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Original Article

Light therapy for insomnia symptoms in fatigued cancer survivors: a secondary analysis of a randomized controlled trial

Garland, Sheila N.a,b,∗; Johnson, Jillian A.c; Carlson, Linda E.d,e; Rash, Joshua A.a; Savard, Joséef; Campbell, Tavis S.d,e

Author Information
Journal of Psychosocial Oncology Research and Practice: October 2020 - Volume 2 - Issue 3 - p e27
doi: 10.1097/OR9.0000000000000027

Abstract

Background

Cancer-related fatigue and insomnia symptoms

Cancer-related fatigue (CRF) is one of the most common symptoms experienced by survivors, with an overall prevalence between 50% and 90%, depending on time and method of assessment.[1] The experience of CRF is described as persistent physical, emotional, and/or cognitive exhaustion that is not relieved or improved by adequate rest or sleep.[2] CRF can present before diagnosis, during treatment and after treatment completion, and can affect individuals across all types and stages of the disease.[3,4] Research to date supports that cancer and its treatment contribute to the development and maintenance of CRF.[2,5,6] Furthermore, the burden associated with CRF can persist long after a patient has concluded treatment and is deemed “cancer free,” with many individuals experiencing CRF symptoms years into remission.[7,8]

Similar to CRF, insomnia symptoms commonly occur alongside side effects of cancer and/or treatment. Symptoms of insomnia include dissatisfaction with sleep quantity or quality characterized by difficulty initiating and/or maintaining sleep. Criteria for Insomnia Disorder are met when these symptoms occur at least 3 times per week for >3 months and are associated with significant daytime functioning impairments or psychological distress.[9] The prevalence of insomnia disorder is estimated to be between 30% and 60%, making it the most common sleep disorder amongst cancer patients and survivors.[10,11] Insomnia symptoms are known contributing factors to, and predictors of, fatigue in cancer survivors.[12,13] In a 2012 study with 114 women with breast cancer,[14] the prevalence of insomnia symptoms was 44% in patients with CRF compared to 16% in those without CRF. The comorbidity of CRF and sleep disturbance suggests that these 2 symptoms may result from shared mechanisms or be worsened by similar physiological, psychological, and behavioral factors.

Despite the combined pervasiveness and impact of CRF and insomnia symptoms, the shared mechanisms remain poorly understood. Researchers have suggested a multifactorial mechanism whereby physiologic factors (eg, hormonal changes, lack of exercise, drug side effects), psychosocial factors (eg, depression, anxiety), and chronobiological factors (eg, altered circadian rhythms, changes in sleep/wake schedules, time off work) co-occur and interact with patients’ unique risk factors for insomnia symptoms and CRF.[15–17] Extending from the chronobiological factor theory, bright light therapy (BLT) in the morning is hypothesized to correct circadian rhythm dysregulation by advancing these rhythms and thus realigning them with the sleep-wake cycle of the individual.[18] The link between sleep and fatigue implies that treatment aimed at improving one may also simultaneously target the other. This mechanistic hypothesis was examined in a cross-sectional study of 163 individuals diagnosed with cancer.[19] Greater minutes and intensity of light exposure was significantly associated with better sleep quality, shorter sleep onset latency, longer total sleep time, and higher sleep efficiency.

BLT has been shown to improve sleep outcomes among noncancer populations experiencing various mood and sleep disorders,[20–22] but further insight is needed on the specific effects of light therapy on sleep in cancer populations and what factors may influence its efficacy (eg, pre-treatment insomnia severity). We conducted a placebo-controlled randomized trial of a 4-week BLT intervention in post-treatment cancer patients with clinically significant CRF.[23] The BLT group reported a significantly greater reduction in CRF compared to the dim light comparison group. The objectives of this prespecified secondary analysis were to examine the impact of bright white light (BWL) versus dim red light (DRL) on: 1) insomnia symptoms, and 2) subjective and objective sleep quality and continuity, in cancer survivors with moderate-to-severe baseline insomnia severity compared to those without insomnia symptoms. An understanding of whether severity of insomnia influences the impact of light therapy on sleep outcomes among individuals with persistent fatigue can inform more nuanced treatment approaches.

Methods

Design

As described in detail previously,[24] the present study was a 4-week placebo-controlled randomized trial comparing the effects of morning exposure to either BWL or DRL on fatigue in a heterogeneous sample of 81 cancer survivors with CRF. Insomnia severity was assessed at three time points: baseline, mid-intervention (2 weeks), and post-intervention (4 weeks). Participants tracked their sleep daily using sleep logs and actigraphy for one week at baseline and during the final week of the intervention (week 4), while sleep quality and continuity were assessed at baseline and after the 4-week intervention. Participants provided written informed consent before beginning the study. All study procedures were reviewed and approved by the Conjoint Health Research Ethics Board of the University of Calgary.

Participants

Participants were recruited from Calgary, Alberta, and surrounding areas during the fall and winter months of 2013 to 2015 to control for seasonal variation in sunlight that occurs in Calgary. Men and women were eligible if they had nonmetastatic cancer stages 0 to III, were 18 years of age or older, and completed treatment at least 3 months before enrolling in the study. If individuals were currently receiving hormonal or maintenance treatments and/or psychotropic medications, they were eligible only if their dose had remained stable over the previous 6 weeks. A diagnosis of CRF was also required, as outlined in the International Classification of Diseases-10th Revision (ICD-10).[25] Exclusion criteria included the following: The presence of another sleep or psychiatric condition (excluding insomnia); another medical condition that could influence fatigue levels; an eye disease; recent eye surgery; the use of photosensitizing medications; or current employment requiring shift work.

Blinding and random assignment

Participants were told they would be assigned to receive 1 of 2 types of light devices during the consent process, but were given no further information regarding what the types were or how the devices differed. Before recruitment, participant numbers were assigned to either BWL or DRL using a blocked randomized design (blocks of 4, 6, and 8) created by a computer-based random number generator with a 1:1 allocation ratio. The randomization sequence was used to label the light devices with each participant number. There was no indication of the type of device on the packaging of each light, which ensured that participants and researchers were blind to condition. Participants and researchers were made aware of the assignment of each intervention only after participants had completed the study.

Intervention

The light therapy device used in this study was the Litebook Elite (The Litebook Company Ltd., Medicine Hat, AB). The Litebook is a small (12.5 cm × 12.5 cm × 2.5 cm) and lightweight (284 g) device that is designed to be placed 30 to 60 cm from the user's face and offset at a 45-degree angle from the visual midline. The BWL device contained 25 white light-emitting diode (LED) lights that emitted white-blue light at 1250 lx, within the shorter wavelengths of visible light (∼465 nm). A device identical in appearance was used in the DRL condition but contained 25 red LEDs that emitted red light at <400 lx, within the longer wavelengths of visible light (∼633 nm). The devices were programmed to shut off after 30 minutes of continuous use. Participants were asked to use the device every morning for 30 minutes, within 30 minutes of waking, for a period of 4 weeks (28 days).

Measures

Primary outcome

The Insomnia Severity Index (ISI)[26] was used to assess insomnia symptomatology. The ISI is a 7-item measure that assesses difficulty falling asleep, difficulty staying asleep, early morning awakenings, satisfaction with current sleep patterns, interference with daily functioning, sleep-related impairment, and distress level caused by sleep problems over the last 2 weeks. Total scores of 0 to 7 are classified as no clinically significant insomnia, 8 to 14 as mild insomnia, 15 to 21 as clinical insomnia of moderate severity, and 22 to 28 as severe clinical insomnia.[26,27] Concurrent, content, and predictive validity have been demonstrated and Chronbach alpha has been estimated as .90.

Secondary outcomes

The Consensus Sleep Diary (CSD)[28] is a standardized tool used for tracking night-by-night self-report of sleep duration, disruption, and perceived quality of sleep. The CSD is filled out every day for 7 consecutive nights and is used to calculate subjective reports of sleep onset latency (SOL), wake after sleep onset (WASO), sleep efficiency (SE), and total sleep time (TST). SE is a calculated percentage based on the ratio of time spent sleeping over time spent in bed multiplied by 100. The daily values were averaged over each week to produce a weekly average. The CSD is considered to be a reliable and valid self-report measure of nightly insomnia symptoms.[29]

The Pittsburgh Sleep Quality Index (PSQI)[30] is a 19-item self-report scale designed to assess subjective sleep quality over the past month. It is composed of seven “component” scores (subjective sleep quality, sleep latency, sleep duration, SE, sleep disturbances, use of sleep medication, and daytime dysfunction), and a global score. Designed for clinical populations, higher scores indicate worse sleep quality and a global score of 5 or greater is indicative of “poor sleep”. The PSQI demonstrates discriminant and convergent validity and Chronbach alpha (internal consistency) has been estimated as .75.

Actigraphs are small devices that resemble watches that are worn on the nondominant wrist and record gross motor activity levels throughout the day and night. Actigraphy monitoring provides objective information on indices of SOL, WASO, SE, and TST. Actigraphy has demonstrated sensitivity to treatment effects while being less costly and intrusive than polysomnography, the current criterion standard in sleep measurement. The actigraphy device used in this study was the Motionlogger, a model that provides a 95% sensitivity; a 65% specificity; and an approximate 90% agreement to polysomnography, which is 11%+ more accurate than other actigraphy devices on the market.[31]

Statistical analysis

Frequencies and percentages were calculated for all categorical demographic and medical history data. Means, standard deviations, and ranges were calculated for all continuous demographic and medical history data.

Objective 1

To assess our first objective, we used 2 analytic approaches to accommodate the repeated measures structure of the data. Given that our primary outcome of insomnia symptoms (total ISI score) was assessed at 3 time points (baseline, week 2, week 4), we employed a linear mixed models analysis. In this model, random effects were subjects and intercept, and the fixed effects were time (baseline, week 2, week 4), group (BWL, DRL), and the group-by-time interaction. Separate analyses were performed for participants who were considered to have moderate-to-severe insomnia symptoms (baseline ISI score ≥15) and those who had mild to no insomnia symptoms (baseline ISI score ≤14). Demographic variables (including age, sex, marital status, employment status, race/ethnicity, education level, cancer type, cancer treatments received, and time since last cancer treatment) were tested in the model as potential covariates, but none were significant and were therefore not included in the final model. The restricted maximum likelihood estimate method was used to estimate the model parameters and standard errors. Missing data accounted for <3% of the data on the ISI, and no values were imputed. The covariance structure was set to variance components.

Objective 2

Our secondary outcomes of sleep quality (PSQI), and sleep diary and actigraphy measured sleep continuity (SOL, WASO, TST, SE) were assessed at baseline and week 4, so generalized estimating equations analyses were employed. For each model, the fixed effects were time (baseline, week 4), group (BWL, DRL), and the group-by-time interaction. The demographic variables listed above were also tested in the model as potential covariates, but none were significant and were therefore not included in the final model; however, the baseline score on the measure was included in the model. Separate analyses were performed for participants who were considered to have moderate-to-severe insomnia symptoms (baseline ISI score ≥15) and those who had mild to no insomnia symptoms (baseline ISI score ≤14). The restricted maximum likelihood estimate method was used to estimate the model parameters and standard errors. Compound symmetry was used as the covariance structure. Only data that were available were used for the analysis.

Supplemental analyses

We ran the above analyses for the primary and secondary outcomes across the entire sample (ie, not grouped by insomnia severity) to facilitate comparisons with previous research.[32] Given that it is was not the objective of the present manuscript, these results are presented in Supplementary Tables 1-3, http://links.lww.com/OR9/A14.

The significance level for all analyses was set at P <.05. Using the means, standard deviations, and correlations, effect sizes (d) were calculated within each group from baseline to post-intervention. Statistical analyses were carried out using IBM SPSS v.24 (SPSS Inc, Chicago, IL).

Results

Participants

A total of 252 potential participants were assessed for eligibility and 81 participants consented and were randomized. All 81 participants completed baseline measures and started the intervention. Two participants withdrew from the study, but all available data from all participants were included in the analyses (refer to the Consort Diagram in Figure 1). Table 1 outlines participants’ demographic information.

Figure 1
Figure 1:
Participant flow through study. BWL = bright white light, CRF = cancer-related fatigue, DRL= dim red light.

Table 1
Table 1:
Demographic and clinical characteristics.

Adherence

Of the 76 participants who provided complete intervention adherence data, the light devices were used for an average of 30 minutes per day (SD = .6), turned on within 30 minutes of waking (SD = 23.2), and devices were used for a total of 26.7 days (SD = 2.2). There were no significant differences between the BWL and DRL conditions on any of the adherence outcomes. Complete adherence data were reported previously.[24]

Insomnia Severity

The mean scores on the ISI for both groups at each time point are reported in Table 2. Forty participants (49%) reported an ISI score ≥15 at baseline, indicating moderate-to-severe insomnia symptoms. For those individuals with no or mild insomnia symptoms, there was a significant group-by-time interaction, F (2, 75.55) = 4.15, P = .020. In the BWL group, ISI scores decreased from 8.5 (baseline) to 7.4 (mid-intervention) to 6.0 (post-intervention) compared to 10.9 (baseline) to 8.4 (mid-intervention) and 10.4 (post-intervention) in the DRL group. The effect size was medium (d = −.54) in the BWL group and small in the DRL group (d = −.11). In participants with moderate-to-severe insomnia symptoms, there was a significant main effect of time, F (2, 74.50) = 32.71, P < .001, with both groups reporting improved insomnia severity; however, the interaction did not meet the criteria for significance (P = .054). The effect sizes for the moderate-to-severe insomnia symptoms group were large (BWL: d = −1.09; DRL: d = −1.16).

Table 2
Table 2:
Insomnia outcomes by severity using linear mixed models.

Secondary subjective sleep outcomes

Mean PSQI scores, sleep diary, and actigraphy measured sleep continuity for both groups at each time point are reported in Table 3.

Table 3
Table 3:
Sleep quality and sleep diary outcomes by insomnia severity using generalized estimating equations.

Sleep quality

Seventy-one participants (87.7%) reported a PSQI score greater than or equal to 5 at baseline, indicating “poor sleep.” For the participants with no or mild insomnia at baseline (ie, ISI total score <15), there was a group-by-time interaction, F (1, 39.25) = 7.66, P = .009, such that participants in the BWL condition showed greater improvements at week 4 in overall sleep quality compared to those in the DRL condition. For the participants who had moderate-to-severe insomnia symptoms at baseline (ie, ISI scores ≥15), there was a main effect of time, F (1, 38.80) = 47.27, P < .001, but no significant group-by-time interaction. Similar to the ISI, the effect sizes for the moderate-to-severe insomnia symptoms group were larger than those for the no or mild insomnia symptoms group.

Sleep diary

Only 78 participants had sleep diary data available for analysis. For participants reporting moderate-to-severe insomnia symptoms at baseline on the ISI, there was a significant time effect for WASO, F (1, 37.77) = 8.11, P = .007, such that the mean number of minutes decreased from 44 to 36 minutes. There was also a main effect of time for SE, F (1, 36.51) = 13.63, P = .001, revealing an increase in efficiency from 78.1% to 82.2%. TST and SOL did not show any main effects of time or group, nor significant group-by-time interactions. For participants with no or mild insomnia symptoms at baseline, there was a significant time effect for SOL, F (1, 38.44) = 4.49, P = .041, with a decrease from 27.8 to 20.6 minutes at week 4. There was also a significant time effect for SE, F (1, 38.36) = 5.62, P = .023, showing an increase from 81.5% to 84.2%. No main effects or interactions were observed for the outcomes of WASO and TST. Effect sizes ranged from small to medium.

Secondary objective sleep outcome

Actigraphy

Only 80 participants (39 of which had moderate-to-severe insomnia symptoms) had actigraphy data available for analysis for the outcomes SOL and WASO, whereas 79 had data available for the outcomes TST and SE. Missing data were related to device malfunction. Mean scores on all actigraphy outcomes are presented in Table 4. For participants with moderate-to-severe insomnia symptoms at baseline on the ISI, both of the intervention conditions showed a significant improvement in WASO over time, F (1, 36.75) = 6.74, P = .013, with overall means decreasing from 37.4 to 27.5 minutes. There was also a significant improvement over time observed on the outcome of SE, F (1, 37) = 4.44, P = .042, with a mean increase from 93.3% to 94.5%. No significant main effects of time or group, or the group-by-time interactions, were observed for the objective outcomes of SOL and TST. In the participants with no or mild insomnia symptoms at baseline, there were no main effects of time or group, and no significant time-by-group interaction, observed for any of the objective outcomes of sleep (including SOL, WASO, TST, and SE). Effect sizes for both groups were mostly small in magnitude.

Table 4
Table 4:
Actigraphy outcomes by insomnia severity using generalized estimating equations.

Supplemental Analyses

The effect of light therapy across time on insomnia severity, sleep quality, and sleep diary and actigraphy measured sleep continuity when analyzed for all patients, pooled across insomnia severity, are presented in Supplemental Tables 1-3, http://links.lww.com/OR9/A14. There was a significant group-by-time interaction for insomnia severity, F (2,152.22) = 3.51, P = .030. In the BWL group, ISI scores decreased from 12.91 (baseline) to 10.65 (mid-intervention) to 9.47 (post-intervention) compared to 14.9 (baseline) to 10.16 (mid-intervention) and 11.34 (post-intervention) in the DRL group. Group-by-time interactions were not observed for sleep quality, nor sleep diary and actigraphy measured sleep continuity. Significant effects of time were observed for actigraphy measured sleep quality, and sleep diary measured SOL, SE, and WASO. Patients demonstrated improvement across time, regardless of group.

Discussion

This study investigated the impact of BWL vs. DRL therapy on insomnia severity and sleep quality using subjective and objective sleep parameters in cancer survivors with clinically significant levels of fatigue. We sought to determine whether differences exist on sleep outcomes for individuals presenting with moderate-to-severe insomnia symptoms at baseline on the ISI compared to fatigued cancer survivors with no or mild insomnia symptoms. Despite not being an inclusion criterion, close to half (49%) of the participants entered the study reporting clinically significant insomnia symptoms and 88% could be considered to have poor sleep quality based on the PSQI. In participants with no or mild insomnia symptoms, there was a group-by-time interaction with the BWL condition reporting greater improvement in insomnia severity and sleep quality than those in the DRL condition. We also found a larger effect across sleep outcomes regardless of intervention condition for the subsample of participants with moderate-to-severe baseline insomnia symptoms on subjective ratings of insomnia severity and sleep quality, diary measured WASO and SE, and objective actigraphy measured WASO and SE; however, participants remained in the clinical range for insomnia symptoms on the ISI and poor sleep quality on the PSQI. Of interest, supplemental analyses of the entire sample irrespective of baseline insomnia severity obscured the more nuanced pattern of results observed when insomnia status at treatment outset was considered. This suggests that the severity of pre-treatment insomnia symptoms may impact responsiveness to light therapy in fatigued cancer survivors, but that light therapy alone is not likely sufficient to produce a clinically relevant change in sleep outcomes.

Only one previous study has examined the potential of BLT to impact sleep in fatigued cancer survivors compared to a dim light comparison condition, which used the Pittsburgh Sleep Quality Index and actigraphy as the measures of sleep.[32] Although they did not examine groups by severity of insomnia symptoms, of their sample of 54 cancer survivors, 77% met or exceeded the cut-off of greater than or equal to 5 on the PSQI. This study failed to find a significant effect of either light condition on sleep quality or a difference between the two, but a similar pattern of moderate to large effect sizes was reported for WASO (partial η2 = .16), TST (partial η2 = .16), and SE (partial η2 = .28). Regardless of statistical significance and effect sizes, the overall magnitude of change in both studies was small and not clinically significant.[33] This also suggests that light therapy alone may not be powerful enough to address significant sleep issues. Reliable placebo effects have been reported when insomnia is assessed by self-report.[34] Additional research is needed to fully understand the unique impact of light therapy in insomnia symptoms and sleep quality above that of nonspecific effects such as expectation or regression to the mean.

A key component in the use of BLT for the treatment of insomnia via the entrainment of circadian rhythm is the timing of administration.[35] In this study, we instructed participants to use the light for 30 minutes each morning within 30 minutes of waking but did not instruct participants to set a consistent wake up time. This may have weakened our ability to detect the potential effects of BLT on sleep outcomes in patients with and without insomnia symptoms. Despite this, the mere action of engaging in a regular morning activity appears to benefit people with moderate-to-severe insomnia symptoms more than those without these symptoms. Future research should ensure that the administration of BLT is appropriately timed to promote a strong and regular homeostatic pressure for sleep.

The recommended treatment for insomnia disorder in adults is Cognitive Behavior Therapy for Insomnia (CBT-I).[36] Individuals treated with CBT-I also report improvements in fatigue[37] and comorbid depressive symptoms.[38] This treatment explicitly promotes circadian entrainment through the establishment of a strictly adhered-to wake-up time. Despite being the recommended treatment for insomnia, there remains a considerable proportion of individuals who do not respond or respond suboptimally to CBT-I.[39] Although it remains to be tested in cancer populations, it is possible that the combination of BLT and CBT-I might be synergistic, strengthening circadian entrainment and promoting overall better outcomes for the treatment of insomnia.[40,41]

This study has several notable strengths including rigorous inclusion criteria and blinding, the use of an active comparator group, excellent intervention adherence, and the multimethod assessment of sleep. The primary limitation of this study is that is represents a secondary analysis and was not powered to detect a difference in insomnia severity. Despite that, nearly half of the sample presented with moderate-to-severe insomnia symptoms, reiterating that this is a prevalent concern in cancer survivorship. Furthermore, although participants were screened for the presence of other sleep disorders, such as obstructive sleep apnea, they did not undergo formal testing with polysomnography and information on current prescription or over the counter sleep aid use was not available. The sample was also primarily comprised of well-educated females with a breast cancer diagnosis and had a limited representation from males and ethnically or demographically diverse groups. As such, it is not known whether the results are generalizable to males, diverse populations, and people with less education.

Despite these limitations, our results suggest that the sleep of individuals with moderate-to-severe insomnia symptoms may respond differently to a light therapy intervention than those with no or mild insomnia symptoms when comorbid with fatigue. Future adequately powered trials of light therapy for insomnia in cancer survivors (with or without co-morbid fatigue) are needed to properly address this question. Further, trials of light therapy for other symptoms (eg, fatigue, depression, among others) should consider insomnia severity as a possible moderator of treatment effect. Given that more individuals diagnosed with cancer are living longer, with or without evidence of disease, efforts to improve sleep and quality of life are of paramount importance.

Conflicts of interest

The authors declare they have no conflicts of interest.

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Keywords:

Clinical trial; Fatigue; Neoplasms; Phototherapy; Sleep initiation and maintenance disorders; Sleep

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Copyright © 2020 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the International Psycho-Oncology Society.