Effects of Chronotype-tailored Bright Light Intervention on Symptoms and Quality of Life in Breast Cancer Survivors

Purpose Bright light therapy holds promise for reducing common symptoms, e.g., fatigue, experienced by individuals with cancer. This study aimed to examine the effects of a chronotype-tailored bright light intervention on sleep disturbance, fatigue, depressive mood, cognitive dysfunction, and quality of life among post-treatment breast cancer survivors. Methods In this two-group randomized controlled trial (NCT03304587), participants were randomized to receive 30-min daily bright blue-green light (12,000 lux) or dim red light (5 lux) either between 19:00–20:00 h or within 30 min of waking in the morning. Self-reported outcomes and in-lab overnight polysomnography sleep study were assessed before (pre-test) and after the 14-day light intervention (post-test). Results The sample included 30 women 1–3 years post-completion of chemotherapy and/or radiation for stage I to III breast cancer (mean age = 52.5 ± 8.4 years). There were no significant between-group differences in any of the symptoms or quality of life (all p > 0.05). However, within each group, self-reported sleep disturbance, fatigue, and depressive mood, and quality of life-related functioning showed significant improvements over time (all p < 0.01); the extent of improvement for fatigue and depressive mood was clinically relevant. Polysomnography sleep findings showed that number of awakenings significantly decreased (p = 0.011) among participants received bright light, while stage 2 sleep significantly increased (p = 0.015) among participants received dim-red light. Conclusion The findings provide some evidence to support using chronotype-tailored light therapy to manage sleep disturbance, fatigue, depressive mood in post-treatment breast cancer survivors. The unexpected symptom improvements among dim-red light controls remain unexplained and requires further investigation. ClinicalTrials.gov Identifier: NCT03304587 Study was registered on October 19, 2017.


INTRODUCTION
Breast cancer survivors currently represent the largest cancer survivor group, comprising more than 3.8 million women in the U.S. [1] and the number of breast cancer survivors continues to grow.Many cancer-related symptoms emerge or amplify during breast cancer treatment and persist long after treatment terminates.A study showed that 88% of breast cancer survivors experienced multiple residual symptoms after treatment completion; half of them experienced six or more concurrent symptoms [2].Among those, fatigue, sleep disruption, emotional distress, and cognitive dysfunction are most common [3,4].These symptoms often exacerbate one another and amplify symptom distress, thus, impeding survivors' return to a normal and productive life.
In cancer patients, morning bright light has shown the bene t in curbing fatigue, [20,21,23,[25][26][27]29] but its effects on sleep disturbance were modest [20,22,30].Sleep as measured by actigraphy showed that morning bright light prevented worsening of nighttime sleep disruption and daytime napping during chemotherapy for breast cancer.However, as perceived by individuals, its effect on sleep was suboptimal [31].A previous study tailored the timing of the light administration according to the individual's circadian chronotype and showed promise in managing sleep disturbance during chemotherapy [28].Circadian chronotype (known as morningness-eveningness) is an individual's natural propensity for sleep/wake timing [12,32] that stems from the period of endogenous circadian rhythms relative to the 24-hour day/night cycle (circadian phase) [33].A morningness chronotype demonstrates an earlier diurnal alertness and sleep propensity rhythm (sleep/wake schedule), i.e., tendency of phase advanced from the 24-hour day/night cycle.An eveningness chronotype shows a later sleep/wake schedule, i.e., tendency of circadian phase delay as their circadian period is likely to be longer than 24 hours [34,35].
Appropriately timed light exposure can augment the effect of bright light [36].The optimum timing of light exposure is well established [9,12,16,37].Light exposure in the morning elicits an advance in the time of internal circadian clock relative to external 24-hour clock time.Conversely, light exposure in the later afternoon through early evening delays the circadian rhythm to a later clock time [9,12,16,37].As an example, for someone who experiences the issue of unintentionally waking up too early (e.g., many older adults), receiving morning light will worsen the problem.It is thought that considering differences in individuals' chronotypes and customizing the timing of light exposure accordingly can avoid inducing changes in an unwanted direction and worsening already disrupted sleep/wake patterns.Although the chronotype-tailored approach is logically sound, its e cacy is yet to be proven.Thus, the purpose of this study was to estimate the effects of a chronotype-tailored bright light intervention on four symptoms (sleep disturbance, fatigue, depressive mood, cognitive dysfunction) and quality of life among posttreatment breast cancer survivors.Speci cally, the hypothesis was: compared to their dim light counterparts, breast cancer survivors who receive bright light intervention would report a signi cantly greater reduction in sleep disturbance, fatigue, depressive mood, and cognitive dysfunction, and improved quality of life from baseline to post-completion of a 14-day chronotype-tailored light therapy.

The Chronotype-tailored Intervention Protocol
In this two-group randomized controlled trial (NCT03304587) with pre-and post-tests, participants were randomized to either the intervention or control condition using a computer-generated list (Fig. 1).The protocol for both intervention and control groups consisted of a 14-day daily light intervention.Light therapy was self-administered using a light visor cap (Physician Engineered Products, Fryeburg, ME) worn in the individual's home.Participants in the intervention group self-administered bright blue-green light (~ 500 nm peak; 12,000 lux) once a day for 30 minutes; participants in the control group self-administered dim red light (~ 620nm peak; 5 lux) once a day for 30 minutes.The timing of light administration for both groups was tailored to the individual's circadian chronotype, based on their natural propensity for sleep/wake time.Chronotype was self-reported based on the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) [38].For evening chronotypes (MEQ scores of ≤ 41), light was delivered within 30 minutes of waking with the goal of advancing circadian phase and, therefore, inducing sleep onset to an earlier time.For morning chronotypes (MEQ ≥ 59), light was delivered in early evening (between 1900-2000 hours) with the goal of delaying circadian phase and, therefore, postponing sleep onset to a later time.Individuals with intermediate types (MEQ scores 42-58) were excluded in this study.Participants were encouraged to use the light therapy at the same time for 30 minutes every day during the study.
Although the light visor contained a timer and automatically turned off after being on for 30 minutes, to promote adherence to the treatment protocol, a multiple-alarm watch with set timed reminders was offered.Most of the participants, however, preferred using the alarm reminder on their own smartphone.
The on and off times of each light treatment were self-reported using a daily log to assess adherence.

Samples and Settings
Participants who resided in the Greater Lansing area in Michigan and within the St. Louis bi-state metropolitan area in Missouri and Illinois were recruited to participate in this three-week long study.
Eligible participants were female, 21 years of age or older, 1-3 years post-completion of chemotherapy or/and radiation therapy for stage I-III breast cancer, experience ≥ 2 concurrent symptoms (fatigue, sleep disruption, depressive symptoms, and/or cognitive dysfunction), be either morning or evening chronotypes (MEQ ≥ 59 or ≤ 41), sighted, mentally competent to consent, and able to understand English.Exclusion criteria included a concurrent malignancy; undergoing other cancer treatments; engaged in shift work or traveled across more than three time zones within two weeks prior to the study; a known history of seasonal affective disorder or substance abuse; a current diagnosis of major Axis I psychiatric disorders, neurological impairments, or muscular dystrophies; regular use of steroidal or other immunosuppressive medications; taking prescribed sedative hypnotics or sleep medications; eye conditions (glaucoma or retinal disease) or problems triggered by bright light (e.g., migraine); or taking photosensitizing medications (e.g., some porphyrin drugs, antipsychotics, antiarrhythmic agents).The study was approved by the Institutional Review Boards at Michigan State University in East Lansing, Michigan (IRB #2776) and the Human Investigation Committee at Washington University in St. Louis, Missouri (HRPO#201703147).

Outcome Variables and Measures
The outcome variables included sleep disturbance, fatigue, depressive mood, cognitive dysfunction, physical function, and quality of life.In addition to subjective report, objective data on sleep disturbance were obtained by in-lab polysomnography (PSG).A description of outcome measures is provided in Table 1.

Procedure
Potential subjects were recruited via referrals by oncologists or clinic nurses, mail and/or email invitations using patient registries, social media (i.e., Facebook), ResearchMatch.org, and recruitment yers posted at public areas.The in-person consent/screening visit lasted for one to two hours and was scheduled either on the day of the individual's clinical appointment or at the individual's convenience.After giving informed consent, individuals rst completed the demographic information followed by the MEQ and four screening instruments with established cut off scores for clinical symptoms, including PSQI, ICD-10 criteria for cancer-related fatigue [39,40], CES-D, and MoCA.Those who reported the presence of ≥ 2 of the four symptoms were then individually interviewed for the exclusion criteria using a standardized checklist.
After screening, eligible participants were scheduled for the study activities, including three overnight stays at a sleep laboratory.The rst overnight stay at the sleep laboratory was an adaptation night.The adaptation night was to facilitate adaptation to sleep study procedures and a new sleep environment and thus controlled for the rst night effect.The recorded PSG data during the adaptation night was not analyzed as per standard sleep research methodology.
Baseline data collection occurred on the day following the adaptation night.Prior to checking in to the sleep laboratory, participants were instructed to complete a battery of self-reported instruments.The participants were asked to return to the sleep laboratory around 1900 hours.After checking in, MoCA was administered in person by a trained research assistant.After the completion of the cognition tests, participants were encouraged to relax and engage in their bedtime ritual, e.g., watching TV, reading, etc.The participants were connected to the PSG recording during their normal bedtime hours and underwent overnight PSG monitoring.The recording for the PSG analysis started at the time of lights out and ended at the time of nal awakening in the morning.
Starting on the day after the baseline data collection, the participants were instructed to wear the light visor cap at home for 14 consecutive days.A light visor cap and individualized written instructions were provided to the participants before they left the sleep laboratory.Post-test was on the day following the completion of the 14-day intervention protocol using the same protocol procedure as the baseline data collection.

Data Analysis
The analysis was conducted on an intent-to-treat basis.Demographic and baseline characteristics were tabulated by group and compared using a two-sample t-test, Mann-Whitney rank-sum test, or Chi-square test, as appropriate.The pre-and post-test endpoints in each group were summarized using mean, standard deviation (SD), median, and interquartile range for continuous outcomes, e.g., PROMIS T-scores, or using counts and frequencies for ordinal outcomes, e.g., PSQI component scores.Linear mixed models (for continuous outcomes) or generalized estimating equations (GEE) with cumulative log link function (for ordinal outcomes) were tted to examine between-group differences, while adjusting for correlation among repeated measures taken from the same participant.Three signi cance tests were performed simultaneously in each model, including pre-post change in the control group, pre-post change in the experimental group, and the difference in over-time changes between groups.All data analyses were performed using SAS 9.4 (SAS Institutes.Cary, NC) and statistical signi cance was de ned as a twotailed p-value of < 0.05 for all analyses.

RESULTS
The data from a convenience sample of 30 female survivors of breast cancer were included in this analysis.Table 2 summarizes the demographics of the study participants.There were no signi cant differences in individuals' characteristics between the experimental and control groups.Two participants (one for each group) reported headaches exaggerated by light.Among those who completed the study (n = 28), counting missed daily records as non-adherence, the intervention vs. control group completed 92% vs. 96% of the planned light treatment sessions.The intervention vs. control group turned on the light visor for an average of 29.78 (± 1.89) vs. 29.73(± 2.20) minutes per day for an average of 12.9 (± 2.5) vs. 13.4 (± 1.1) days.
Subjective sleep disturbance.The symptom scores are listed in Table 3.While between-group differences were not signi cant, self-reported sleep disturbance signi cantly decreased in both intervention and control groups after 14 days of light therapy.PROMIS-Sleep Disturbance scores signi cantly decreased by an average of 6.41 (± 7.31) vs. 6.50 (± 9.61) points in the intervention group vs. control group (with p = 0.009 and p = 0.009, respectively).The reduction in both groups exceeded the pre-set 4.4 MIDs, suggesting the improvements in sleep disturbance are clinically relevant.
REM (%) Compared to baseline in each group: a p< .05 Fatigue, depressive mood, and cognitive dysfunction.Fatigue severity signi cantly decreased in both intervention and control groups after 14 days of light therapy, but between-group differences were not signi cant.PROMIS-fatigue scores signi cantly decreased by an average of 6.96 (± 5.84) vs. 6.89 (± 6.60) points in the intervention group vs. control group (both p < 0.001).The reduction in fatigue in both groups exceeded the pre-set 4.0 MIDs, suggesting the changes are clinically relevant.
Depressive mood signi cantly declined in both intervention and control groups after 14 days of light therapy, but between-group differences were not signi cant.PROMIS-Depression scores signi cantly decreased in both intervention and control groups by an average of 4.57 (± 3.82) and 5.06 (± 6.19) (p = 0.003 and p = 0.001), respectively.The reduction in depressive mood in both groups exceeded the pre-set 4.0 MIDs.
Unexpectedly, neither bright nor dim light condition demonstrated a positive effect on cognitive dysfunction.After adjusting for the baseline MoCA scores, no meaningful changes were observed in either group (intervention: 0.00 ± 0.92, p = 0.99; control: 0.64 ± 2.17, p = 0.251).

Physical Function and Quality of Life
The quality of life scores are listed in Table 3.After receiving 14 days of light therapy, the intervention group reported signi cant improvements in global health status / quality of life (QOL) and QOL-related functioning while the control group reported signi cant improvements in QOL-related symptomology and functioning.QOL-global health status improved in both intervention group (9.52 ± 11.72, p = 0.006) and control group (5.36 ± 12.06, p = 0.104), though the change in the control group was not statistically signi cant.On the other hand, QOL-related symptomology signi cantly decreased in the control group (7.69 ± 9.43, p = 0.018) but the reduction in the intervention group was only marginally signi cant (6.13 ± 13.06, p = 0.051).QOL-related functioning signi cantly improved in both intervention and control groups by an average of 7.94 (± 9.29) and 8.10 (± 10.55) points (p = 0.006 and p = 0.005), respectively.However, only the control group showed signi cant improvements in the PROMIS-physical function scores (2.83 ± 6.27, p = 0.035).

DISCUSSION
The ndings from this study did not support our hypothesis that bright blue-green light is superior to dimred light in reducing self-reported sleep disturbance, fatigue, depressive mood, and cognitive dysfunction, and improving physical function and QOL.Although no signi cant group effects were displayed by the end of the 14-day light intervention, changes over time were signi cant within each light condition after adjusting for baseline values.In contrast to our hypothesis, the study results are equally favorable to the dim red-light condition that intended to serve as the control.The ndings of dim-red light effects were unexpected.However, similar ndings have been reported in existing cancer studies.In the study conducted by Starreveld and colleagues [27], the dim-white light (8 lux) controls reported signi cant reductions in fatigue and depression and improvements in sleep quality and QOL after receiving 25 days of light therapy.In the study by Johnson and colleagues [23], the dim-red light (< 400 lux) controls reported signi cant over time improvements in fatigue, mood disturbance, depression, and QOL after 28 days of light therapy.Like our ndings, no signi cant group differences were found.In these two studies, both bright and dim light conditions demonstrated signi cant over time improvements, with some changes that could be clinically meaningful.Other studies also reported signi cant improvements in fatigue in their dim-red light controls [25,26].
Rationale for the improvement observed in dim light controls includes diminished exposure or darkness effects (with light visor caps), social cue and daily routine, response shift, and placebo effects [23,27,29].Dim-red light is often used as the control to overcome placebo effects in studies involving bright light therapy [26,41] as intrinsically photosensitive retinal ganglion cells (ipRGCs) was thought to be insensitive to long wavelength (red) light [42,43].Although it is yet to be proven, it is plausible that exposure to dim red light produces therapeutic effects.It has been suggested that humans may be more sensitive to light than currently known [44].Relatively dim (as low as 10 lux) light exposure in the evening showed effects on circadian rhythms among healthy adults [45].To rule out the effect of dim light requires the comparison between two light conditions with either xed intensity or spectrum/wavelength.However, in this study, two different light spectrums (blue-green: ~500 nm peak vs. red: ~620nm peak) each with different light intensity (bright: 12,000 lux vs. dim: 5 lux) were used.Therefore, we were unable to tease out which elements of light (i.e., spectrum or intensity) contributed to the observed improvements.
Furthermore, different from previous studies in which bright light was uniformly delivered in the morning, our participants received either morning or evening light according to their chronotypes.It is known that the response varies with not only light intensity but also timing of light exposure [9,12,16,37].The majority (73%) of our participants received evening light because of their morning chronotypes.Although it is conceivable that the timing of light administration coupled with the wavelength enhanced the effects, the explanation of the observed effect of dim light conditions remains open and in need of further research.
Light exposure at the appropriate portion of the phase response curve has been suggested to augment the effect of bright light [36].Although the observed sleep improvements after the 14 days of chronotypetailored light therapy in either of our light conditions are compelling, whether the chronotype-tailored approach is superior to morning light remains unanswered.Because of the differences in instruments, patient populations (during chemotherapy vs. post-treatment), light intensities (1,250 to 1,500 lux), intervention duration (25 days to 12 weeks), and other concurrent treatment (cognitive behavioral therapy), [21,27,30,31] comparisons cannot be made across the studies.
The major weaknesses are small sample size and the limited generalizability of the results.Because the samples were all females, post-menopaused, diagnosed with mostly early-stage breast cancer, either morning or evening chronotypes, the ndings may not be applicable to males, late-stage breast and/or other cancers, and intermediate chronotypes.In addition, the inclusion criterion was limited to the rst three years after completion of chemotherapy and/or radiation, the ndings may not be applicable to long-term survivors.Furthermore, the sustainability of the effects of light is unknown.

Fatigue
measuring fatigue experience (frequency, duration, and intensity) and fatigue impact (physical, mental, and social activities) during the past 7 days with 5-point rating scales(1 = not at all or never, 5 = very much or always) • Higher T-scores indicate worse fatigue.• Developed based on rigorous methodologies.Psychometric properties have been established across chronic illnesses including cancer • T-scores of 2.5-5.0 for MIDs of the PROMIS-fatigue were previously established in advanced cancer patients; MID of 4.0 was selected as used in an existing study of breast cancer with 5-point rating scales (1 = never to 5 = always) measuring affective and cognitive manifestations of depressive mood in the past 7 days • Higher T-scores indicate worse depression • In a sample of depressed outpatients, PROMIS-Depression showed greater reliability when compared to the CES-D and the Patient Health Questionnaire (PHQ-9).Convergent validity with the CES-D and PHQ-9 was supported by strong correlations, ranging from 0.72 to 0.84 • T-scores of 3.0-4.5 for MIDs of the PROMIS-depression were previously established in the oncology population; MID of 4.0 was set as used in an existing study of breast cancer

Figures
Figures

Table 1
• The 19 items yield seven sleep characteristics/components., i.e., sleep quality, latency, duration, e ciency, disturbance, medication use, and daytime dysfunction.•Eachcomponentscore is rated on a 0-3 rating scale; the global PSQI score is the accumulative score of seven components, range 0-21, with higher scores indicating more severe sleep disturbance• A global PSQI score greater than 5 was found to have a sensitivity of 89.6% and a speci city of 86.5% in differentiating good and poor sleepers.In a sample of cancer patients, internal consistency reliability was α = 0.81 and 0.69 for the global sleep quality sleep and disturbance subscales, respectively.Polysomnography• 10 mm gold cup disc electroencephalograph (EEG), electromyograph (EMG), and electrooculograph (EOG) electrodes were connected to a Sandman system, version 10.1.3(Natus,Middleton, WI)• A standard sleep montage for PSG was used.Scalp electrodes were applied following the internationally recognized 10/20 system for electrode placement to record brain waves (electroencephalogram).Eye electrodes were placed one centimeter above or below the outer canthus of the right and left eye to record eye movements (electrooculogram) and one chin electrode were placed on the mental midline to record

Table 3
Mean (SD) Symptom and quality of life scores by group condition However, the pre-post changes in PSQI global score (1.36 ± 2.37, p = 0.140) and sleep onset latency (4.29 ± 12.38 minutes less, p = 0.244) were not statistically signi cant.Objective PSG FindingsThe sleep parameters measured by PSG are listed in Table4.There were no signi cant between-group differences in any of the PSG sleep parameters (all p > 0.05).Within the intervention group, number of awakenings signi cantly decreased by an average of 4.82 (± 7.28) awakes from pre-test to post-test (p = 0.011); however, wake after sleep onset (WASO) signi cantly increased by an average of 21.18 (± 39.35) minutes (p = 0.057).Within the control group, stage 2 sleep signi cantly increased by 6.20 (± 9.15)% from pre-test to post-test (p = 0.015) (40.87 ± 84.47 minutes, p = 0.056).In addition, although the differences were not statistically signi cant, the intervention group had shortened sleep latency by 15.67 (± 50.84) minutes while control group had prolonged total sleep time by 22.83 (± 99.04) minutes.However, both groups showed non-signi cant decreases in stage 3 sleep and rapid eye movement (REM) sleep from pretest to post-test.
Those who received dim red-light reported signi cant improvements in self-reported sleep disturbance, fatigue, depressive mood, physical function, QOL-related symptomology, and QOL-related functioning while those who received bright blue-green light reported signi cant improvements in fatigue, depressive mood, and QOL-global health status.Both light conditions demonstrated signi cant and bene cial effects on fatigue and depressive mood.In either light condition, the extent of improvement for fatigue and depressive mood exceeded the pre-selected MIDs and thus was clinically relevant.