Benefits of Melatonin for Women with Metastatic Breast Cancer

Innominato PF, Lim AS, Palesh O, et al. The effect of melatonin on sleep and quality of life in patients with advanced breast cancer. Support Care Cancer. 2016;24(3):1097-1105.

To assess the effect of melatonin on circadian biomarkers, sleep, and quality of life in patients with advanced breast cancer

Prospective, open label phase II trial

Thirty-two patients with metastatic breast cancer (31 female, 1 male) between the ages of 33 and 69 were included. Participants with stable disease, receiving bisphosphonates, hormonal therapy (tamoxifen, aromatase inhibitors, progestins), trastuzumab, or no systemic treatment were eligible.  

 

Exclusion criteria were shift work, taking steroids or beta blockers, or an ECOG performance status >2. The ECOG Scale of Performance Status is a measure of how a disease affects a patient’s daily living activities. Patients are graded on a scale of 0 to 5, with 0 reflecting full performance; the higher the grade, the lower the performance.

 

Participants were removed from the study if there was clinical or radiological evidence of progression during the 2 months.

Oral administration of 5 mg melatonin at participants’ regular bedtime for 2 months

Primary outcome was within-patient changes in sleep quality and circadian rhythmicity calculated from actigraphy. Secondary outcomes included other changes in actigraphy parameters, diurnal patterns of serum cortisol, expression of core clock genes PER2 and BMAL1, and quality of life. 

Participants wore a Basic Motionlogger actigraph on the nondominant wrist for a minimum of 4 days at baseline, and again for the last week of melatonin supplementation. The device assessed rest-activity patterns before and after melatonin supplementation. The primary endpoints were 2 validated parameters of the device: circadian parameter (r24), which measures circadian pattern, and sleep parameter (pRA), a measure of sleep fragmentation. 

 

Nine secondary parameters were calculated from the actigraphy, including 3 estimating circadian rest-activity pattern, 1 estimating sleep, and 5 related to physical activity.

 

Serum cortisol was measured in blood samples obtained at 8 am and 4 pm at baseline and again after 2 months of melatonin supplementation. 

 

Clock gene expression (PER2 and BMAL1) was measured in peripheral blood mononuclear cells (PBMCs) with blood samples obtained at 8 am and 4 pm at baseline and again after 2 months of melatonin supplementation. 

 

Quality of life (QOL) was assessed at baseline and again after 2 months of melatonin supplementation, using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC CLQ-C30) version 3.0. 

Circadian parameter (r24): No significant difference after melatonin treatment [-0.06; 95% confidence interval (CI): -0.58-0.37; P=0.11]. Sleep fragmentation (pRA): Significantly reduced after treatment with melatonin (P=0.0015), relative reduction 40%.

Significant improvements in global quality of life, social functioning domain, cognitive functioning domain, self-rated sleep disturbance, and fatigue. A clinically meaningful increase (>10 points) occurred in 35.7% of patients for global quality of life, and 39.5% of patients for social and cognitive functions. A clinically meaningful decrease (<10 points) in sleep disturbance and fatigue occurred in 50% and 47.4% of patients, respectively.

 

Secondary actigraphy parameters: Improved rest quality and duration as measured by significant post-treatment changes in L6, pAR, SFI, and total duration of rest. Circadian parameters and overall activity-related parameters did not show significant changes. 

Significant increase in morning expression of PER2 and BMAL1 (P=0.006) and no change in afternoon expression of either gene 

No change in average morning or afternoon cortisol patterns (P=0.89)

There was no melatonin-related toxicity in the 2-month trial.

Sleep disturbance and fatigue are common concerns in patients with breast cancer.² Fatigue is the most commonly reported symptom in this population, present in 25% to 99% of patients during active treatment, and 20% to 35% post-treatment.¹ As many as 75% of women with breast cancer report difficulty falling asleep or maintaining sleep, with 19% meeting the criteria of insomnia.¹ Insomnia is significantly correlated with worsening quality of life across all domains of the EORTC QLQ-C30 in patients with cancer.³

Sleep is not only important for quality of life (QOL), but it is also a predictor of survival in women with advanced breast cancer.⁴ Better sleep efficiency, as measured by actigraphy, is associated with decreased overall mortality at 6 years follow-up (HR: 0.96; 95% CI: 0.94-0.98). This association remained significant after controlling for age, estrogen receptor status, cancer treatment, metastatic spread, cortisol levels, and depression. Specific sleep efficiency parameters that were related to survival included less wake after sleep onset (HR: 0.41; 95% CI: 0.25-0.67), fewer wake episodes (HR: 0.93; 95% CI: 0.88-0.98) and shorter wake episode duration (HR: 0.29; 95% CI: 0.14-0.58).³ Another study found that lower subjective fatigue, as measured by the EORTC QLQ-C30, was also a predictor of longer recurrence-free and overall survival in women with primary breast cancer at a median follow-up of 12.9 years.⁵ Whether treating sleep disturbance can improve overall survival is yet unknown, but certainly these studies provide further clinical reason beyond QOL to improve sleep duration and quality in patients with advanced malignancy. 

 

Although there is a growing body of evidence to support the use of melatonin in women with breast cancer, this is the first study to assess the effect of oral melatonin on sleep quality and QOL in patients with metastatic breast cancer. In studies involving women with earlier-stage breast cancers, 3 mg melatonin per night for 4 months improved subjective sleep quality,⁶ and 6 mg melatonin per night for 3 months post-surgery significantly decreased depressive symptoms.⁷

 

Depression, fatigue, and sleep disturbance frequently present as a symptom cluster in women with breast cancer,⁸ and fatigue may precede symptoms of depression, representing a target for treatment.⁷ Melatonin is a low-cost, safe treatment that can target this entire symptom cluster. 

 

The relationship between circadian rhythm disruption and melatonin in breast cancer risk is  well-documented.^9-11 Several disruptors of circadian rhythm have been shown in meta-analyses to increase risk of breast cancer, including night shift work, exposure to light at night, and work as a flight attendant.^8-10 The most recent meta-analysis of the relationship between circadian disruptors and breast cancer risk found that the relative risk of breast cancer for shift work was 1.19 (95% CI: 1.08-1.32), exposure to light at night 1.12 (95% CI: 1.119-1.121), and employment as a flight attendant 1.56 (95% CI: 1.1-2.21).¹⁰ Melatonin levels, measured by urinary excretion of 6-sulphatoxymelatonin, are inversely associated with breast cancer risk (OR: 0.81; 95% CI: 0.66-0.99) for women in the highest versus lowest quartile of melatonin’s urinary metabolite.⁹

 

Although the major marker of circadian pattern, r24 measured by actigraphy, did not change following melatonin supplementation, the alteration in clock gene expression indicates some biological activity of melatonin levels on circadian rhythm. As the authors state in the discussion, the lack of significant change in r24 may be partially due to the study population, which at baseline did not have significant circadian disruption and exhibited normal diurnal cortisol pattern.¹² The change in core clock gene expression, particularly PER2 expression, is interesting for several reasons. An increase in morning PER2 indicates an increase in the amplitude of circadian rhythmicity.¹¹ Alterations in clock gene expression have been shown to alter cell cycle control, and may play a role in carcinogenesis and cancer progression.¹³ In experimental models, the absence of PER2 is associated with development of various cancers and increased susceptibility to genotoxic stress, and is important for function of the tumor suppressor gene p53.¹² Downregulation of PER2 in experimental models accelerates breast cancer growth.¹⁴ Therefore, improving markers of circadian rhythmicity may play an important role in preventing cancer and slowing disease progression. 

 

Previous studies have looked at the effect of melatonin on survival in solid tumors, although these studies typically use doses of 20 mg per day.^15-17 Several meta-analyses have shown significant improvements in 1-year survival in patients using melatonin alongside conventional care for solid tumors.^14-16 Two of these meta-analyses also looked at the impact of melatonin on side effects of chemotherapy and radiotherapy, with significant improvements in several side effects including myelosuppression and asthenia.^14-15 Some patients are not able to tolerate 20 mg of melatonin due to morning grogginess, vivid dreams, and restless sleep.⁵ The impact of lower doses of melatonin on survival and side effect management is presently unknown.

 

Clinicians should note that short-term use of melatonin for advanced breast cancer may not have beneficial effects on fatigue; a study supplementing patients with 20 mg melatonin before bed for 1 week showed no benefit to fatigue.¹⁸ This may be relevant to explain to patients, because they may stop using melatonin if benefit is not achieved in the first few nights. Clinicians should also consider other interventions to improve sleep and decrease fatigue in patients with advanced cancer; for example, daily exercise (eg, walking)^19-20 and good sleep hygiene practices. 

 

Although melatonin supplementation is common in naturopathic oncology, this study provides new insights into the use of lower doses of melatonin in patients with metastatic breast cancer to improve sleep and QOL. While this dose of melatonin has not been studied for survival outcomes or side effect management during chemotherapy or radiotherapy, given the positive effect on QOL, excellent safety profile, low cost, and potential for improved outcomes, clinicians should strongly consider the use of melatonin in women with metastatic breast cancer.  

The major limitation of this study is the single-arm design. The absence of a control group makes drawing conclusions difficult due to the risk of placebo effect. Future double-blind, placebo-controlled studies are needed to definitively determine the benefit of melatonin in this population. The findings also warrant future studies to assess survival outcomes and effect alongside chemotherapy.