medication vs placebo for 3 months) on cognitive performance in patients undergoing breast cancer surgery. Despite the fact that a lower dose of melatonin did not have positive effects in the previous study, it appears that in addition to the dosage, other practical factors should be considered, as the dose of 20 mg of melatonin did not have a positive and statistically significant effect on physical fatigue in the study by Lund Rasmussen et al. ²⁸

Regarding the toxicity of treatments, all cases of severe nausea in our study were observed in the melatonin group, resulting in withdrawal from the treatment (5 patients out of 102 patients). As mention earlier, there are limited pieces of evidence regarding the interaction of melatonin and chemotherapy. Nevertheless, previous studies have shown that nausea most is among the commonly reported adverse effects of melatonin.^29,30 On the other hand, most chemotherapeutic regimens used in the management of breast cancer are considered as moderately to highly emetogenic chemotherapy regimens. ³¹ It is possible that coadministration of melatonin during chemotherapy might have increased the likelihood of presence of severe nausea. Therefore, it is advised to observe the patients closely to discontinue the melatonin if severe nausea was occurred. Finally, as the multidisciplinary team(MDT) has found its place in medicine, MDT discussion before the initiation of treatment might be required to formulate the best approach. ³²

The current investigation has its limitations, as with all research. Firstly, the patient’s social and financial situation may have an impact on their fatigue score, which is outside the researchers’ control. Another one is the failure to evaluate the primary serum MLT level, which may have an impact on the effectiveness of the intervention. Finally, failure to address other confounding factors of fatigue levels beside the potential adverse effects of adjuvant therapies and their connection to CRF would be other limitations of the present study.

Conclusion

Our findings support using melatonin as an effective therapeutic method for improving cancer-related fatigue in breast cancer survivors in patients who can tolerate the melatonin-induced nausea that might have been considerable if prescribed during the chemotherapy in a portion of patients. According to our search, no other study evaluated the long-term prescription of melatonin in breast cancer patients. Given the long-term side effects of breast cancer and its treatments, large-scale randomized controlled trials might be advantageous to determine the effects of this intervention on the level of fatigue, quality of life and potentially, survival of long-term breast cancer survivors.