Effects of melatonin on physical fatigue and other symptoms in patients with advanced cancer receiving palliative care: A double-blind placebo-controlled crossover trial
We wish to thank Steen Mejlgaard, Glostrup Pharmacy, and project nurse Liv Frich. We also wish to thank all the patients participating in the trial.
Abstract
BACKGROUND
Patients with advanced cancer often experience fatigue and other symptoms that negatively impact their quality of life. The current trial investigated the effect of melatonin on fatigue and other symptoms in patients with advanced cancer.
METHODS
Patients who were aged ≥18 years, had a histologically confirmed stage IV cancer (TNM Classification), and who reported feeling significantly tired were recruited from the palliative care unit at the study institution. The study was a double-blind, randomized, placebo-controlled crossover trial. Patients received 1 week of melatonin at a dose of 20 mg or a placebo orally each night, before crossing over and receiving the opposite treatment for 1 week. Between the 2 periods, a washout period of 2 days was implemented. Outcomes were measured using the Multidimensional Fatigue Inventory (MFI-20) and The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Physical fatigue from the MFI-20 was the primary outcome. The primary analysis was a complete complier analysis (ie, it included only those patients who had consumed at least 5 capsules per week and who had answered the MFI-20 on days 1, 7, 10, and 17). Sensitivity analysis using multiple imputations including all randomized patients and all patients completing the intervention were conducted.
RESULTS
A total of 72 patients were randomized. Fifty patients completed the intervention and 44 patients were complete compliers. No significant differences between the placebo and melatonin periods were found for physical fatigue, secondary outcomes, or explorative outcomes.
CONCLUSIONS
In the current study, oral melatonin at a dose of 20 mg was not found to improve fatigue or other symptoms in patients with advanced cancer. Cancer 2015;121:3727–3736. © 2015 American Cancer Society.
INTRODUCTION
Patients with advanced cancer often experience fatigue, depression, insomnia, loss of appetite, and pain, symptoms that can have a profound impact on quality of life (QoL).1-6
Melatonin (N-acetyl-5-methoxytryptamine; MLT), is a neurohormone primarily produced and secreted by the pineal gland. MLT secretion is closely tied to the circadian rhythm and under natural circumstances it is secreted in greater quantities during the night.
When administered orally in doses between and 2 mg and 4 mg, exogenous MLT reaches peak concentrations after 52 to 60 minutes and has a half-life of 60 minutes.7 However, bioavailability varies greatly between subjects and doses from 1 mg to 5 mg result in peak plasma levels ranging between 10 and 100 times that of normal.8
There are several reasons for believing that MLT may improve fatigue and QoL in patients with cancer. A study regarding the sleeping patterns of patients with cancer described their sleep as being abnormal, with frequent interruptions and the consequent need for sleep during the day.9 This disrupted sleeping pattern could be the result of, or eventually result in, a skewed or unsettled circadian rhythm. Such disturbances can lead to fatigue and depression.2, 5, 10
MLT is a regulator of the sleep cycle and studies have shown that the use of oral MLT supplements may correct sleeping patterns and improve sleep quality in healthy individuals aged >55 years.11 Patients with cancer generally have lower levels of MLT than healthy controls.12, 13 The lowered MLT levels and disrupted circadian rhythm in patients with cancer may therefore contribute to their fatigue and lowered QoL. Previous studies have found an effect of MLT in cancer therapy. Several nonclinical trials have demonstrated that MLT inhibits cell division in tumors,11, 14-18 and several clinical trials, primarily conducted by Lissoni et al,19-26 have shown MLT to have a positive effect on survival in patients with cancer.19, 20, 23 Studies by the same group have reported that patients with cancer receiving MLT experienced improvements in depressive symptoms, asthenia, malaise, mood, and weakness. Unfortunately, these articles did not specify how and when the QoL-related outcomes were measured and in the majority of cases they were not patient self-reported. Therefore, the validity of these results may be questionable.
To our knowledge, no trials to date have investigated the effects of MLT on fatigue in patients with cancer. Given the role of MLT in the sleep cycle, the lowered levels of MLT noted among patients with cancer, and the findings that MLT may improve sleep in healthy persons aged >55 years, we found it relevant to test this drug, with its favorable toxicity profile, in relation to sleep, fatigue, and other symptoms in patients with advanced cancer. The primary objective of the current study was to determine whether oral MLT administered at night would reduce physical fatigue in patients with advanced cancer who were being treated in a palliative care facility. The effect of MLT on other cancer-related symptoms including mental fatigue, insomnia, pain, emotional function, loss of appetite, and overall QoL were also investigated.
MATERIALS AND METHODS
Trial Design
The trial was conducted at the Department of Palliative Medicine at Bispebjerg Hospital in Copenhagen, Denmark. The study consisted of 2 parts.
Part 1 was a prospective, double-blind, randomized, crossover trial. Patients received either MLT or placebo followed by a washout period of 2 days, after which the patients crossed over and received the opposite of the first week (Fig. 1). Both patients and investigators were blinded to the order of administration.
Study design. Patients in treatment arm 1 started with melatonin (MLT), whereas those in treatment arm 2 started with placebo.
Part 2 was a prospective, nonrandomized, open-label study consisting of patients who had completed part 1 and chose to continue with the MLT treatment.
Intervention
MLT at a dose of 20 mg and placebo were compounded into capsules by Glostrup Pharmacy (Glostrup, Denmark). All capsules were identical with regard to taste, color, and size. Patients were instructed to consume the capsules orally each night approximately 1 hour before going to sleep.
Patients
Patients were screened using the 15-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Version (EORTC QLQ-C15-PAL).27 Eligible patients were aged ≥18 years, had histologically confirmed stage IV cancer29, had provided written informed consent, and had answered “quite a bit” or “very much” to the QLQ-C15-PAL question “During the past week: were you tired?”
Patients with untreated anemia, untreated hypercalcemia, or systolic blood pressure <100 mm Hg; those receiving warfarin, various doses of methylphenidate, corticosteroids, or sleeping pills within the previous 2 weeks; and/or those with a thyroid-stimulating hormone level <0.5 or >5.5 µL/mL also were excluded, as were pregnant or lactating women and patients who were unable or unwilling to provide informed consent or complete a questionnaire.
Assessments and Measurements
In part 1 of the trial, patients received the MFI-20 and EORTC QLQ-C15-PAL questionnaires at the beginning and end of each treatment period (days 1, 7, 10, and 17). In part 2 of the trial, the patients received the same 2 questionnaires at the end of each week.
The MFI-20 questionnaire consists of 20 items forming 5 4-item scales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. The questionnaire was translated into Danish according to EORTC guidelines and used in a Danish context previously.30
The EORTC QLQ-C15-PAL measures QoL, functional status (physical and emotional functioning), and symptom severity (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, and constipation). The questionnaire is an abbreviated version of the EORTC QLQ-C30 developed for palliative care.27
Patients were asked to complete 3 additional items developed for this trial by the end of part 1: they were asked to evaluate in which week of the trial they had felt the most tired, in which week they had experienced the most sleeping problems, and in which week they had felt the best overall.
To investigate serious adverse events, we registered acute hospitalizations and deaths from the medical record during the part 1 trial period. Patients were asked to keep a daily diary to check for compliance.
Outcomes
The primary outcome of the current study was the difference in physical fatigue as measured by the physical fatigue scale of the MFI-20 during part 1.31 Secondary outcomes were the differences in fatigue, insomnia, loss of appetite, pain, emotional functioning, and overall QoL measured with the EORTC QLQ-C15-PAL. Explorative outcomes were the differences in the 4 other fatigue scales in the MFI-20 and the 5 remaining scales in the EORTC QLQ-C15-PAL.
Part 2 used the same measurements and outcomes as shown above. However, in part 2 each outcome was defined as the difference between scores recorded at the start of part 2 (day 17) and every subsequent week for 5 weeks.
Randomization and Blinding
Eligible patients were randomly assigned (1:1) to either MLT followed by placebo (arm 1) or placebo followed by MLT (arm 2) by Glostrup Pharmacy. The allocation sequence was generated by computer and block sizes remained unknown to all investigators. The treatment allocations were kept centrally and were concealed from patients, investigators, and the study coordinators enrolling the patients. All patients who died or were acutely hospitalized were discussed with the principal investigator to decide whether it could be a suspected unexpected serious adverse reaction (SUSAR). After the death of 1 patient, the blinding was broken for this patient by the sponsor contacting Glostrup Pharmacy. This was done to rule out the possibility of SUSAR. The patient's allocation was kept hidden from investigators and all other individuals involved in the trial and was not available during the analysis.
Sample Size Estimation
Previous studies from the study institution have shown the standard deviation (SD) for a difference between repeated measurements (3 weeks apart) in scales in the MFI-20 to range from approximately 20 to 25 points on a scale of 0 to 100 (unpublished data). To be considered of clinical relevance, a difference of 10 points on a scale of 0 to 100 was deemed necessary.32 With a risk of type I error of 0.05 with 2-sided 95% confidence intervals and a risk of type II error of 0.10 (90% power), each intervention group needed between 22 and 26 patients for an SD of 20 or 25, respectively. From this, a sample size of 25 patients in each group (ie, a total of 50 patients) was decided on.
Statistical Analysis
The data were analyzed with SAS statistical software (version 9.3; SAS Institute Inc, Cary, NC).33 Outcomes for arm 1 were calculated as the difference in mean change scores between week 1 and week 2 (scores for day 7 to day 1-scores for day 17 to day 10). Outcomes for arm 2 were calculated as the difference in mean change scores between week 2 and week 1 (scores for day 17 to day 10-scores for day 7 to day 1).
Before pooling the 2 groups, we tested primary and secondary outcomes for period and carryover effect using the calculations of Pocock.34 If these were satisfactory, we continued to pool the data.
The primary analysis was a per protocol analysis including only complete compliers, defined as those patients who had consumed at least 5 capsules per week for the 2 weeks in part 1 and who had answered the MFI-20 on days 1, 7, 10, and 17. A Student t test for paired data was used to evaluate the differences in mean scores. A significance level of .05 was used for the primary outcome and a significance level of .01 was used for the secondary outcomes to adjust for the familywise error rate.
As a sensitivity analysis, an intention-to-treat (ITT) analysis including all 72 randomized patients using multiple imputations for missing values was conducted.35 A total of 10 different data sets were created with imputations based on regression models with the following independent variables included: baseline scores on MFI-20 and EORTC QLQ-C15-PAL, treatment arm (MLT or placebo in the first week), age, sex, diagnosis, and World Health Organization performance score. An additional sensitivity analysis including the 50 patients who had completed the intervention, using multiple imputations for missing values, was conducted. For the imputations, the MI and MI analysis procedure in the SAS statistical software was used.
We used a sign test for independence to determine which week the patients felt most tired, experienced the most sleeping problems, and felt the best according to the 3 additional evaluation questions and to test for differences in the number of acute hospitalizations and deaths during the week in which the patients received MLT versus placebo. Patients included in this analysis had consumed at least 1 capsule.
All outcomes for part 2 were explorative and included complete compliers only. For part 2, complete compliers were defined as those patients who had consumed at least 5 capsules per week and had completed the physical fatigue scale of the MFI-20 on day 17 (T0), T1, and at ≥1 of the T2, T3, T4, or T5 timepoints. P values were calculated for T5 minus T0.
Permits
This trial was approved by the locoregional Ethics Committee (journal number H-C-2009-006), the National Board of Health (journal number 2612-3953), and the Danish Data Protection Agency (BBH-2009-02). It was registered at www.clinicaltrials.gov (identifier 00925899) in June 2009. The study followed good clinical practice, and was monitored by the Good Clinical Practice unit of the Copenhagen University Hospitals (journal number 2008-249).
RESULTS
Patients
A total of 72 patients were recruited from October 2009 to January 2013 and randomly assigned to either arm 1 (34 patients) or arm 2 (38 patients) (Fig. 2). Eleven patients in each treatment arm withdrew before completing part 1 of the study. Of the remaining 50 patients, 44 were complete compliers. Of the 50 patients who completed part 1, 36 chose to continue in part 2, 18 of whom completed the 5 weeks of treatment (Fig. 3).
Flowchart for part 1 of the current study. ITT indicates intention-to-treat; MFI-20, Multidimensional Fatigue Inventory.
Flowchart for part 2 of the current study.
Baseline characteristics of patients in arm 1 and arm 2 demonstrated slight overweight noted among patients with breast cancer in treatment arm 2 and those with gynecological cancer in treatment arm 1 (Table 1).
| Arm 1 | Arm 2 | |||
|---|---|---|---|---|
| No. of Patients (%) | No. of Patients (%) | |||
| Characteristics | Complete Compliers | ITT Analysis | Complete Compliers | ITT Analysis |
| Sex | ||||
| Male | 8 (38) | 10 (29) | 7 (30) | 13 (34) |
| Female | 13 (62) | 24 (71) | 16 (70) | 25 (66) |
| Age | ||||
| Mean (range) | 64 (35−84) | 65 (35−84) | 60 (33−86) | 62 (33−89) |
| WHO performance status | ||||
| 1 | 4 (19) | 7 (21) | 6 (26) | 7 (19) |
| 2 | 17 (81) | 25 (74) | 16 (70) | 25 (68) |
| 3 | 0 (0) | 2 (6) | 1 (4) | 5 (14) |
| Cancer diagnosis | ||||
| Breast | 5 (24) | 9 (38) | 10 (43) | 14 (37) |
| Lung | 1 (5) | 2 (6) | 1 (4) | 4 (11) |
| Gastrointestinal (liver, extrahepatic bile duct, pancreas, ventricle, colon, rectal) | 5 (24) | 10 (29) | 8 (35) | 8 (21) |
| Gynecological (ovarian, cervical, uterine) | 6 (29) | 10 (29) | 2 (9) | 4 (11) |
| Other (brain, leukemia, laryngeal, esophageal, prostate, kidney, malignant melanoma, unknown) | 4 (19) | 5 (15) | 2 (9) | 8 (21) |
- Abbreviations: ITT, intention-to-treat; WHO, World Health Organization.
Part 1 Outcomes
Pocock calculations demonstrated no significant period or carryover effect for primary (P = .47 and P = .14, respectively) or secondary outcomes.34 The data were then pooled.
Analysis of the primary outcome indicated no significant difference between MLT and placebo (Table 2). The difference in change of the mean score was 2.8 on a scale of 0 to 100 favoring placebo (P = .47). Similarly, the ITT analysis demonstrated no significant difference (Table 3), with a difference with regard to physical fatigue of −2.1 favoring MLT (P = .56). The sensitivity analysis of the 50 patients who had completed the intervention demonstrated no difference (data not shown).
| Mean Baseline Score [SD]b | Mean Change in Score After MLT [SD] | Mean Change in Score After Placebo [SD] | Mean Difference in Change Between Week With MLT and Placebo [SD] (N) | P | |
|---|---|---|---|---|---|
| Primary outcome | |||||
| Physical fatiguec | 72.0 [21.2] | −1.1 [15.9] | −3.9 [18.1] | 2.8 [25.6] (N=44) | .47 |
| Secondary outcomes | |||||
| Fatigued | 60.9 [15.6] | −3.2 [18.6] | −2.1 [24.8] | −1.4 [34.1] (N=41) | .80 |
| Insomniad | 32.6 [33.3] | −9.9 [23.4] | −4.6 [30.9] | −5.3 [38.0] (N=44) | .36 |
| Loss of appetited | 33.3 [30.5] | −0.8 [25.4] | −3.2 [21.6] | −0.8 [33.3] (N=44) | .88 |
| Paind | 34.9 [27.3] | 0.8 [19.3] | 1.9 [22.2] | −1.1 [32.6] (N=44) | .82 |
| Emotional functiond | 76.6 [23.8] | −0.6 [23.5] | 3.3 [18.5] | −4.4 [30.9] (N=42) | .36 |
| Overall QoLd | 56.6 [18.6] | −0.8 [13.6] | −3.2 [19.2] | 2.9 [21.7] (N=41) | .41 |
| Explorative outcomes | |||||
| General fatiguec | 65.5 [16.6] | −5.9 [19.3] | 2.7 [21.5] | −8.7 [32.9] (N=44) | .09 |
| Reduced activityc | 67.1 [26.4] | −4.2 [20.8] | −0.4 [14.9] | −3.8 [22.9] (N=44) | .28 |
| Reduced motivationc | 33.5 [20.6] | −1.6 [16.7] | 2.9 [13.3] | −4.6 [19.1] (N=44) | .12 |
| Mental fatiguec | 34.9 [24.2] | −0.9 [19.2] | −2.9 [16.9] | 2.0 [28.2] (N=44) | .63 |
| Dyspnead | 25.0 [27.9] | 3.0 [22.5] | 4.6 [23.4] | −1.5 [35.9] (N=44) | .78 |
| Constipationd | 18.3 [25.7] | −0.8 [20.2] | 1.6 [25.5] | −3.3 [35.6] (N=41) | .56 |
| Physical functiond | 47.6 [19.4] | 3.6 [11.4] | −1.4 [13.5] | 5.1 [18.8] (N=43) | .09 |
| Nausea/vomitingd | 8.7 [13.7] | 2.3 [19.2] | −2.3 [12.4] | 5.1 [18.8] (N=43) | .11 |
- Abbreviations: EORTC-QLQ-C15-PAL, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative; MFI-20, Multidimensional Fatigue Inventory; MLT, melatonin; QoL, quality of life; SD, standard deviation.
- All scores range from 0 to 100. In all scores except emotional function, physical function, and overall QoL, a higher score indicated more symptoms/problems.
- a Complete compliers were patients who consumed a minimum of 5 capsules each week and answered the MFI-20 physical fatigue subscale at days 1, 7, 10, and 17.
- b Baseline is scores from day 1.
- c Item from MFI-20.
- d Item from EORTC-QLQ-C15-PAL.
| Mean Baseline Score (95% CI)a | Mean Change in Score After MLT (95% CI) | Mean Change in Score After Placebo (95% CI) | Mean Difference in Change Between Week With MLT and Placebo (95% CI) | P | ||
|---|---|---|---|---|---|---|
| Primary outcome | ||||||
| Physical fatigueb | 73.8 (72.3 to 75.3) | −3.4 (−7.9 to 1.2) | −1.3 (−5.6 to 3.0) | −2.1 (−9.1 to 4.9) | .56 | |
| Secondary outcomes | ||||||
| Fatiguec | 66.0 (61.4 to 70.6) | −5.9 (−12.6 to 0.7) | −3.8 (−10.5 to 2.8) | −2.1 (−12.3 to 8.1) | .68 | |
| Insomniac | 36.6 (28.3 to 44.8) | −9.2 (−16.6 to −1.8) | −7.9 (−17.3 to 1.4) | −1.2 (−13.4 to 11.0) | .84 | |
| Loss of appetitec | 43.9 (36.4 to 51.6) | −6.8 (−13.7 to 0.1) | −4.6 (−10.8 to 1.5) | −2.2 (−10.9 to 6.5) | .62 | |
| Painc | 36.8 (30.7 to 42.9) | −1.7 (−7.6 to 4.3) | 1.5 (−4.3 to 7.3) | −3.2 (12.2 to 5.8) | .82 | |
| Emotional functionc | 69.9 (63.8 to 75.9) | 2.1 (−4.8 to 9.1) | 6.6 (−0.5 to 12.7) | −4.5 (−13.2 to 4.2) | .31 | |
| Overall QoLc | 50.4 (45.9 to 54.8) | 0.7 (−3.7 to 5.1) | 0.2 (−4.8 to 5.2) | 0.5 (−5.9 to 6.8) | .68 | |
| Explorative outcomes | ||||||
| General fatigueb | 69.9 (65.7 to 74.3) | −5.9 (−12.0 to 0.2) | −0.7 (−6.4 to 4.9) | −5.2 (−14.4 to 3.9) | .26 | |
| Reduced activityb | 70.3 (64.6 to 75.9) | −4.3 (−9.8 to 1.2) | −1.0 (−5.5 to 3.5) | −3.3 (−9.9 to 3.3) | .33 | |
| Reduced motivationb | 37.2 (31.6 to 42.8) | −1.6 (−6.4 to 3.2) | 1.4 (−3.0 to 5.9) | −3.0 (−9.0 to 2.9) | .32 | |
| Mental fatigueb | 39.5 (33.8 to 45.2) | −2.3 (−7.3 to 2.7) | −5.0 (−11.1 to 0.9) | −2.8 (−5.2 to 10.8) | .49 | |
| Dyspneac | 26.4 (19.7 to 33.1) | −2.8 (−9.7 to 4.1) | 3.1 (−4.2 to 10.4) | −5.9 (−16.8 to 4.9) | .78 | |
| Constipationc | 20.9 (14.2 to 27.7) | −0.9 (−7.4 to 5.5) | 1.4 (−4.9 to 7.8) | −2.4 (−12.3 to 7.5) | .63 | |
| Physical functionc | 43.5 (38.9 to 48.1) | 3.1 (−0.8 to 11.6) | −0.5 (−4.8 to 3.9) | 3.6 (−2.3 to 9.4) | .23 | |
| Nausea/vomitingc | 14.8 (9.7 to 19.9) | 0.9 (−4.5 to 6.4) | −4.4 (−8.8 to 0.1) | 5.4 (−0.8 to 11.6) | .09 | |
- Abbreviations: 95% CI, 95% confidence interval; EORTC-QLQ-C15-PAL, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative; ITT, intention-to-treat; MFI-20, Multidimensional Fatigue Inventory; MLT, melatonin; QoL, quality of life.
- All scores ranged from 0 to 100. In all scores except emotional function, physical function, and overall QoL, a higher score indicated more symptoms/problems.
- a Baseline was scores from day 1.
- b Item from MFI-20.
- c Item from EORTC-QLQ-C15-PAL.
For the secondary outcomes, the complete complier analyses demonstrated no significant effect of the intervention. A difference of −1.4 (P = .80) was found for fatigue and overall QoL demonstrated a difference of 2.9 (P = .41).
The ITT analysis yielded similar insignificant results (Table 3). No significant differences in the mean scores for any of the explorative outcomes were found. The largest difference was observed for general fatigue (difference of −8.7 favoring MLT [P = .09]).
The 3 additional questions showed that 14 patients reported feeling the most tired while receiving MLT and 24 while receiving placebo (P = .14). Seventeen patients reported having the least trouble sleeping while receiving placebo and 11 while receiving MLT (P = .34). Twenty-one patients reported feeling better overall while receiving MLT and 11 while receiving placebo (P = .63).
There was no difference in the number of acute hospitalizations (6 patients receiving MLT vs 12 patients receiving placebo) or deaths (1 patient receiving MLT vs 2 patients receiving placebo) occurring during the 2 weeks (P = .30 and P =.1, respectively) among the 71 patients who had consumed at least 1 capsule. No SUSARs were recorded.
Part 2 Results
Results from part 2 indicated an overall deterioration in the patients’ health (Table 4). Pain scores increased by 8.9 (SD, 21.5) after 2 weeks, fatigue scores increased by 9.7 (SD, 18.1) after 3 weeks, and insomnia scores increased by 10.7 (SD, 26.8) after 3 weeks. Loss of appetite scores increased by 15.0 points (SD, 16.1) during week 5.
| Mean Baseline Score (Day 17) [SD] (No.) | Mean After 1 Week [SD] (No.) | Mean After 2 Weeks [SD] (No.) | Mean After 3 Weeks [SD] (No.) | Mean After 4 Weeks [SD] (No.) | Mean After 5 Weeks [SD] (No.) | P | |
|---|---|---|---|---|---|---|---|
| Outcomes | |||||||
| Physical fatigueb | 65.8 [26.3] (N=36) | 5.2 [17.8] (N=36) | 0.4 [13.9] (N=29) | 1.8 [17.7] (N=25) | 2.3 [17.7] (N=22) | 1.7 [18.5] (N=18) | .69 |
| Fatiguec | 47.3 [15.8] (N=35) | 3.5 [21.5] (N=35) | 1.2 [20.8] (N=28) | 9.7 [18.1] (N=23) | 3.5 [23.1] (N=22) | 2.8 [23.1] (N=20) | .59 |
| Insomniac | 13.9 [25.7] (N=36) | 3.7 [27.4] (N=36) | 6.9 [27.3] (N=29) | 10.7 [26.7] (N=25) | 3.0 [20.3] (N=22) | 3.3 [18.4] (N=20) | .43 |
| Loss of appetitec | 28.7 [29.9] (N=36) | 3.7 [22.2] (N=36) | 8.3 [23.4] (N=28) | 12.0 [25.2] (N=25) | 13.6 [35.1] (N=22) | 15.0 [25.3] (N=20) | .02 |
| Painc | 29.6 [25.2] (N=36) | 2.3 [22.2] (N=36) | 8.9 [21.5] (N=28) | 6.7 [30.4] (N=25) | 7.6 [35.9] (N=22) | 5.8 [27.7] (N=20) | .36 |
| Emotional functionc | 81.0 [30.4] (N=36) | −0.9 [16.9] (N=36) | −1.4 [13.7] (N=29) | 1.7 [20.7] (N=25) | −4.9 [22.8] (N=22) | −1.3 [20.9] (N=20) | .79 |
| Overall QoLc | 56.9 [19.3] (N=36) | −1.9 [13.5] (N=34) | −1.7 [13.6] (N=29) | −6.7 [19.8] (N=25) | −4.6 [12.8] (N=22) | 1.7 [16.1] (N=20) | .65 |
- Abbreviations: EORTC-QLQ-C15-PAL, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative; MFI-20, Multidimensional Fatigue Inventory; MLT, melatonin; QoL, quality of life; SD, standard deviation.
- All scores ranged from 0 to 100. In all scores except emotional function, physical function, and overall QoL, a higher score indicated more symptoms/problems.
- a Analyses were based on complete compliers (ie, patients who had consumed at least 5 capsules per week and had completed the physical fatigue scale of the MFI-20 on day 17 and at least one of the following timepoints: time 1, 2, 3, 4, or 5).
- b Item from MFI-20.
- c Item from EORTC-QLQ-C15-PAL.
DISCUSSION
In the current study, MLT was not found to improve physical fatigue or other symptoms or overall QoL among patients with advanced cancer receiving treatment in the palliative medicine department.
We chose to conduct a per protocol analysis as our primary analysis to adhere as closely as possible to the original study protocol. Because we had a slightly higher than expected SD of 26 and a slightly lower “complete compliance,” the current study had an actual power of 70%.
An analysis of those patients who had completed the intervention (50 patients) and the total number of randomized patients (72 patients) was conducted using multiple imputations and demonstrated results similar to those of the primary analysis. Thus, the relatively low power of the primary analysis was unlikely to be the cause of the negative result.
The general trend noted among all study subjects was toward a worsening of symptoms during the trial period, which, given the critically ill nature of the current study participants, was to be expected. We were not able to demonstrate an ameliorating effect of MLT on this downward trend. Patients who are eligible for palliative care are a heterogeneous group, with a wide range of symptoms and underlying causes. Although poor quality of sleep and disrupted circadian rhythm may contribute to fatigue, factors such as infection, cachexia, anorexia, nausea, pain, depression, and adverse effects of treatment are likely to play a larger role. It may be the case that a small effect of MLT is simply “drowned out” by the cumulative negative effects of terminal illness. Anecdotally, our clinical investigator noted large improvements in younger women receiving MLT.
Compared with consecutive patients referred to the study institution during a previous study period, the patients recruited to the current study were found to have lower symptom scores according to the EORTC QLQ-C15-PAL and MFI-20, indicating a population of better functioning patients than the average patient receiving palliative care.1, 36 This tendency also could be observed in our relatively low dropout rates, deaths, and hospitalizations. However, there is no reason to believe that MLT would have had a greater impact on patients with a higher symptom burden.
The EORTC QLQ-C30 questionnaire has been thoroughly validated, and the shortened QLQ-C15-PAL produces directly compatible scores.27, 31 The MFI-20 has been validated with a wide range of conditions and previous studies have shown good internal consistency for all subscales in the MFI-20 and with a stable multidimensional factorial structure.37, 38 Furthermore, studies have demonstrated the MFI-20 to be sensitive in differentiating between chronically ill and healthy populations as well as able to identify changes in the MFI after other interventions such as exercise, counseling, and pharmacological interventions.31, 39-42
Despite the previous validation of the questionnaires used herein, the 3 additional evaluating questions developed for the current trial were originally included to provide an additional source of comparison for results gathered from the MFI-20 and EORTC QLQ-C15-PAL. Although a slight tendency toward patients feeling less tired while receiving MLT was found from the additional questions, this finding was not statistically significant and thus corroborates our primary results.
Strengths of the current study include the double-blind, randomized, placebo-controlled, crossover design, the benefits of which include direct comparison of the interventions under investigation among the same patients, thereby eliminating between-subject variability.43 Our trial period of 1 week was initially selected to ensure that any potential findings would be directly applicable in a clinical palliative setting, in which fast-acting treatments with significant effects are preferable. Other trials investigating oral MLT supplements in otherwise healthy patients with insomnia have shown significant improvements after a single dose using intervention periods of 5 to 7 days.44-46 This supports the timeframe chosen for the current study. However, we cannot rule out that we could have found an effect of MLT if our intervention period had been longer.
Our MLT dose of 20 mg is unlikely to be the cause of the negative results. Trials using the same or lower doses have reported positive effects.47 Several studies regarding the pharmacokinetics of MLT have demonstrated a large degree of variability in bioavailability ranging from 10% to 56% among healthy subjects, resulting in a difference in serum levels of 10 to 100 times that of normal values in individuals receiving the same dose. This complicating factor introduces an element of uncertainty, further obscuring results.11
A recent meta-analysis of 19 studies involving 21 trials on the use of MLT in patients with cancer found significantly lower occurrences of cancer-related symptoms such as asthenia, anemia, and thrombocytopenia and improved 1-year mortality rates.47 Of the 19 studies included, all but 1 were conducted by the group of investigators lead by Lissoni et al. None of the included trials was blinded, and only 1 included details regarding randomization. Furthermore, the trials did not specify how and when the potential effects of MLT on cancer symptoms were evaluated.19 Although this finding in and of itself is not grounds for an inference of bias, it highlights the need for further independent investigations.
We were unable to replicate the positive results of previous studies. This also was the case in the study by Del Fabbro et al.28 Although the purpose of their study was to determine the effect of MLT on cancer-associated cachexia, QoL was also measured and found not to differ significantly from placebo controls.28
The current study investigated the potential use of MLT in late-phase palliative treatment. As a patient's disease progresses, their symptoms, concerns, and challenges are constantly changing. It may well be that interventions that demonstrate no effect in the final stages of a disease could make a difference if applied earlier.
Conclusions
In the current trial, a dose of 20 mg of MLT taken orally at night did not improve physical fatigue in patients with advanced cancer. Furthermore, we were unable to identify improvements with regard to any other symptoms measured with the EORTC QLQ-C15-PAL or MFI-20. Further research is needed to determine whether MLT has a role in the earlier stages of palliative care.
FUNDING SUPPORT
Supported by the IM Daehnfeldt Foundation, the Aase and Ejnar Danielsens Foundation, the Beckett Foundation, and the Danish Cancer Society (journal number A1013).
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
