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Original Article

Effects of Melatonin on Physical Fatigue and Other Symptoms


in Patients With Advanced Cancer Receiving Palliative Care:
A Double-Blind Placebo-Controlled Crossover Trial
Charlotte Lund Rasmussen, BSc1; Marc Klee Olsen, BSc1; Anna Thit Johnsen, MSc, PhD1; Morten Aagaard Petersen, MSc1;
Helena Lindholm, MSc1; Line Andersen, MD1; Birgit Villadsen, MPH1; Mogens Groenvold, MD, DrMedSci1,2;
and Lise Pedersen, MD, PhD, MedSci1

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 sig-
nificantly 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;121:3727-36.
C 2015 American Cancer Society.
V

KEYWORDS: fatigue, hospice and palliative care nursing, melatonin, neoplasms, palliative care, quality of health care, quality of life.

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 pin-
eal 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

Corresponding author: Charlotte Lund Rasmussen, BSc, Research Unit, Department of Palliative Medicine, Bispebjerg Hospital, Parmagade 58, 4. Tv, 2300
Copenhagen, Denmark; Fax: (011) 35 31 33 44; Charlotte@r-team.dk
1
Research Unit, Department of Palliative Medicine, Bispebjerg Hospital, Copenhagen, Denmark; 2Institute of Public Health, University of Copenhagen, Copenhagen,
Denmark

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.

DOI: 10.1002/cncr.29563, Received: March 25, 2015; Revised: May 27, 2015; Accepted: June 17, 2015, Published online July 15, 2015 in Wiley Online Library
(wileyonlinelibrary.com)

Cancer October 15, 2015 3727


Original Article

therefore contribute to their fatigue and lowered QoL. Pre- color, and size. Patients were instructed to consume the
vious studies have found an effect of MLT in cancer ther- capsules orally each night approximately 1 hour before
apy. Several nonclinical trials have demonstrated that MLT going to sleep.
inhibits cell division in tumors,11,14-18 and several clinical
trials, primarily conducted by Lissoni et al,19-26 have shown
Patients
MLT to have a positive effect on survival in patients with
Patients were screened using the 15-item European
cancer.19,20,23 Studies by the same group have reported that
Organisation for Research and Treatment of Cancer
patients with cancer receiving MLT experienced improve-
Quality of Life Questionnaire Core 15 Palliative Version
ments in depressive symptoms, asthenia, malaise, mood,
(EORTC QLQ-C15-PAL).27 Eligible patients were aged
and weakness. Unfortunately, these articles did not specify
18 years, had histologically confirmed stage IV cancer28,
how and when the QoL-related outcomes were measured
had provided written informed consent, and had
and in the majority of cases they were not patient self-
answered quite a bit or very much to the QLQ-C15-
reported. Therefore, the validity of these results may be
PAL question During the past week: were you tired?
questionable.
Patients with untreated anemia, untreated hypercal-
To our knowledge, no trials to date have investi-
cemia, or systolic blood pressure <100 mm Hg; those
gated the effects of MLT on fatigue in patients with can-
receiving warfarin, various doses of methylphenidate, cor-
cer. Given the role of MLT in the sleep cycle, the
ticosteroids, or sleeping pills within the previous 2 weeks;
lowered levels of MLT noted among patients with can-
and/or those with a thyroid-stimulating hormone level
cer, and the findings that MLT may improve sleep in
<0.5 or >5.5 mL/mL also were excluded, as were preg-
healthy persons aged >55 years, we found it relevant to
nant or lactating women and patients who were unable or
test this drug, with its favorable toxicity profile, in rela-
unwilling to provide informed consent or complete a
tion to sleep, fatigue, and other symptoms in patients
questionnaire.
with advanced cancer. The primary objective of the cur-
rent study was to determine whether oral MLT adminis-
tered at night would reduce physical fatigue in patients Assessments and Measurements
with advanced cancer who were being treated in a pallia- In part 1 of the trial, patients received the MFI-20 and
tive care facility. The effect of MLT on other cancer- EORTC QLQ-C15-PAL questionnaires at the beginning
related symptoms including mental fatigue, insomnia, and end of each treatment period (days 1, 7, 10, and 17).
pain, emotional function, loss of appetite, and overall In part 2 of the trial, the patients received the same
QoL were also investigated. 2 questionnaires at the end of each week.
The MFI-20 questionnaire consists of 20 items
MATERIALS AND METHODS forming 5 4-item scales: general fatigue, physical fatigue,
Trial Design mental fatigue, reduced activity, and reduced motivation.
The trial was conducted at the Department of Palliative The questionnaire was translated into Danish according
Medicine at Bispebjerg Hospital in Copenhagen, Den- to EORTC guidelines and used in a Danish context
mark. The study consisted of 2 parts. previously.29
Part 1 was a prospective, double-blind, randomized, The EORTC QLQ-C15-PAL measures QoL, func-
crossover trial. Patients received either MLT or placebo tional status (physical and emotional functioning), and
followed by a washout period of 2 days, after which the symptom severity (fatigue, nausea and vomiting, pain,
patients crossed over and received the opposite of the first dyspnea, insomnia, loss of appetite, and constipation).
week (Fig. 1). Both patients and investigators were The questionnaire is an abbreviated version of the
blinded to the order of administration. EORTC QLQ-C30 developed for palliative care.27
Part 2 was a prospective, nonrandomized, open- Patients were asked to complete 3 additional items
label study consisting of patients who had completed developed for this trial by the end of part 1: they were
part 1 and chose to continue with the MLT treatment. asked to evaluate in which week of the trial they had felt
the most tired, in which week they had experienced the
Intervention most sleeping problems, and in which week they had felt
MLT at a dose of 20 mg and placebo were compounded the best overall.
into capsules by Glostrup Pharmacy (Glostrup, To investigate serious adverse events, we registered
Denmark). All capsules were identical with regard to taste, acute hospitalizations and deaths from the medical record

3728 Cancer October 15, 2015


Effects of Melatonin on Physical Fatigue/Lund Ramussen et al

Figure 1. Study design. Patients in treatment arm 1 started with melatonin (MLT), whereas those in treatment arm 2 started with
placebo.

during the part 1 trial period. Patients were asked to keep involved in the trial and was not available during the
a daily diary to check for compliance. analysis.

Outcomes Sample Size Estimation


The primary outcome of the current study was the differ- Previous studies from the study institution have shown
ence in physical fatigue as measured by the physical the standard deviation (SD) for a difference between
fatigue scale of the MFI-20 during part 1.30 Secondary repeated measurements (3 weeks apart) in scales in the
outcomes were the differences in fatigue, insomnia, loss of MFI-20 to range from approximately 20 to 25 points on a
appetite, pain, emotional functioning, and overall QoL scale of 0 to 100 (unpublished data). To be considered of
measured with the EORTC QLQ-C15-PAL. Explorative clinical relevance, a difference of 10 points on a scale of
outcomes were the differences in the 4 other fatigue scales 0 to 100 was deemed necessary.31 With a risk of type I
in the MFI-20 and the 5 remaining scales in the EORTC error of 0.05 with 2-sided 95% confidence intervals and a
QLQ-C15-PAL. risk of type II error of 0.10 (90% power), each intervention
Part 2 used the same measurements and outcomes as group needed between 22 and 26 patients for an SD of 20 or
shown above. However, in part 2 each outcome was 25, respectively. From this, a sample size of 25 patients in
defined as the difference between scores recorded at the each group (ie, a total of 50 patients) was decided on.
start of part 2 (day 17) and every subsequent week for
5 weeks. Statistical Analysis
The data were analyzed with SAS statistical software (ver-
Randomization and Blinding sion 9.3; SAS Institute Inc, Cary, NC).32 Outcomes for
Eligible patients were randomly assigned (1:1) to either arm 1 were calculated as the difference in mean change
MLT followed by placebo (arm 1) or placebo followed by scores between week 1 and week 2 (scores for day 7 to day
MLT (arm 2) by Glostrup Pharmacy. The allocation 1-scores for day 17 to day 10). Outcomes for arm 2 were
sequence was generated by computer and block sizes calculated as the difference in mean change scores between
remained unknown to all investigators. The treatment week 2 and week 1 (scores for day 17 to day 10-scores for
allocations were kept centrally and were concealed from day 7 to day 1).
patients, investigators, and the study coordinators enroll- Before pooling the 2 groups, we tested primary and
ing the patients. All patients who died or were acutely hos- secondary outcomes for period and carryover effect using
pitalized were discussed with the principal investigator to the calculations of Pocock.33 If these were satisfactory, we
decide whether it could be a suspected unexpected serious continued to pool the data.
adverse reaction (SUSAR). After the death of 1 patient, The primary analysis was a per protocol analysis
the blinding was broken for this patient by the sponsor including only complete compliers, defined as those
contacting Glostrup Pharmacy. This was done to rule out patients who had consumed at least 5 capsules per week
the possibility of SUSAR. The patients allocation was for the 2 weeks in part 1 and who had answered the
kept hidden from investigators and all other individuals MFI-20 on days 1, 7, 10, and 17. A Student t test for

Cancer October 15, 2015 3729


Original Article

Figure 2. Flowchart for part 1 of the current study. ITT indicates intention-to-treat; MFI-20, Multidimensional Fatigue Inventory.

paired data was used to evaluate the differences in mean the MI and MI analysis procedure in the SAS statistical
scores. A significance level of .05 was used for the pri- software was used.
mary outcome and a significance level of .01 was used We used a sign test for independence to determine
for the secondary outcomes to adjust for the familywise which week the patients felt most tired, experienced the
error rate. most sleeping problems, and felt the best according to the
As a sensitivity analysis, an intention-to-treat (ITT) 3 additional evaluation questions and to test for differen-
analysis including all 72 randomized patients using multi- ces in the number of acute hospitalizations and deaths
ple imputations for missing values was conducted.34 A during the week in which the patients received MLT ver-
total of 10 different data sets were created with imputa- sus placebo. Patients included in this analysis had con-
tions based on regression models with the following inde- sumed at least 1 capsule.
pendent variables included: baseline scores on MFI-20 All outcomes for part 2 were explorative and
and EORTC QLQ-C15-PAL, treatment arm (MLT or included complete compliers only. For part 2, complete
placebo in the first week), age, sex, diagnosis, and World compliers were defined as those patients who had con-
Health Organization performance score. An additional sumed at least 5 capsules per week and had completed the
sensitivity analysis including the 50 patients who had physical fatigue scale of the MFI-20 on day 17 (T0), T1,
completed the intervention, using multiple imputations and at 1 of the T2, T3, T4, or T5 timepoints. P values
for missing values, was conducted. For the imputations, were calculated for T5 minus T0.

3730 Cancer October 15, 2015


Effects of Melatonin on Physical Fatigue/Lund Ramussen et al

patients in each treatment arm withdrew before complet-


ing part 1 of the study. Of the remaining 50 patients, 44
were complete compliers. Of the 50 patients who com-
pleted part 1, 36 chose to continue in part 2, 18 of whom
completed the 5 weeks of treatment (Fig. 3).
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).

Part 1 Outcomes
Pocock calculations demonstrated no significant period or
carryover effect for primary (P 5 .47 and P 5 .14, respec-
tively) or secondary outcomes.33 The data were then pooled.
Analysis of the primary outcome indicated no signif-
icant 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 5 .47). Similarly, the
ITT analysis demonstrated no significant difference
(Table 3), with a difference with regard to physical fatigue
of 22.1 favoring MLT (P 5 .56). The sensitivity analysis
of the 50 patients who had completed the intervention
demonstrated no difference (data not shown).
For the secondary outcomes, the complete complier
analyses demonstrated no significant effect of the interven-
tion. A difference of 21.4 (P 5 .80) was found for fatigue
and overall QoL demonstrated a difference of 2.9 (P 5 .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 larg-
est difference was observed for general fatigue (difference
Figure 3. Flowchart for part 2 of the current study. of 28.7 favoring MLT [P 5 .09]).
The 3 additional questions showed that 14 patients
reported feeling the most tired while receiving MLT and
Permits 24 while receiving placebo (P 5 .14). Seventeen patients
This trial was approved by the locoregional Ethics Com- reported having the least trouble sleeping while receiving
mittee (journal number H-C-2009-006), the National placebo and 11 while receiving MLT (P 5 .34). Twenty-
Board of Health (journal number 2612-3953), and the one patients reported feeling better overall while receiving
Danish Data Protection Agency (BBH-2009-02). It was MLT and 11 while receiving placebo (P 5 .63).
registered at www.clinicaltrials.gov (identifier 00925899) There was no difference in the number of acute hospi-
in June 2009. The study followed good clinical practice, talizations (6 patients receiving MLT vs 12 patients receiving
and was monitored by the Good Clinical Practice unit of placebo) or deaths (1 patient receiving MLT vs 2 patients
the Copenhagen University Hospitals (journal number receiving placebo) occurring during the 2 weeks (P 5 .30
2008-249). and P 5.1, respectively) among the 71 patients who had
consumed at least 1 capsule. No SUSARs were recorded.
RESULTS
Patients Part 2 Results
A total of 72 patients were recruited from October 2009 Results from part 2 indicated an overall deterioration in
to January 2013 and randomly assigned to either arm 1 the patients health (Table 4). Pain scores increased by 8.9
(34 patients) or arm 2 (38 patients) (Fig. 2). Eleven (SD, 21.5) after 2 weeks, fatigue scores increased by 9.7

Cancer October 15, 2015 3731


Original Article

TABLE 1. Baseline Characteristics of Study Participants

Arm 1 Arm 2

No. of Patients (%) No. of Patients (%)

Complete ITT Complete ITT


Characteristics Compliers Analysis Compliers Analysis

Sex
Male 8 (38) 10 (29) 7 (30) 13 (34)
Female 13 (62) 24 (71) 16 (70) 25 (66)
Age
Mean (range) 64 (35284) 65 (35284) 60 (33286) 62 (33289)
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, 5 (24) 10 (29) 8 (35) 8 (21)
ventricle, colon, rectal)
Gynecological (ovarian, cervical, uterine) 6 (29) 10 (29) 2 (9) 4 (11)
Other (brain, leukemia, laryngeal, esophageal, prostate, kidney, 4 (19) 5 (15) 2 (9) 8 (21)
malignant melanoma, unknown)

Abbreviations: ITT, intention-to-treat; WHO, World Health Organization.

TABLE 2. Complete Compliers Analysis of MFI-20 and EORTC QLQ-C15-PAL Scores at Baseline and
Changes in Scores After Treatment With MLT and Placeboa

Mean Mean Difference


Mean Change in Mean Change in Change Between
Baseline Score After in Score After Week With MLT and
Score [SD]b MLT [SD] Placebo [SD] Placebo [SD] (N) P

Primary outcome
Physical fatiguec 72.0 [21.2] 21.1 [15.9] 23.9 [18.1] 2.8 [25.6] (N544) .47
Secondary outcomes
Fatigued 60.9 [15.6] 23.2 [18.6] 22.1 [24.8] 21.4 [34.1] (N541) .80
Insomniad 32.6 [33.3] 29.9 [23.4] 24.6 [30.9] 25.3 [38.0] (N544) .36
Loss of appetited 33.3 [30.5] 20.8 [25.4] 23.2 [21.6] 20.8 [33.3] (N544) .88
Paind 34.9 [27.3] 0.8 [19.3] 1.9 [22.2] 21.1 [32.6] (N544) .82
Emotional functiond 76.6 [23.8] 20.6 [23.5] 3.3 [18.5] 24.4 [30.9] (N542) .36
Overall QoLd 56.6 [18.6] 20.8 [13.6] 23.2 [19.2] 2.9 [21.7] (N541) .41
Explorative outcomes
General fatiguec 65.5 [16.6] 25.9 [19.3] 2.7 [21.5] 28.7 [32.9] (N544) .09
Reduced activityc 67.1 [26.4] 24.2 [20.8] 20.4 [14.9] 23.8 [22.9] (N544) .28
Reduced motivationc 33.5 [20.6] 21.6 [16.7] 2.9 [13.3] 24.6 [19.1] (N544) .12
Mental fatiguec 34.9 [24.2] 20.9 [19.2] 22.9 [16.9] 2.0 [28.2] (N544) .63
Dyspnead 25.0 [27.9] 3.0 [22.5] 4.6 [23.4] 21.5 [35.9] (N544) .78
Constipationd 18.3 [25.7] 20.8 [20.2] 1.6 [25.5] 23.3 [35.6] (N541) .56
Physical functiond 47.6 [19.4] 3.6 [11.4] 21.4 [13.5] 5.1 [18.8] (N543) .09
Nausea/vomitingd 8.7 [13.7] 2.3 [19.2] 22.3 [12.4] 5.1 [18.8] (N543) .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.

(SD, 18.1) after 3 weeks, and insomnia scores increased DISCUSSION


by 10.7 (SD, 26.8) after 3 weeks. Loss of appetite scores In the current study, MLT was not found to improve
increased by 15.0 points (SD, 16.1) during week 5. physical fatigue or other symptoms or overall QoL among

3732 Cancer October 15, 2015


Effects of Melatonin on Physical Fatigue/Lund Ramussen et al

TABLE 3. ITT Analysis of MFI-20 and EORTC QLQ-C15-PAL Scores at Baseline and Changes in Scores
After Treatment With MLT and Placebo

Mean Difference in
Mean Change in Mean Change Change Between
Mean Baseline Score After MLT in Score After Week With MLT and
Score (95% CI)a (95% CI) Placebo (95% CI) Placebo (95% CI) P

Primary outcome
Physical fatigueb 73.8 (72.3 to 75.3) 23.4 (27.9 to 1.2) 21.3 (25.6 to 3.0) 22.1 (29.1 to 4.9) .56
Secondary outcomes
Fatiguec 66.0 (61.4 to 70.6) 25.9 (212.6 to 0.7) 23.8 (210.5 to 2.8) 22.1 (212.3 to 8.1) .68
Insomniac 36.6 (28.3 to 44.8) 29.2 (216.6 to 21.8) 27.9 (217.3 to 1.4) 21.2 (213.4 to 11.0) .84
Loss of appetitec 43.9 (36.4 to 51.6) 26.8 (213.7 to 0.1) 24.6 (210.8 to 1.5) 22.2 (210.9 to 6.5) .62
Painc 36.8 (30.7 to 42.9) 21.7 (27.6 to 4.3) 1.5 (24.3 to 7.3) 23.2 (12.2 to 5.8) .82
Emotional functionc 69.9 (63.8 to 75.9) 2.1 (24.8 to 9.1) 6.6 (20.5 to 12.7) 24.5 (213.2 to 4.2) .31
Overall QoLc 50.4 (45.9 to 54.8) 0.7 (23.7 to 5.1) 0.2 (24.8 to 5.2) 0.5 (25.9 to 6.8) .68
Explorative outcomes
General fatigueb 69.9 (65.7 to 74.3) 25.9 (212.0 to 0.2) 20.7 (26.4 to 4.9) 25.2 (214.4 to 3.9) .26
Reduced activityb 70.3 (64.6 to 75.9) 24.3 (29.8 to 1.2) 21.0 (25.5 to 3.5) 23.3 (29.9 to 3.3) .33
Reduced motivationb 37.2 (31.6 to 42.8) 21.6 (26.4 to 3.2) 1.4 (23.0 to 5.9) 23.0 (29.0 to 2.9) .32
Mental fatigueb 39.5 (33.8 to 45.2) 22.3 (27.3 to 2.7) 25.0 (211.1 to 0.9) 22.8 (25.2 to 10.8) .49
Dyspneac 26.4 (19.7 to 33.1) 22.8 (29.7 to 4.1) 3.1 (24.2 to 10.4) 25.9 (216.8 to 4.9) .78
Constipationc 20.9 (14.2 to 27.7) 20.9 (27.4 to 5.5) 1.4 (24.9 to 7.8) 22.4 (212.3 to 7.5) .63
Physical functionc 43.5 (38.9 to 48.1) 3.1 (20.8 to 11.6) 20.5 (24.8 to 3.9) 3.6 (22.3 to 9.4) .23
Nausea/vomitingc 14.8 (9.7 to 19.9) 0.9 (24.5 to 6.4) 24.4 (28.8 to 0.1) 5.4 (20.8 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 Ques-
tionnaire 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.

patients with advanced cancer receiving treatment in the to fatigue, factors such as infection, cachexia, anorexia,
palliative medicine department. nausea, pain, depression, and adverse effects of treatment
We chose to conduct a per protocol analysis as our are likely to play a larger role. It may be the case that a
primary analysis to adhere as closely as possible to the small effect of MLT is simply drowned out by the cu-
original study protocol. Because we had a slightly higher mulative negative effects of terminal illness. Anecdotally,
than expected SD of 26 and a slightly lower complete our clinical investigator noted large improvements in
compliance, the current study had an actual power of younger women receiving MLT.
70%. Compared with consecutive patients referred to the
An analysis of those patients who had completed the study institution during a previous study period, the
intervention (50 patients) and the total number of patients recruited to the current study were found to have
randomized patients (72 patients) was conducted using lower symptom scores according to the EORTC QLQ-
multiple imputations and demonstrated results similar to C15-PAL and MFI-20, indicating a population of better
those of the primary analysis. Thus, the relatively low functioning patients than the average patient receiving
power of the primary analysis was unlikely to be the cause palliative care.1,35 This tendency also could be observed in
of the negative result. our relatively low dropout rates, deaths, and hospitaliza-
The general trend noted among all study subjects tions. However, there is no reason to believe that MLT
was toward a worsening of symptoms during the trial pe- would have had a greater impact on patients with a higher
riod, which, given the critically ill nature of the current symptom burden.
study participants, was to be expected. We were not able The EORTC QLQ-C30 questionnaire has been
to demonstrate an ameliorating effect of MLT on this thoroughly validated, and the shortened QLQ-C15-PAL
downward trend. Patients who are eligible for palliative produces directly compatible scores.27,30 The MFI-20 has
care are a heterogeneous group, with a wide range of been validated with a wide range of conditions and previous
symptoms and underlying causes. Although poor quality studies have shown good internal consistency for all sub-
of sleep and disrupted circadian rhythm may contribute scales in the MFI-20 and with a stable multidimensional

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TABLE 4. Results From Part 2 of the Study (ie, MFI-20 and EORTC QLQ-C15-PAL Scores at Baseline and
Changes From Baseline in Scores After 1 to 5 Weeks With MLT)a

Mean Baseline Mean After Mean After Mean After Mean After Mean After
Score (Day 17) 1 Week 2 Weeks 3 Weeks 4 Weeks 5 Weeks
[SD] (No.) [SD] (No.) [SD] (No.) [SD] (No.) [SD] (No.) [SD] (No.) P

Outcomes
Physical fatigueb 65.8 [26.3] (N536) 5.2 [17.8] (N536) 0.4 [13.9] (N529) 1.8 [17.7] (N525) 2.3 [17.7] (N522) 1.7 [18.5] (N518) .69
Fatiguec 47.3 [15.8] (N535) 3.5 [21.5] (N535) 1.2 [20.8] (N528) 9.7 [18.1] (N523) 3.5 [23.1] (N522) 2.8 [23.1] (N520) .59
Insomniac 13.9 [25.7] (N536) 3.7 [27.4] (N536) 6.9 [27.3] (N529) 10.7 [26.7] (N525) 3.0 [20.3] (N522) 3.3 [18.4] (N520) .43
Loss of appetitec 28.7 [29.9] (N536) 3.7 [22.2] (N536) 8.3 [23.4] (N528) 12.0 [25.2] (N525) 13.6 [35.1] (N522) 15.0 [25.3] (N520) .02
Painc 29.6 [25.2] (N536) 2.3 [22.2] (N536) 8.9 [21.5] (N528) 6.7 [30.4] (N525) 7.6 [35.9] (N522) 5.8 [27.7] (N520) .36
Emotional functionc 81.0 [30.4] (N536) 20.9 [16.9] (N536) 21.4 [13.7] (N529) 1.7 [20.7] (N525) 24.9 [22.8] (N522) 21.3 [20.9] (N520) .79
Overall QoLc 56.9 [19.3] (N536) 21.9 [13.5] (N534) 21.7 [13.6] (N529) 26.7 [19.8] (N525) 24.6 [12.8] (N522) 1.7 [16.1] (N520) .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.

factorial structure.36,37 Furthermore, studies have demon- Our MLT dose of 20 mg is unlikely to be the cause
strated the MFI-20 to be sensitive in differentiating of the negative results. Trials using the same or lower
between chronically ill and healthy populations as well as doses have reported positive effects.46 Several studies
able to identify changes in the MFI after other interventions regarding the pharmacokinetics of MLT have demon-
such as exercise, counseling, and pharmacological interven- strated a large degree of variability in bioavailability rang-
tions.30,38-41 ing from 10% to 56% among healthy subjects, resulting
Despite the previous validation of the questionnaires in a difference in serum levels of 10 to 100 times that of
used herein, the 3 additional evaluating questions developed normal values in individuals receiving the same dose. This
for the current trial were originally included to provide an complicating factor introduces an element of uncertainty,
additional source of comparison for results gathered from further obscuring results.11
the MFI-20 and EORTC QLQ-C15-PAL. Although a A recent meta-analysis of 19 studies involving 21 tri-
slight tendency toward patients feeling less tired while als on the use of MLT in patients with cancer found sig-
receiving MLT was found from the additional questions, nificantly lower occurrences of cancer-related symptoms
this finding was not statistically significant and thus corrob- such as asthenia, anemia, and thrombocytopenia and
orates our primary results. improved 1-year mortality rates.46 Of the 19 studies
Strengths of the current study include the double- included, all but 1 were conducted by the group of investi-
blind, randomized, placebo-controlled, crossover design, gators lead by Lissoni et al. None of the included trials
the benefits of which include direct comparison of was blinded, and only 1 included details regarding ran-
the interventions under investigation among the same domization. Furthermore, the trials did not specify how
patients, thereby eliminating between-subject variabili- and when the potential effects of MLT on cancer symp-
ty.42 Our trial period of 1 week was initially selected to toms were evaluated.19 Although this finding in and of
ensure that any potential findings would be directly appli- itself is not grounds for an inference of bias, it highlights
cable in a clinical palliative setting, in which fast-acting the need for further independent investigations.
treatments with significant effects are preferable. Other We were unable to replicate the positive results of
trials investigating oral MLT supplements in otherwise previous studies. This also was the case in the study by Del
healthy patients with insomnia have shown significant Fabbro et al.47 Although the purpose of their study was to
improvements after a single dose using intervention peri- determine the effect of MLT on cancer-associated
ods of 5 to 7 days.43-45 This supports the timeframe cho- cachexia, QoL was also measured and found not to differ
sen for the current study. However, we cannot rule out significantly from placebo controls.47
that we could have found an effect of MLT if our inter- The current study investigated the potential use of
vention period had been longer. MLT in late-phase palliative treatment. As a patients

3734 Cancer October 15, 2015


Effects of Melatonin on Physical Fatigue/Lund Ramussen et al

disease progresses, their symptoms, concerns, and chal- activity and relevance of urinary determinations. Clin Chim Acta.
1992;209:153-167.
lenges are constantly changing. It may well be that inter- 13. Jung B, Ahmad N. Melatonin in cancer management: progress and
ventions that demonstrate no effect in the final stages of a promise. Cancer Res. 2006;66:9789-9793.
14. Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night:
disease could make a difference if applied earlier. the neuroendocrine/circadian melatonin signal. Endocrine. 2005;27:
179-188.
Conclusions 15. Altun A, Ugur-Altun B. Melatonin: therapeutic and clinical utiliza-
tion. Int J Clin Pract. 2007;61:835-845.
In the current trial, a dose of 20 mg of MLT taken orally 16. Hoang BX, Shaw DG, Pham PT, Levine SA. Neurobiological effects of
at night did not improve physical fatigue in patients with melatonin as related to cancer. Eur J Cancer Prev. 2007;16:511-516.
17. Ravindra T, Lakshmi NK, Ahuja YR. Melatonin in pathogenesis and
advanced cancer. Furthermore, we were unable to identify therapy of cancer. Indian J Med Sci. 2006;60:523-535.
improvements with regard to any other symptoms meas- 18. Malhotra S, Sawhney G, Pandhi P. The therapeutic potential of
ured with the EORTC QLQ-C15-PAL or MFI-20. Fur- melatonin: a review of the science. MedGenMed. 2004;6:46.
19. Lissoni P. Is there a role for melatonin in supportive care? Support
ther research is needed to determine whether MLT has a Care Cancer. 2002;10:110-116.
role in the earlier stages of palliative care. 20. Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and
increased efficacy of cancer chemotherapy using the pineal hormone
melatonin in metastatic solid tumour patients with poor clinical sta-
FUNDING SUPPORT tus. Eur J Cancer. 1999;35:1688-1692.
21. Lissoni P, Barni S, Fossati V, et al. A randomized study of neuroim-
Supported by the IM Daehnfeldt Foundation, the Aase and Ejnar munotherapy with low-dose subcutaneous interleukin-2 plus melato-
Danielsens Foundation, the Beckett Foundation, and the Danish nin compared to supportive care alone in patients with untreatable
Cancer Society (journal number A1013). metastatic solid tumour. Support Care Cancer. 1995;3:194-197.
22. Lissoni P, Mandala M, Brivio F. Abrogation of the negative influ-
ence of opioids on IL-2 immunotherapy of renal cell cancer by mela-
CONFLICT OF INTEREST DISCLOSURES tonin. Eur Urol. 2000;38:115-118.
23. Lissoni P, Tancini G, Barni S, et al. Treatment of cancer
The authors made no disclosures.
chemotherapy-induced toxicity with the pineal hormone melatonin.
Support Care Cancer. 1997;5:126-129.
REFERENCES 24. Lissoni P, Barni S, Rovelli F, et al. Neuroimmunotherapy of
advanced solid neoplasms with single evening subcutaneous injection
1. Stromgren AS, Goldschmidt D, Groenvold M, et al. Self-assessment
of low-dose interleukin-2 and melatonin: preliminary results. Eur
in cancer patients referred to palliative care: a study of feasibility and
symptom epidemiology. Cancer. 2002;94:512-520. J Cancer. 1993;29A:185-189.
2. Fernandes R, Stone P, Andrews P, Morgan R, Sharma S. Compari- 25. Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of
son between fatigue, sleep disturbance, and circadian rhythm in can- chemotherapy with cisplatin plus etoposide versus chemoendocrine
cer inpatients and healthy volunteers: evaluation of diagnostic criteria therapy with cisplatin, etoposide and the pineal hormone melatonin
for cancer-related fatigue. J Pain Symptom Manage. 2006;32:245- as a first-line treatment of advanced non-small cell lung cancer
254. patients in a poor clinical state. J Pineal Res. 1997;23:15-19.
3. Lundh Hagelin C, Seiger A, Furst CJ. Quality of life in terminal 26. Lissoni P, Viviani S, Bajetta E, et al. A clinical study of the pineal
carewith special reference to age, gender and marital status. Support gland activity in oncologic patients. Cancer. 1986;57:837-842.
Care Cancer. 2006;14:320-328. 27. Groenvold M, Petersen MA, Aaronson NK, et al; EORTC Quality
4. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced can- of Life Group. The development of the EORTC QLQ-C15-PAL: a
cer: relationship to age, gender, and performance status in 1,000 shortened questionnaire for cancer patients in palliative care. Eur
patients. Support Care Cancer. 2000;8:175-179. J Cancer. 2006;42:55-64.
5. Littlewood TJ, Kallich JD, San Miguel J, Hendricks L, Hedenus M. 28. Edge S, Byrd DR, Compton CC, et al.(editors) AJCC Cancer Stag-
Efficacy of darbepoetin alfa in alleviating fatigue and the effect of fa- ing Manual 7th Edition, London: New York, NY: Springer.
tigue on quality of life in anemic patients with lymphoproliferative 29. Koller M, Aaronson NK, Blazeby J, et al; EORTC Quality of Life
malignancies. J Pain Symptom Manage. 2006;31:317-325. Group. Translation procedures for standardised quality of life ques-
6. Morita T, Tsunoda J, Inoue S, Chihara S. Contributing factors to tionnaires: the European Organisation for Research and Treatment
physical symptoms in terminally-ill cancer patients. J Pain Symptom of Cancer (EORTC) approach. Eur J Cancer. 2007;43:1810-1820.
Manage. 1999;18:338-346. 30. Smets EMA, Garssen B, Bonke B, De Haes JC. The Multidimen-
7. DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS sional Fatigue Inventory (MFI) psychometric qualities of an instru-
Jr. The absolute bioavailability of oral melatonin. J Clin Pharmacol. ment to assess fatigue. J Psychosom Res. 1995;39:315-325.
2000;40:781-784. 31. King MT. The interpretation of scores from the EORTC quality of
8. Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH. life questionnaire QLQ-C30. Qual Life Res. 1996;5:555-567.
Effect of inducing nocturnal serum melatonin concentrations in day- 32. SAS Institute Inc. SAS/STAT 9.1 Users Guide. Cary, NC: SAS
time on sleep, mood, body temperature, and performance. Proc Natl Institute Inc; 2004.
Acad Sci USA. 1994;91:1824-1828. 33. Pocock SJ. Clinical Trials: A Practical Approach, Crossover Trials,
9. Spiegel D. Losing sleep over cancer. J Clin Oncol. 2008;26:2431- Chichester, UK: John Wiley & Sons Ltd, 1996:110-122.
2432. 34. Yuan Y. Multiple imputation using SAS software. J Stat Softw.
10. Mormont MC, Waterhouse J, Bleuzen P, et al. Marked 24-h rest/activ- 2011;45:1-25.
ity rhythms are associated with better quality of life, better response, 35. Stromgren AS, Sjogren P, Goldschmidt D, Petersen MA, Pedersen L,
and longer survival in patients with metastatic colorectal cancer and Groenvold M. Symptom priority and course of symptomatology in spe-
good performance status. Clin Cancer Res. 2000;6:3038-3045. cialized palliative care. J Pain Symptom Manage. 2006;31:199-206.
11. Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186- 36. Lin JM, Brimmer DJ, Maloney EM, Nyarko E, Belue R, Reeves
195. WC. Further validation of the Multidimensional Fatigue Inventory
12. Bartsch C, Bartsch H, Schmidt A, Ilg S, Bichler KH, Fluchter SH. in a US adult population sample. Popul Health Metr. 2009;7:18.
Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and 37. Hedlund L, Gyllensten AL, Hansson L. A psychometric study of the
urine of primary prostate cancer patients: evidence for reduced pineal Multidimensional Fatigue Inventory to assess fatigue in patients with

Cancer October 15, 2015 3735


Original Article

schizophrenia spectrum disorders. Community Ment Health J. 2015; 43. Bellon A. Searching for new options for treating insomnia: are mela-
51:377-382. tonin and ramelteon beneficial? J Psychiatr Pract. 2006;12:229-243.
38. Meek PM, Nail LM, Barsevick A, et al. Psychometric testing of fatigue 44. Deacon S, Arendt J. Melatonin-induced temperature suppression
instruments for use with cancer patients. Nurs Res. 2000;49:181-190. and its acute phase-shifting effects correlate in a dose-dependent
39. Dehais C, Souvannavong V, Nguyen BK, et al. An evaluation of fa- manner in humans. Brain Res. 1995;688:77-85.
tigue in patients with glioblastoma relapse treated with the combina- 45. Andrade C, Srihari BS, Reddy KP, Chandramma L. Melatonin in
tion of irinotecan-bevacizumab [in French]. Rev Neurol (Paris). medically ill patients with insomnia: a double-blind, placebo-con-
2011;167:841-846. trolled study. J Clin Psychiatry. 2001;62:41-45.
40. Eichler C, Pia M, Sibylle M, Sauerwald A, Friedrich W, Warm M. 46. Seely D, Wu P, Fritz H, et al. Melatonin as adjuvant cancer care
Cognitive behavioral therapy in breast cancer patientsa feasibility with and without chemotherapy: a systematic review and meta-
study of an 8 week intervention for tumor associated fatigue treat- analysis of randomized trials. Integr Cancer Ther. 2012;11:
ment. Asian Pac J Cancer Prev. 2015;6:1063-1067. 293-303.
41. Riesenberg H, Lubbe AS. In-patient rehabilitation of lung cancer 47. Del Fabbro E, Dev R, Hui D, Palmer L, Bruera E. Effects of mela-
patients-a prospective study. Support Care Cancer. 2009;18:877-882. tonin on appetite and other symptoms in patients with advanced
42. Mills EJ, Chan AW, Wu P, Vail A, Guyatt GH, Altman DG. Design, cancer and cachexia: a double-blind placebo-controlled trial. J Clin
analysis, and presentation of crossover trials. Trials. 2009;10:27. Oncol. 2013;31:1271-1276.

3736 Cancer October 15, 2015