Effects of Melatonin on Appetite and Other Symptoms in Patients With Advanced Cancer and Cachexia: A Double-Blind Placebo-Controlled Trial

Melatonin is a pleiotropic hormone that may modulate multiple mechanisms promoting cancer cachexia, including inflammation, autonomic failure, and malabsorption. Initially believed to be synthesized exclusively in the pineal gland and primarily involved as a circadian messenger of light and dark, melatonin is now recognized to have multiple actions¹ and is synthesized in diverse tissues.² Circulating melatonin is primarily derived from the pineal gland but is synthesized in even greater quantities locally by the GI system,³ possibly in response to feeding.

Melatonin supplementation stimulates appetite in animals,⁴ and its presence in the digestive tract is associated with intestinal transit and nutrient absorption.⁵ Melatonin may also have antitumor activity through an antimitotic⁶ effect and suppression of tumor linoleic acid uptake,⁷ and in a preliminary trial, it improved the efficacy of arterial chemoembolization for hepatocellular carcinoma.⁸

Several studies have evaluated the effect of melatonin on symptoms such as poor appetite, fatigue, and depression in patients with cancer. Patients with metastatic solid tumors randomly assigned to supportive care plus melatonin for 3 months had better weight stabilization and lower levels of tumor necrosis factor α than patients receiving supportive care alone.⁹

A similar subsequent trial of melatonin for patients with untreatable solid tumors showed that cachexia, weakness, anorexia, and depression occurred more frequently in the group receiving supportive care alone.¹⁰ In more recent trials, the same group of investigators reported decreased symptoms, improved survival,¹¹ and fewer adverse effects in patients with solid tumors who were also given melatonin at night. No adverse effects were reported in any of these trials despite the use of a relatively high dose of 20 mg at night. Although patients were randomly assigned, it is important to note that none of the trials were double blind or placebo controlled. On the basis of these studies, it seemed that an inexpensive medication such as melatonin could improve symptoms and quality of life in patients with cancer, without causing adverse effects.

The primary objective of this study was to determine whether melatonin would improve appetite in patients with advanced cancer with cachexia, as defined by an improvement of 1.5 in appetite score from baseline on the Edmonton Symptom Assessment Scale (ESAS). Our secondary objective was to determine whether melatonin would increase weight and lean body mass and improve symptoms and quality of life as measured by the ESAS, Functional Assessment for Chronic Illness Therapy–Fatigue (FACIT-F), and Functional Assessment of Anorexia/Cachexia Therapy (FAACT) scores, respectively.

For each group, the numbers of patients who were randomly assigned, received intended treatment, and were analyzed for the primary outcome are shown in Figure 1. The diagram includes information on the excluded patients. Age-eligible patients were recruited from July 2006 to October 2010. Of the 73 randomly assigned patients with baseline scores, 48 patients had both baseline and week 4 measurements. Baseline characteristics of the two groups are listed in Table 1. No significant differences between groups were found in changes from baseline to week 4 in the appetite score using a one-sided two-sample t test (P = .80). There were also no differences between melatonin and placebo groups after 4 weeks regarding weight, body composition including fat-free mass, symptom scores, and quality-of-life outcomes as measured by FACIT-F and FAACT (Table 2). There was no difference in survival between the two groups (Fig 2), although all patients were given the option of continuing on melatonin after 4 weeks of enrollment. There were no treatment-related deaths, and the number of patients experiencing adverse events by maximum grade was similar in the melatonin (n = 37) and placebo groups (n = 34). We found no significant differences between patients receiving systemic chemotherapy and those on no systemic chemotherapy. The statistical collaborator presented the results to the MDACC Data Monitoring Committee at the yearly Data and Safety Monitoring Board (DSMB) review, while the primary investigator and other collaborators remained blinded. At the fourth yearly DSMB review, when 48 of 50 patients were evaluated for the primary end point, the DSMB requested a modification to the interim test to be made because the number of patients was close to the formal interim stopping rule. The stated early stopping rule was slightly modified to have its first review when 48 patients had been evaluated. The boundary for early stopping was crossed, and the DSMB recommended early stopping because of a low probability of finding significant results for the primary end point if the study were to continue.

This planned interim analysis, when half of the patients were enrolled, had stopping rules in place a priori that allowed for the early termination of the study in light of evidence that patients in the two groups had similar improvement (early stopping as a result of futility). Although there were no significant findings for group differences in appetite, when melatonin and placebo patients were analyzed as a group, significant correlations were found between percent weight change (from baseline to day 28) and appetite (P = .024) and depression (P = .03). The change in C-reactive protein (CRP) levels from baseline to day 28 showed no difference (P = .98) between the melatonin and placebo arms. Subgroup analysis was performed on 15 patients receiving melatonin who had CRP levels obtained at baseline and at day 28. Wilcoxon two-sample tests did not find significant differences in appetite (P = .75), fatigue (P = .18), or other ESAS scores when comparing patients with a decline in CRP versus those with the same or an increase in CRP.

Melatonin was not effective for improving appetite or other symptoms and did not improve quality of life in patients with advanced GI or lung cancer. Our study was stopped for futility after interim analysis of the data, which suggested that the results were not likely to change even with a larger sample size. Our dose of 20 mg of melatonin is unlikely to be the cause of the negative result. This dose is much higher than the 0.5- to 5-mg dose typically used for other conditions such as jet lag,¹⁷ and there was no difference in the frequency of adverse effects between melatonin and placebo. Other trials showing improved clinical outcomes also used doses of 20 mg, but unfortunately, interpretation of their results is severely limited by methodologic issues such as a lack of blinding and absence of placebo controls.^9,10 The 4-week duration of treatment is also of sufficient length to obtain benefit from an effective intervention for appetite. Past studies of thalidomide and megestrol acetate have shown a rapid improvement of symptoms within 10 days and 2 weeks, respectively. There was no difference in survival between the two groups, and although patients receiving placebo were allowed to receive melatonin after the primary end point had been measured, the median survival of patients was only 134 days on placebo and 140 days on melatonin. Despite the option to change treatment and the possibility of a wash out of any positive effects on survival, analysis of survival was reasonable because patients were on study for more than 20% of the time until death.

There may be other reasons why no difference was found between melatonin and placebo regarding appetite and other clinical outcomes. Both melatonin and placebo groups in our study received symptom control and palliative care in an outpatient clinic throughout the duration of the study, and there was a significant association between weight gain (or less weight loss) and improved appetite and depression. There was no difference, however, in the change from baseline to day 28 between the two arms. It is possible that the measured benefit from a specific therapeutic intervention such as melatonin may be not be as marked when accompanied by optimal symptom management in the placebo arm. Although melatonin is reported to modulate tumor necrosis factor α levels and other cytokines^19,20 in patients with solid tumors, melatonin had no effect on CRP levels in our study. Elevated CRP levels have been associated with poor prognosis in patients with cancer, and CRP is regarded as a surrogate marker for the proinflammatory cytokine interleukin-6.

This apparent lack of an anti-inflammatory effect is compatible with the findings of another study in patients with advanced GI cancer, in whom melatonin had no effect on tumor necrosis factorα and other proinflammatory cytokines.²¹ The overall inconsistent effect of melatonin on the proinflammatory response associated with cachexia is difficult to explain but may be a result of heterogeneity of tumor type and stage between studies. Although some patients in both groups responded with improvement in symptoms, it is possible that others may have been refractory²² to the intervention because of their advanced disease. However, all patients enrolled onto our study were ambulatory and had similar characteristics as those admitted to previous studies of melatonin reporting positive outcomes. These unblinded studies found melatonin to be an effective intervention for cachexia, fatigue, and depression in patients with advanced cancer with untreatable metastatic solid tumors.^9,10

Other intervention studies using ghrelin²³ and megestrol acetate^15,16 have also shown improved appetite and symptom burden in patient populations with advanced cancer where specific tumor therapy was no longer effective or indicated. A consensus classification of cancer cachexia has attempted to define patients who may be at the early precachexia phase and those who may be at the other end of the cachexia trajectory who are refractory to any interventions targeting weight or lean body mass. The concept of refractory cachexia, as defined by this expert panel, has no empirical confirmation, although a recent trial of fish oil for patients with GI cancer showing objective improvements in lean body mass provides some preliminary support for this model of cachexia staging. Patients were referred at initial diagnosis,²⁴ suggesting the benefit was likely a result of the early inception point, because two large randomized controlled trials and several prior systematic reviews had concluded that fish oil was of no benefit in patients with advanced cancer.

Melatonin might also be a more effective therapy if used much earlier in the disease trajectory, and this should be a consideration in the design of any future intervention trials for appetite or cachexia. However, it should be noted that based on current criteria, which includes a WHO performance status of 3 to 4 and survival less than 3 months, our trial participants would not be considered as having refractory cachexia. Our patients had better performance status, with a Karnofsky score between 70 and 90 in more than 70% of trial participants, and a longer median survival.

The strengths of our study include the double-blind, placebo-controlled design. Although 32% of our patients did not complete the study, this is consistent with other symptom intervention trial^25,26 in the palliative care population with advanced disease. Despite restricting our study population to patients with either advanced lung or GI cancer, there is likely to be some heterogeneity regarding prognosis and functional status because of different tumor types, concurrent chemotherapies, and disease trajectories. Other limitations include the absence of objective functional outcomes and more accurate measures of lean body mass such as dual-energy x-ray absorptiometry (DEXA) or computed tomography (CT) scan. Although there are no guidelines for selecting the most appropriate modalities to measure body composition, DEXA measurements and single-slice CT scans taken in the third lumber vertebra are more precise and reproducible but are more expensive and invasive than BIA.²⁷ We did not use these modalities because our patients were no longer undergoing routine CT scans and the potential benefit of using DEXA measurements was outweighed by the additional costs and the patient burden of further tests. Although the accuracy of BIA is poor compared with CT scan and DEXA, BIA does demonstrate good short-term precision (test-retest reliability) in patients with advanced cancer,²⁸ with a precision error of 1%, and may therefore be useful in measuring changes of body composition over time.²⁹

In cachectic patients with advanced lung or GI cancer, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo. More research is required to determine whether melatonin has a role in the supportive care of patients earlier in their disease trajectory.

The author(s) indicated no potential conflicts of interest.