Scholarly article on topic 'Sleep Disruption in Hematopoietic Cell Transplantation Recipients: Prevalence, Severity, and Clinical Management'

Sleep Disruption in Hematopoietic Cell Transplantation Recipients: Prevalence, Severity, and Clinical Management Academic research paper on "Basic medicine"

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Sleep disruption / Hematopoietic cell transplant / Management of sleep disruption

Abstract of research paper on Basic medicine, author of scientific article — Heather S.L. Jim, Bryan Evans, Jiyeon M. Jeong, Brian D. Gonzalez, Laura Johnston, et al.

Abstract Sleep disruption is common among hematopoietic cell transplant (HCT) recipients, with over 50% of recipients experiencing sleep disruption pre-transplant, with up to 82% of patients experiencing moderate to severe sleep disruption during hospitalization for transplant and up to 43% after transplant. These rates of sleep disruption are substantially higher than what we see in the general population. Although sleep disruption can be distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. The goal of the current review is to draw attention to sleep disruption and disorders (ie, insomnia, obstructive sleep apnea, restless legs syndrome) as a clinical problem in HCT in order to facilitate patient education, intervention, and research. We identified 35 observational studies published in the past decade that examined sleep disruption or disorders in HCT. Most studies utilized a single item measure of sleep, had small sample size, and included heterogeneous samples of patients. Six studies of the effects of psychosocial and exercise interventions on sleep in HCT have reported no significant improvements. These results highlight the need for rigorous observational and interventional studies of sleep disruption and disorders in HCT recipients..

Academic research paper on topic "Sleep Disruption in Hematopoietic Cell Transplantation Recipients: Prevalence, Severity, and Clinical Management"

Biol Blood Marrow Transplant xxx (2014) 1—20

Sleep Disruption in Hematopoietic Cell Transplantation Recipients: Prevalence, Severity, and Clinical Management

Heather S.L. Jim1 *, Bryan Evans1, Jiyeon M. Jeong2, Brian D. Gonzalez1, Laura Johnston2, Ashley M. Nelson3, Shelli Kesler2, Kristin M. Phillips2, Anna Barata1,4, Joseph Pidala1, Oxana Palesh 2

1 Moffitt Cancer Center, Tampa, Florida

2 Stanford School of Medicine, Stanford Cancer Institute, Stanford, California

3 University of South Florida, Tampa, Florida

4 Psychiatry and Legal Medicine PhD Program, Universitat Autonoma de Barcelona, Barcelona, Spain

American Society for Blood and Marrow Transplantation

Article history:

Received 27 December 2013

Accepted 9 April 2014

Key Words: Sleep disruption Hematopoietic cell transplant Management of sleep disruption

ABSTRACT

Sleep disruption is common among hematopoietic cell transplantation (HCT) recipients, with over 50% of patients experiencing sleep disruption pretransplantation, up to 82% experiencing moderate to severe sleep disruption during hospitalization for transplant, and up to 43% in the post-transplantation period. These rates of sleep disruption are substantially higher than the general population. Although sleep disruption can be distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. The goal of the current review is to draw attention to sleep disruption as a clinical problem in HCT to facilitate patient education, intervention, and research. The review opens with a discussion of sleep disruption measurement and clinical diagnosis of sleep disorders. An overview of the prevalence, severity, and chronicity of sleep disruption and disorders in patients receiving HCT follows. Current evidence regarding sociodemo-graphic and clinical predictors of sleep disruption and disorders is summarized. The review concludes with suggestions for behavioral and pharmacologic management of sleep disruption and disorders as well as directions for future research.

© 2014 American Society for Blood and Marrow Transplantation.

INTRODUCTION

The number of both autologous and allogeneic hemato-poietic cell transplants (HCTs) has increased dramatically in recent years, with more than 50,000 performed worldwide each year [1]. This increase in HCT is due to a greater number of indications for its use as well as advances in therapy, including more frequent use of peripheral blood stem cells, reduced-intensity conditioning regimens, greater use of cells from unrelated and alternative donors, improvements in supportive care, and advances in histocompatibility typing. Survival has generally improved as well [1], resulting in a growing number of patients living with the short- and long-term side effects of HCT.

Sleep disruption is frequently overlooked as a side effect of HCT. Sleep disruption includes difficulty falling asleep, staying asleep, awakening earlier than intended, and/or nonrestorative sleep [2]. It can occur without a clinical diagnosis of a sleep disorder, although a clinical diagnosis may be warranted if sleep disruption is chronic and impairs daily functioning. Sleep disruption is common after HCT, distressing to patients [3], and associated with greater fatigue and reduced quality of life [3,4]. Nevertheless, sleep disruption is seldom the focus of patient—provider communication. A survey of 180 HCT physicians found that only 17%

Financial disclosure: See Acknowledgments on page 18.

* Correspondence and reprint requests: Heather S. L. Jim, PhD, Department of Health Outcomes and Behavior, Moffitt Cancer Center, MRC-PSY, 12902 Magnolia Drive, Tampa, FL 33612.

E-mail address: heather.jim@moffitt.org (H.S.L Jim).

1083-8791/$ - see front matter © 2014 American Society for Blood and Marrow http://dx.doi.org/10.1016/j.bbmt.2014.04.010

discussed sleep with their patients during at least half of clinical visits [5].

The goal of the current review is to draw attention to sleep disruption as a clinical problem in HCT and to provide clinicians and researchers with an overview of current evidence to facilitate diagnosis, patient education, intervention, and research. The review begins with a brief discussion of the assessment and clinical diagnosis of sleep disruption and common sleep disorders (ie, insomnia, obstructive sleep apnea [OSA], and restless legs syndrome [RLS]). We then synthesize and critically review evidence regarding the prevalence, severity, and chronicity of sleep disruption and disorders in patients before HCT, during the acute transplantation phase, and early, middle, and long-term survivorship. This review focuses on HCT studies published in the past decade to ensure greater relevance to current transplant practices. Sociodemographic and clinical risk factors are described, with an emphasis on those relevant to HCT. We conclude with recommendations for management of sleep disruption and disorders in the transplant setting as well as directions for future research.

ASSESSMENT OF SLEEP DISRUPTION

Objective and self-report measures of sleep disruption have been developed to facilitate differential diagnosis and to monitor sleep over time. The gold standard for objective measurement is polysomnography, which measures multiple biologic processes of sleep, including electrical activity in the brain and heart, limb movement, and eye movements. In addition to collecting essential data for diagnosing sleep disorders, polysomnography allows the additional advantage Transplantation.

of monitoring the progression of sleep stages (eg, rapid eye movement sleep or dreaming) and brain arousal during sleep, which can elucidate the occurrence of sleep interruptions. It is typically conducted in a sleep lab or hospital, although home-based polysomnography is increasingly used because of its lower cost.

An alternative to polysomnography is actigraphic monitoring in which a small, nonintrusive piezoelectric monitor similar to a wristwatch is worn on the nondominant wrist to detect and record motion. Specialized software is used to determine sleep versus waking using algorithms validated against polysomnography. Actigraphy data, in combination with patients' self-reports of bedtime and rising time, have been found to be a reliable and valid measure of circadian sleep patterns [6]. Parameters assessed include time in bed asleep, time until sleep onset, number and length of nighttime awakenings, number and length of daytime naps, and circadian variation in sleep and activity. Periodic limb movement can also be assessed. Actigraphs are relatively inexpensive and can be worn at home or in the hospital for several days or weeks, enabling the naturalistic study of sleep disruption over time. Actigraphy is typically used for research rather than diagnostic purposes.

Despite the widespread availability of polysomnography and actigraphy, to our knowledge only 1 study in HCT patients has been published using these measures to assess sleep [7]. Thus, objective sleep patterns of HCT patients are largely unknown.

Regarding self-report measures of sleep, several have been validated in cancer patients [8,9]. The most common are the Insomnia Severity Index [10] and the Pittsburgh Sleep Quality Index [11]. These measures typically ask patients to estimate how long it takes them to fall asleep, how many hours they sleep each night, their use of sleep medications, and their perceptions of sleep quality. Additional measures used include the Epworth Sleepiness Scale [12] to evaluate daytime sleepiness and the International Restless Legs Syndrome Study Group rating scale to evaluate RLS symptomatology [13].

In addition to self-report measures, sleep diaries can play an important role in research and clinical diagnosis. Patients are typically asked to fill out the diary on a daily basis for several days or weeks. Requested information includes bedtime and rising times as well as duration of sleep, sleep quality, difficulty initiating and maintaining sleep, daytime napping, medications taken, and other details [14,15]. Diaries can be particularly useful in both the research and clinical settings for obtaining detailed information regarding patterns of disruption, contributing factors, and targets of intervention.

CLINICAL DIAGNOSIS OF SLEEP DISORDERS

Guidelines for clinical evaluation of sleep disorders depend on the disorder under consideration. Regarding insomnia, diagnosis is based on a detailed sleep, medical, substance, and psychiatric history in addition to a physical and mental status examination. Sleep diaries are often used as well. The goal is to establish the type and evolution of insomnia, perpetuating factors, extent of daytime dysfunction, and identification of comorbid medical, substance, and/ or psychiatric conditions [16].

Diagnostic criteria for insomnia include (1) difficulty initiating sleep, maintaining sleep, and/or early morning awakening with the inability to return to sleep; (2) significant distress and/or impairment in functioning; (3) sleep

difficulty that occurs at least 3 nights a week for at least 3 months; (4) sleep difficulty that occurs despite adequate opportunity to sleep; and (5) symptoms that cannot be explained by another mental or medical disorder [2].

Regarding OSA, a sleep history and physical exam including symptoms and risk factors (eg, snoring, gasping/ choking at night, daytime sleepiness, obesity, type 2 diabetes, congestive heart failure, treatment-refractory hypertension) are indicated [17]. Patients deemed to be at high risk should then be evaluated using polysomnography or home-based monitoring for definitive diagnosis [17]. Criteria for diagnosis are (1) evidence by polysomnography of at least 5 apneas or hypopneas per hour of sleep (ie, snoring, snorting/ gasping, breathing pauses); (2) daytime sleepiness, fatigue, or unrefreshing sleep despite sufficient opportunity for sleep; (3) symptoms are not better explained by another mental or sleep disorder or medical condition; or (4) evidence by polysomnography of 15 or more obstructive apneas and/or hypopneas per hour of sleep regardless of accompanying symptoms [2].

Regarding RLS, diagnosis is based primarily on self-report, although polysomnography and actigraphy can be used [18]. Diagnostic criteria for RLS are (1) an urge to move the legs accompanied by or in response to uncomfortable and unpleasant sensations in the legs; (2) the urge begins or worsens during periods of rest or inactivity, is partially or totally relieved by movement, and is worse or occurs only in the evening or at night; (3) symptoms occur at least 3 times a week for 3 months; (4) symptoms are accompanied by significant distress and/or impairment in functioning; and (5) symptoms are not attributable to another mental or medical disorder [2].

SLEEP DISRUPTION AND DISORDERS BEFORE TRANSPLANT

Research on sleep disorders before HCT is limited to case studies of lymphomas presenting as OSA (eg, [19]). In addition, a study of polysomnography in 12 multiple myeloma patients receiving high-dose chemotherapy [7] reported greater respiratory events and lower-than-normal levels of arterial oxygen saturation, on average. Periodic limb movements in the sample were high and increased during the course of chemotherapy. No studies have reported on the incidence or prevalence of pretransplant sleep disorders.

Numerous precipitating factors can contribute to sleep disruption in patients before transplant, however. Patients typically undergo several rounds of standard-dose chemotherapy that is associated with short- and long-term sleep disruption [20]. Side effects of chemotherapy, such as peripheral neuropathy, may also contribute to sleep disruption [20]. Among cancer patients treated with standarddose chemotherapy, the prevalence of RLS was 18% (ie, double that of the general population), with longer chemotherapy associated with greater risk of RLS [21]. In addition, many patients have elevated levels of anxiety and depressive symptomatology [22]; anxiety can contribute to sleep disruption, whereas both insomnia and hypersomnia are symptoms of depression and share some common etiology [2].

Regarding the prevalence of sleep disruption outside the context of a diagnosable sleep disorder, 16 studies have examined sleep before transplantation (Table 1). Of these, 9 studies did not provide estimates of prevalence of sleep disruption or comparisons with individuals not receiving HCT [7,23-30]. The remaining 7 studies are heterogeneous in

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Table 1

Observational Studies of Sleep in HCT Recipients

Sample

Demographics

Time Frame

Sleep Measures

Statistical Analyses

Main Relevant Findings

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Anderson et al. (2007) [31]

Andrykowski et al. (2005)[48]

Bevans et al. (2008) [3]

Bieri et al. (2008) [49,50]

Auto-HCT (N = 100) Included both disease-free and relapsed patients NHL (34%), MM (66%)

Mean = 53.6 (9.7)

Range = 24-75

Gender:

M = 60%

F = 40%

Caucasian = 81% African American = 12% Hispanic = 5% Other = 2%

HCT survivors (N = 662) and age- and sex-matched healthy control subjects (N = 158) Allo (41%), auto (59%), missing (1%)

AML (29%), CML (19%), ALL (7%), Breast cancer (23%), lymphoma (20%), other (1%) Allo-HCT (N = 76) RIC (54%), myeloablative (46%) Included patients in remission and with progressive disease Acute leukemia (17%), chronic leukemia (38%), lymphoma or MM (29%), MDS (12%), nonhematologic malignancy (4%)

Allo-HCT (N = 124) AML (n = 40), ALL (n = 20), CML (n = 31), CLL(n = 1), MDS (n = 8), lymphoma (n = 14), MM (n = 1), MPS (n = 3), AA (n = 6)

Mean age: 50.1 (14.2) Gender: M = 30% Race:

White = 95%

Mean age: 40.2 (13.5)

Gender:

M = 67%

F = 33%

White = 46% Hispanic = 30% Asian = 9% Black = 7% Other = 8%

Median = 34 Range = 14-65 Gender: M = 79 F 45

Longitudinal; 5 assessments: pre-HCT, 3rd-4th day ofconditioning, day 0, nadir, day 30

MDASI-BMT (a single-item measure of sleep disruption)

Repeated measures ANOVA

Cross-sectional; mean of 7 yr (84 mo) post-HCT (inclusion criteria: >12 mo post-HCT)

Longitudinal; baseline (before transplant conditioning), day 0, day 30, day 100

MOS-Sleep

MANOVA (univariate analyses)

Symptom Distress Scale

Univariate descriptive analyses

Cross-sectional; median of 7.3 yr post-HCT

EORTC QLQ-C30

Descriptive statistics, t-test

The percentage of patients reporting disturbed sleep at moderate or severe levels at each time point were as follows: 8% at baseline, 34% at conditioning, 39% at nadir, 14% at day 30. 8% reported sleep disruption at baseline, 34% at conditioning, 26% at transplant, 39% at nadir, and 14% at day 30. Sleep disruption was one of most severe symptoms at nadir, returned to pre-HCT levels by day 30 post-HCT Sleep disruption was significantly worse for NHL than MM patients (p = .024) HCT survivor group reported more sleep problems than healthy control group (effect size = .39, P < .001).

At baseline, approximately 55% of patients reported insomnia, 86% had insomnia at day 0, nearly 70% had insomnia at day 30, and at day 100 insomnia levels went down to baseline levels. Insomnia was the most distressing symptom at day 0 (reported by 32% of participants). Significantly higher sleep disruption among HCT patients compared with Norwegian population norms. Unclear where normative data came from. Difference of .33 SD. Univariate analysis indicated that employment status was associated with sleep disruption.

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Table 1

(continued )

Sample

Demographics

Time Frame

Sleep Measures

Statistical Analyses

Main Relevant Findings

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Bishop et al. (2007) [50]

Boland et al. (2013)[60]

Boonstra et al. (2011) [37]

Cohen et al. (2012)[28]

Danaher et al. (2006) [24]

HCT (N = 177), partners (N = 177), control subjects (N = 133) Allogeneic = 78 (44%), Autologous = 99 (56%) AML or ALL (39%), CML (22%), breast cancer (18%), lymphoma (21%)

Auto-HCT (n = 29), allo-HCT (n = 3), tandem HCT (n = 10) MM (100%)

MEL (n = 29), maintenance lenalidomide (n = 3), maintenance interferon-a (n = 1)

Hospitalized HCT (N = 69) Allo (n = 46), auto (n = 23) Disease sites not reported

Mean age: 50 (10) Gender: F = 50% Race:

White = 94%

Median: 60 Range: 41-71 Gender: M = 17 F = 15

Gender: Male = 41 Female = 26

Diverse HCT (N = 164) Alio (62%), auto (38%) Disease sites not reported HD (n = 24), NHL (n = 21), AML (n = 11)

38 Chemotherapy, 20 radiochemotherapy

HCT (N = 20 at baseline; N = 17 post-HCT)

Auto = 10 (59%), allo = 7 (41%) Lymphoma (23%), CML (6%), AML (18%), ALL (6%), MM (29%), myelofibrosis (12%), plasma cell leukemia (6%)

Mean age: 45 Range = 19-74 Gender: M = 56% F = 44% Race:

Black = 15%

Latino = 23%

White = 62%

Mean age: 48.65 (23-64)

Gender:

M = 45%

F = 55%

White = 35%, Black = 40%, Latino = 15%, Asian = 5%, Other = 5%

Cross-sectional; mean of 7 yr (84 mo) post-HCT (inclusion criteria: >12 mo post-HCT)

Cross-sectional: mean 5.5 yr post-diagnosis (range, 2-12)

Cross-sectional; day 14 post-HCT (reflective of 2-week period)

MOS-Sleep

Mixed Effect Linear Models

EORTC QLQ C-30

Spearman's correlations

Descriptives and chi-square tests

Longitudinal; 8 assessments: pre-HCT to day 100 post-HCT

Longitudinal linear mixed models, correlations

Longitudinal; pre-HCT and 5 and 8 d post-HCT

EORTC QLQ-C30

Patients showed significantly higher rates of sleep problems than control subjects (ES = .39). Partners showed significantly higher rates of sleep problems than control subjects (ES = .22). Sleep disruption significantly correlated with serum IL-6 levels (p = .02)

No insomnia = 26%, subthreshold insomnia = 48%, clinically significant insomnia (moderate) = 23%, clinically significant insomnia (severe) = 3%. Female and allo patients were more likely to report insomnia (no observed differences in age). Toileting (85%), staff interruptions (80%), physical symptoms (41%), anxiety-self (39%), anxiety-others (35%), and noise (24%) most common reasons for sleep disruption.

Sleep disruption was 1 of the 5 worst reported symptoms; associated with myeloablative regimens and worse functional status.

Sleep disruption significantly worse post-HCT.

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De Souza et al. (2002) [77]

Diez-Campelo et al. (2004)[39]

Enderlin et al. (2013)[7]

Faulhaber et al. (2010)[44]

Frick et al. (2006)[23]

Allo-HCT (N = 26)

All in complete remission

BM (n = 13), PBSC (n = 13)

CML (n = 21), AML (n = 3), MDS

(n = 1), ALL (n = 1)

RIC allo-HCT (n = 47), auto-HCT

(n = 70)

AML (n = 15), ALL (n = 3), CML (n = 5), MDS (n = 7), NHL (n =

3), HD (n = 11), breast cancer (n = 6), MM (n = 29), CLL (n =

4), amyloidosis (n = 1) FLU/MEL or FLU/BU (n = 47), BEAM (n = 37), BU/MEL (n = 8), CY/carboplatin/thiotepa (n = 6), MEL (n = 11), BU/CY (n = 7), CY/ TBI (n = 1)

Auto-HCT (N = 12) MM only

All participants on the Total Therapy 3 protocol

Allo-HCT (N = 61) CML (37.7%), severe AA (21.3%), AML (14.7), ALL (8.1%), NHL (6.5%), HD (4.9%), Other (6.5%) BU/CY (65.6%), RIC (18%), Cy (9.8%), TBI/CY (6.6%)

HCT (N = 282) Allo (35%), auto (62%) AML/MDS (11.7%), ALL (5%), CML (16%), HD (4.3%), NHL (29.9%), MM (29.5%), Other (3.6%); (97% hematologic malignancies)

Range = 19-61 Gender: M = 14 F = 12

Age range, 16-70

Cross-sectional; mean of 1248 d post-HCT

Longitudinal; 6

assessments:

days +7, +14, +21, +90,

+270, +360 post-HCT

WH0Q0L-100: single-item assessment: "Do you have difficulties with sleeping?"

FACT sleep disruption item: "I am sleeping well"

Wilcoxon rank sum, Kruskal-Wallis tests

Descriptives

Mean = 61 Range = 48-72 Gender: M = 10 F=2 Race:

White = 10 African American = 2 Mean age: 36.5 (12.3) Gender: M = 54.1% F 45.9%

Median = 48.5 SD = 11.9 Gender: F = 39%

Cross-sectional; pre-HCT (1 assessment before, 1 assessment after chemo cycle)

Cross-sectional; 1-10 yr post-HCT

Polysomnography

Descriptives

DSM-IV-TR criteria for sleep disorders

Multivariate analysis

Cross-sectional; pre-HCT

EORTC QLQ-C30

Pearson's correlation coefficient

No differences in sleep between patients receiving BM versus PBSC.

14.3% of allo-RIC and 26.3% of auto patients had problems sleeping at 1 yr post-transplant (P = .29).

Patients had a short sleep time, excessive time spent awake after sleep onset, poor sleep efficiency, more time in non-REM sleep, low arterial oxygen saturation, elevated periodic limb movements as measured by polysomnography. The prevalence of sleep disorders was 26.2%. Multivariate analysis indicated that busulfan-cyclophosphamide was an independent risk factor for sleep disorders (included sex and age). Compared patients with sample of German population—36.6 patients versus 16.4 population (no SDs or SEs given). Sleep disruption was positively correlated with problematic social support (.183)

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Table 1

(continued )

Sample

Demographics

Time Frame

Sleep Measures

Statistical Analyses

Main Relevant Findings

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Frodin et al. (2011) [25]

Gallardo et al. (2009)[61]

Gruber et al. (2003) [29]

Grulke et al. (2011) [26]

Auto-HCT (N = 111) MM (n = 56), lymphoma (n = 32), testicular cancer (n = 3), AML (n = 2), multiple sclerosis (n = 1)

Conditioning: MEL (n = 56), BEAM (n = 33), CEC (n = 3), BU/ MEL (n = 2), ZAM (Aavados, ARA-C, melphalan) (n = 2)

Allogeneic BMT (N = 820; N = 150 QOL assessed) Peripheral blood group (N = 410): AML (25.9%), ALL (24.1%), CML (30.7%), MM (2.7%), NHL (7.3%), HD (0.5%), MDS (7.8%), Other (1%)

Bone marrow group (N = 410): AML (25.9%), ALL (24.1%), CML (30.7%), MM (2.7%), NHL (7.3%), HD (0.5%), MDS (7.8%), Other (1%)

Peripheral blood group: conditioning regimen with TBI = 198 (48.3%) Bone marrow group: conditioning regimen with TBI = 200 (48.8%) HCT (N = 163)

Allo (85%), auto (12%), syngenic (3%)

Included both disease-free and relapsed patients CLL/CML (n = 69), ALL/AML (n = 58), Other (n = 36) Quantitative review of 33 papers reporting EORTC scores in HCT and covering 2800 patients

Range of participants (15-415), total N = 2804 Allo = 52.6% Auto = 48.4%

Acute leukemia (28%), CML (15.3%), other hematologic diseases (42.1%), solid tumors (14.8%)

Based on 96 patients: Age:

Mean = 54 (12) Gender: M = 62 F = 34

Peripheral blood group

(N = 410):

Median = 35 Range = 15-59 Gender: M = 58.9% F = 41.1%

Bone marrow group

(N = 410):

Median = 35 Range = 15-59 Gender: M = 62.3% F 37.7%

Age at BMT: Median = 34 (9.2) Gender: M = 62.6% F = 37.4%

Age Range (14-70) Gender: M = 50.1%

Longitudinal; baseline, week 1, week 2, week 3, week 4, month 2, month 3, month 6, year 1, year 1.5, year 2, year 2.5, and year 3

EORTC QLQ-C30

Cross-sectional; within 16 yr post-HCT; (inclusion criteria: > 2 yr post-HCT, transplanted b/w 19791996)

Longitudinal; pre-HCT, during hospitalization, at discharge, up to 6 mo, 7-12 mo, 1-3 yr, >3 yr

The results are presented using descriptive statistics, means adjusted for gender and age

Retrospective; follow up for alive patients: median 43.8 mo for patients receiving peripheral blood, median 46.6 mo for patients receiving bone marrow.

EORTC QLQ-C30, Spanish Version

Chi-square, t tests

SF-36, EORTC QLQ-C30, SIP, Herschbach Stress in Cancer Patients

EORTC QLQ-C30

Mann-Whitney analysis, correlations

Categorized data by time of assessment, unweighted arithmetic means.

Worst sleep disruption at 2 weeks post-HCT. Sleep returned to baseline levels by 2 mo post-HCT, and remained relatively stable thereafter through the 3-year follow up. Increase of 1.1 SD from pre-HCT baseline to 2 wk follow up.

Sleep disruption did not differ between myeloma and lymphoma patients. There were no significant differences in sleep difficulties reported between patients who received bone marrow (n = 73, M = 15.9, SD = 26.7) versus peripheral blood (n = 77, M = 18.2, SD = 26.2).

Unemployed, divorced, and distressed patients reported significantly greater sleep problems.

Sleep problems increase during inpatient stay then return to baseline levels after discharge (change of 25 points).

Sleep problems described by authors as "persistent" and at a "high level."

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Hacker et al. (2003) [30]

Harder et al. (2002)[78]

Hayden et al. (2004)[53]

Hendriks & Schouten (2002) [45]

Auto-HCT (N = 274) MEL/prednisone only (n = 203), MM only

Not reported

HCT (pre-HCT N = 16, 6 wk post-discharge N = 8) Allo (n = 11), auto (n = 5) Lymphoma (n = 4), CML (n = 3), AML (n = 3), ALL (n = 1), MM (n = 3), myelofibrosis (n = 3)

HCT (N = 40)

Allo HCT (87.5%); allo MRD = 26, allo MUD = 9, auto = 5 ALL (n = 8), AML (n = 10), CML (n = 6), NHL (n = 6), MDS (n = 4), MM (n = 4), AA (n = 2) All had TBI up to 12 Gy, intrathecal treatment (n = 11), conditioning regimen: CY (n = 12), ARA-C/CY (n = 19), VP-16/ CY (n = 9)

Sibling allo-HCT (N = 51) (original sample of 75 HCT patients)

CY/TBI (32%); BU/CY (68%)

HCT (N = 52 atT1; N = 33 atT2) Auto (81%), allo (19%) at T1 Relapse free

Lymphoma (40%), breast cancer (29%), acute leukemia (29%)

Mean age: 46.56 (11.31) Gender: M = 50% F = 50% Race:

White = 10 Black = 2 Latino = 2

Native American = 1 Asian = 1 Age at HCT: Mean = 37.2 Range = 15-55 Gender: M = 24 F = 16

Based on 51 patients alive in 2003: Age at BMT: Median = 35 Range = 14-55 Gender: M = 31 F = 20 Age:

Mean = 41 Gender: M = 42% F = 58%

Longitudinal; pre-HCT, 1 mo, 6 mo, 12 mo, 24 mo, and 36 mo post-HCT

EORTC Q0LQ-C30

Linear regression model with forward stepwise selection

Longitudinal; 4 assessments: pre-HCT, hospital discharge, 2 weeks post-discharge, 6 weeks post-discharge

Cross-sectional; 22-82 mo post-HCT

EORTC QLQ-C30

One-way repeated measures ANOVA with paired samples t-tests and Bonferroni corrections

EORTC QLQ-C30

Descriptives

Cross-sectional; median of 98 mo post-HCT

EORTC QLQ-C30

Descriptives

Longitudinal; mean of 2.5 yr and 4.5 yr post-HCT

EORTC QLQ-C30

Mann-Whitney U test, correlations

Reference population of population-based study of 3000 Norwegians aged 1893 yr

Statistically significant difference between newly diagnosed multiple myeloma patients and population norms, small in magnitude with worse scores in patients. Sleep differences were found between T1 (M = 41.67) and T2 (M = 73.33) (baseline to immediately before discharge) and between T2 and T3 (M = 33.33) (immediately before discharge to 2 wk post-hospitalization). T4 M = 33.33

Sleep disruption M = 18.3 (SD = 22.6)

Sleep disturbances were one of the most commonly reported complaints.

No difference in sleep disruption between HCT patients and reference population.

Reference population not described.

No differences in sleep disruption over time. Patients reported more sleep disruption than general Norwegian population. Physicians tended to underestimate sleep problems.

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Table 1

(continued)

Sample

Demographics

Time Frame

Sleep Measures

Statistical Analyses

Main Relevant Findings

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Hjermstad et al. (2004) [33]

Kiss et al. (2002) [57]

Kopp et al. (2005) [51]

Messerer et al. (2008) [55]

Mosher et al. (2011) [56]

HCT (N = 130), chemotherapy patients (N = 118) Allo (n = 61), auto (n = 69) HCT group: HD (n = 15), highgrade NHL (n = 43), low-grade NHL (n = 11), CML (n = 31), AML (n = 19), ALL (n = 11)

Allo-HCT (N = 28) Included both disease-free and relapsed patients CML only

CY/TBI/ARA-C (n = 27), BU/CY (n = 1)

HCT (N = 34) and age- and sex-matched noncancer control subjects (N = 68) Allo-HCT (61.8%), auto-HCT (38.2%)

Chronic leukemia (14.7%), acute leukemia (47.1%), MM (8.8%), MDS (5.9%), solid tumor (2.9%), lymphoma (17.6%), sarcoma (2.9%)

TBI fractionated (67.6%), TBI single dose (8.8%), no (23.5%) Allo-HCT (N = 121) and chemotherapy (N = 221) Disease free AML Only

HCT (N = 406)

Auto (60.3%), allo (29.1%)

Relapse free

NHL (22.4%), HD (6.2%), AML/ CML (11.6%), ALL/CLL (3.4%), MDS/MPS (8.4%), MM/ amyloidosis (33.7%), Other (1.5%)

Age at baseline: Median = 35 Range = 17-55 Gender: M = 56% F = 44%

Mean = 32.6 Range = 18.2-49.2 Gender: M = 16 F = 12

Mean age: 44.7 (9.4) Gender: M = 50% F 50%

Allogeneic BMT: Age at diagnosis: Median = 38 Gender: F = 52%

Mean age: 49.25 (12.82)

Gender:

M = 51.5%

F = 47.8%

White = 83.7%, African American = 5.7%, Hispanic = 3.9%, West Indian = 1.5%, Other = 4.4%

Longitudinal; pre-HCT and 3-5 yr post-HCT

EORTC QLQ-C30

Cross-sectional; mean of 13.2 yr post-HCT

Cross-sectional; patients were at least 5 yr post-HCT

Single item from a symptom checklist developed at the hospital

EORTC-QLQC30

Cross-sectional; HCT patients were a median of

8 yr post-HCT; chemo patients were a median of

9 yr post-chemo Cross-sectional; mean of 21 mo post-HCT

EORTC QLQ-C30

FACT-BMT

Wilcoxontest or 1-way ANOVA as appropriate. Confidence intervals for graphic illustrations

Descriptives

Mann-Whitney U-tests

Chi-square, stratified Mantel-Haenszel, non parametrics

Percentage

No statistically significant changes in sleep disruption from baseline to 3-5 yr in allo or auto groups, but CT group reported improved sleep quality over time. Allo patients reported better sleep, auto worse sleep than general Norwegian population at baseline and 3-5 yr post-HCT.

21 of 26 patients were mildly bothered by sleep disruption, whereas 5 of 26 were moderately or severely bothered.

No significant differences in sleep between HCT patients and healthy control subjects; patients had worse sleep by .06 SD.

No difference in sleep disruption between allo HCT patients and chemotherapy patients (.06 SD).

80% of patients reported sleeping well.

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Pallua et al. (2010) [47]

Rischer et al. (2009) [4]

Sherman et al. (2003) [35]

Allo-HCT (N = 100) AML (41%), CML (22%), ALL (12%), lymphoma (6%), MDS (б%), MM (4%), AA (4%), MPD (2%), PNH (2%), CLL (1%)

Pre-BMT (N = 61) MM (85.3%), MGUS (8.2%), amyloid (6.6%)

Mean = 46.3 (14.7) Range = 16-76 Gender: M = 55% F = 45%

Cross-sectional; mean of 95.4 mo post-HCT

EORTC QLQ-C30

Effect Sizes = Cohen's d, t-tests, 1-way ANOVA

HCT (N = 50 at pre-HCT, N = 32 at day 100 post-HCT) Allo (78%), auto (22%) AML (36%), MM (22%), NHL (14%), MDS (10%), osteomyelofribrosis (10%), Others (8%)

Mean age: 53.3 (12.6) Gender: M = 74% F = 26%

Longitudinal; 3 assessments: pre-HCT, during hospital stay, and day 100 post-HCT

PSQI, sleep diary

Chi-square, McNemar tests, repeated measures ANOVA Spearman's correlation coefficients

Mean = 57 (12.3) Gender: M = 63.9% F = 36.1% Race:

White = 91.8% Other = 8.2%

Cross-sectional; mean of 7.4 mo post-diagnosis; all were assessed before BMT

Epworth Sleepiness Scale

Descriptives, percentages, and Spearman correlations

No significant association between sleep disruption and time since transplant. Sleep disruption was greater in patients with ongoing GVHD compared with patients with no GVHD (ES = .31; not significant). Difference in sleep disruption between HCT patients and the reference Austrian population (ES = .31).

Prevalence of sleep disruption 32% before HCT, 77% during hospitalization, 28% at day 100. During hospitalization: difficulties maintaining sleep was the most reported sleep dimension (81.8% moderate to severe, mainly caused by noises and toileting), then nonrestorative sleep (61.4%), difficulties falling asleep (52.3%), difficulties falling back asleep (47.7%), and early a.m. awakenings (20.5%).

Allo patients had significantly worse sleep than auto patients. Increases in sleep disruption correlated with increases in fatigue, physical functioning, treatment-specific distress but not anxiety and depression Pilot study 43.33% exceeded the clinical cut-off of daytime sleepiness.

Older age associated with more daytime sleepiness. Lower hemoglobin levels associated with more daytime sleepiness.

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Table 1

(continued )

Sample

Demographics

Time Frame

Sleep Measures

Statistical Analyses

Main Relevant Findings

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Syrjala et al. (2005)[52]

Watson et al. (2004)[59]

Wettergren et al. (2008)[34]

Worel et al. (2002)[46]

HCT survivors (N = 137) and age- and sex-matched control subjects from the NHANES study (N = 4020) Allo (88%), auto (12%) CML (chronic phase) (45%), CML (accelerated or blast crisis) (7%), acute leukemia in remission (14%), acute leukemia in relapse (8%), lymphoma in remission (10%), lymphoma in relapse (7%), MDS (7%), Other (4%) HCT (N = 171) and chemotherapy (n = 310) Allo (n = 97), auto (n = 74) CY (n = 147), BU (n = 26), mesna (n = 27), MEL (n = 18), TBI (n = 135)

Auto-HCT (N = 22), compared with Swedish population norms

HD (n = 1), NHL (n = 3), AML (n = 6), MM (n = 12)

Allo or syngeneic HCT (N = 155) Disease free

ALL/AML (n = 9/43), CML (n = 56), MM (n = 5), MDS (n = 7), NHL (n = 15), AA(n = 19), testicular cancer (n = 1) TBI/CY, CY, CY/ATG, BU/CY

BMT survivors: Mean Age: 34.6 (9.0) Gender: M = 48% Race:

White = 95% non-white, non-Hispanic = 3% Hispanic = 2%

For all groups: Age:

Median = 39 Range = 15-58 Gender: M = 45% F = 55%

Median = 50

Range = 31-66

Gender:

M = 13

Median = 34 Range = 17-57 Gender: M = 86 F 69

Cross-sectional; 10 yr post-HCT

Checklist of symptoms developed for the study

Paired t-tests, McNemar, Wilcoxon signed ranks tests Alphas set at .01.

Cross-sectional; at least 1 yr post-HCT

EORTC QLQ-C30

Wilcoxon 2 sample test, t-test, generalized linear models

Longitudinal; pre-HCT and 1 yr post-HCT

Cross-sectional; at least 2 yr post-HCT

EORTC QLQ-C30

EORTC QLQ-C30

McNemar test, paired t-test

Descriptives

14% of survivors reported moderate or severe sleep problems compared with 9% of control subjects; results were not statistically significant.

45% of patients reported sleep disruption. Sleep disruption more severe in older patients than younger patients. No difference in sleep disruption between allo, auto, or chemotherapy groups. No differences in sleep disruption between males and females. No significant changes in sleep disruption (ES = .03), no differences compared with Swedish population

Divided patients 2-5 yr post-HCT and more than 5 yr post-HCT. Of all patients, 45% had none or slight sleep disruption, 43% had moderate sleep disruption, and 12% had severe sleep disruption. Percentages were comparable for patients 2-5 yr post-HCT and more than 5 yr post-HCT.

AA indicates aplastic anemia; ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; ARA-C, cytarabine; ATG, anti-thymocyte globulin; BEAM, carmustine, etoposide, cytarabine, melphalan; BM, bone marrow; BU, Q11 busulfan; CEC, ; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CY, cyclophosphamide; DSM-IV-TR, Diagnostic and statistical manual of mental disorders, 4th edition, Text Revision; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; ES, ; FACT-BMT, Functional Assessment of Cancer Therapy—Bone Marrow Transplant; FLU, fludarabine; HD, hodgkin disease; ISI, Insomnia Severity Index; MDASI, M.D. Anderson Symptom Inventory; MDS, myelodysplastic syndrome; MEL, melphalan; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MOS, medical outcomes study; MPS, myeloproliferative syndrome; MRD, matched related donor; MUD, matched unrelated donor; NHL, non-Hodgkin's lymphoma; PBSC, peripheral blood stem cell; PNH, paroxysmal nocturnal hemoglobinuria; PSQI, Pittsburgh Sleep Quality Index; REM, rapid eye movement; RIC, reduced-intensity conditioning; SF-36, medical outcomes study short form—36; SIP, sickness impact profile; TBI, total body irradiation; VP-16, etoposide; WHOQOL100, World Health Organization Quality of Life Questionnaire 100.

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terms of their sample composition, sample size, measure of sleep, and clinical cut-off [3,4,31-35]. Thus, it is not surprising that there is substantial heterogeneity among study findings. Studies using single-item measures of sleep disruption suggest that approximately 8% of autologous patients report moderate to severe sleep disruption [31], whereas more than 50% of allogeneic patients report sleep disruption of any severity [3]. In contrast, the 2 studies using validated measures (ie, Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale) found that 32% of patients reported clinically significant sleep disruption before autolo-gous or allogeneic transplant [4] and 43% of multiple myeloma patients reported clinically significant daytime sleepiness before autologous transplantation [35]. A direct comparison of sleep disruption between patients receiving allogeneic versus autologous HCT using a single-item measure suggested that sleep was significantly better among allogeneic patients, although sample sizes were small and findings were confounded by group differences in diagnosis and remission status [33]. Comparisons between HCT patient and population norms are mixed, with 1 large study reporting that patients reported significantly worse sleep before autologous transplant or treatment with melphalan or prednisone [32], whereas 2 smaller studies found no differences, perhaps due to low statistical power [33,34]. In summary, although findings are mixed, available data suggest that sleep disruption before transplant is common but relatively mild on average.

SLEEP DISRUPTION AND DISORDERS DURING THE ACUTE TRANSPLANT PERIOD

The first 100 days post-transplant are typically characterized by multiple acute side effects of the conditioning regimen, including mucositis, enteritis, nausea and emesis, episodes of delirium, and, in the case of allogeneic transplant, acute graft-versus-host disease (GVHD) and immunosup-pressive therapies. These side effects and their treatment may disrupt sleep [36]. Moreover, these side effects frequently occur in the context of hospitalization, which can have an additive effect on disrupted sleep [4]. Consequently, sleep disruption tends to be most pronounced in the first 100 days post-transplant. The most extensive research on sleep disruption in HCT patients has also been conducted during this period [3,4,24-26,30-32,37-39], although it is characterized by several limitations, including small samples, which are heterogeneous in terms of diagnosis and transplant type as well as low statistical power. In addition, data are lacking regarding the prevalence and onset of sleep disorders during this time, with the exception of 1 study reporting a prevalence rate of clinically significant insomnia of 26% [37]. Available data suggest that sleep disruption was the most distressing symptom among allogeneic HCT recipients at day 0 and was significantly correlated with bowel changes and fatigue [3]. Sleep disruption significantly increased during the first 100 days, with greatest disruption seen during the conditioning regimen and WBC count nadir [31]. Mean changes of 27 points on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 sleep disruption item were observed from pretransplant baseline to its peak approximately 2 weeks after HCT [25], corresponding to a large increase and effect size of 1.1 standard deviations (SDs) [25]. These data are consistent with a quantitative review of all published studies using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 to

assess quality of life in HCT patients, which found large increases in sleep disruption during hospitalization [26].

Difficulty maintaining sleep was the most common problem in hospitalized HCT patients (82%), followed by nonrestorative sleep (61%), problems falling asleep (52%), difficulties falling back to sleep once awake (48%), and early morning awakening (21%) [4]. Patients largely attributed these problems to the hospital environment, such as noise from medical equipment and nursing staff, and to emotional agitation and stress [4,37]. A small study found that alloge-neic transplant patients reported better sleep before transplant but worse sleep during hospitalization [4]. At the time of hospital discharge, the average severity of sleep disruption among allogeneic and autologous patients was still moderately elevated relative to baseline symptomatology (ie, .51 SD) [26]. Nevertheless, it appeared that increases in sleep disruption were generally transient; by day 100, sleep disruption returned to levels comparable with pre-HCT [4,25,31], although these levels were substantially elevated even before the transplant. Patients receiving allogeneic HCT demonstrate similar levels of sleep disruption near day 100 to patients receiving autologous transplant [4].

SLEEP DISRUPTION AND DISORDERS AFTER THE ACUTE TRANSPLANT PERIOD

New precipitating factors of sleep disruption may occur after the acute transplant period. Patients who experienced resolved sleep disruption or never experienced sleep disruption during transplantation may develop late-onset sleep problems due to corticosteroid treatment for chronic GVHD, inflammation due to GVHD or infection, fear of disease progression, pain, or additional treatments for relapsed disease. For example, evidence suggests that long-term corticosteroid use is a risk factor for OSA, perhaps because of weight gain [40]. Insomnia is also a common side effects of taking corticosteroids, particularly if the medication is taken closer to bedtime. Muscle cramps and neuropathy have been found to be common among patients with GVHD and to disrupt sleep [41]; neuropathy is also a risk factor for RLS [42]. These factors and others can also perpetuate existing sleep problems and contribute to the development of persistent (lasting more than 3 months) or recurrent sleep problems. Additional perpetuating factors of insomnia include cognitive distortions and maladaptive behaviors that begin in reaction to a stressor and persist after the stressor is resolved [43]. Examples of cognitive distortions that can make sleep disruption worse are as follows: "I'm going to feel terrible tomorrow if I don't sleep well" or "I'm never going to get to sleep." Maladaptive behaviors can include spending prolonged time in bed, going to bed excessively early, sleeping late, and staying in bed while no longer asleep. Although these behaviors may initially be helpful, particularly for people experiencing acute illness, eventually they can contribute to irregular sleep patterns that result in insomnia long after the patient has recovered from the acute stressor or illness [43].

Only 1 study has examined the prevalence of sleep disorders after transplant. Among 61 allogeneic HCT recipients transplanted 1 to 10 years previously, 23% met criteria for a diagnosis of insomnia and 3% for hypersomnia; no other sleep disorders were observed [44]. In addition, no studies have examined precipitating versus perpetuating factors of sleep disruption after the acute transplant period. Nevertheless, 23 studies have reported on sleep disruption outside the context of a diagnosed sleep disorder 90 days or more

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Table 2

Online Resources for Sleep Disorders and Disruption

Type of Intervention Relevant Disorder(s) Resource

Internet Address

Description

Evidence Base

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tö tö

Cognitive-behavioral Insomnia interventions

Insomnia

Education about insomnia and treatment

Insomnia

All sleep disorders

Cancer-specific Insomnia

education about insomnia and treatment

RESTORE

Sleepio

National Sleep Foundation

All sleep disorders Sleep Education

All sleep disorders Your Sleep

American Sleep Apnea Association

www.shuti.me

www.restorecbt.com

www.sleepio.com

www.sleepfoundation.org

www.sleepeducation.com

http://yoursleep.aasmnet.org

http://sleepapnea.org/

Willis-Ekbom Disease http://www.rls.org/ Foundation

National Cancer Institute

General sleep health American Cancer Society

www.cancer.gov

www.cancer.org

Insomnia

Cancer Support Community

www.cancersupportcommunity.org

Interactive online program that includes videos from insomnia experts, interactive quizzes, and vignettes dealing with real-life sleep issues Progress is tracked

Provides recommendations tailored to individuals' sleep difficulties

Treatment consists of 5 modules with instructive videos and downloadable MP3 files

Interactive online treatment is delivered by a

virtual therapist and consists of 6 personally

tailored interactive stages

Progress is tracked and each stage is adjusted

accordingly

Comprehensive information about sleep, support groups, video and audio library, and sleep professional location assistance Comprehensive information about sleep difficulties, video archive, and sleep professional location assistance

Comprehensive information about sleep, self-administered sleep assessments, downloadable sleep diary, online forum, and sleep professional location assistance

Self-administered screening for OSA, information about OSA, and information on support groups for people with OSA

Self-administered screening for RLS, information about RLS, and information on support groups for people with RLS

Information specific to cancer related sleep difficulties, symptom management tips, and modules

To find sleep information type "sleep" into the "search" box located on the upper righthand corner on the home page Information specific to cancer-related sleep difficulties and treatment and symptom management tips, and modules Available in Spanish.

To find sleep information type "sleep" into the "search" box located on the center on the home page

Information specific to cancer-related sleep difficulties, tips for managing insomnia, hyperinsomnia, and nightmares To find sleep information type "sleep" into the "search" box located on the upper righthand corner on the home page

Cancer patients $129.00 For 16 weeks Adults of access

Adults

Adults

N/A N/A N/A

N/A N/A N/A

Cost unspecified. Made available through patients health care provider. Also works with health insurance providers. Three payment plan options: $9.99 per week, $79.99 for 12-week access, and $119.99 for 24-week access.

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1557 after HCT. Notably, 20 assessed sleep using a single item as 1622

1558 part of a larger quality of life scale, whereas only 3 included 1623

1559 validated measures of sleep. Seventeen studies were cross- 1624

1560 sectional; many included mixed samples of autologous and 1625

1561 allogeneic recipients who ranged widely in terms of time 1626

1562 from transplant. Thus, definitive conclusions are difficult to 1627

1563 draw. However, available data suggest that after peaking 1628

1564 during the acute transplant period, the prevalence and 1629

1565 AJ AJ <JJ <JJ severity of sleep disruption remains relatively constant over 1630

1566 time. Most studies found no significant change in sleep 1631

1567 disruption between 1 and 10 years post-transplant [44-47]. 1632

1568 HCT survivors tend to report worse sleep disruption 1633

1569 compared with population norms and noncancer compari- 1634

1570 < < z z son groups (ie, .33 to .39 SD) [45,47-50], but the evidence is 1635

1571 mixed [34,51-53]. A cross-sectional study of allogeneic re- 1636

1572 cipients 1 to 10 years post-transplant found that 23% met 1637

1573 Is criteria for clinical diagnosis of insomnia [44], a rate similar 1638

1574 CX ^ <u M to that of the general population (ie, 22%) [54]. Furthermore, 1639

1575 g <u 13 ^ c c " -a 2 3 £ & sleep disruption in patients treated with HCT also does not 1640

1576 ^ ll -S ° -5 differ from that in patients treated with standard-dose 1641

1577 <Û £ | 3 S C O a chemotherapy at 8 to 9 years post-treatment [55]. 1642

1578 ffl ^ S "i- u 'S J§ u 'S ^ o Although most evidence suggests no significant change in 1643

1579 <u . <u {3 1 3 S3 1 3 3 "5 sleep disruption after the first 100 days post-transplant, es- 1644

1580 1 :§ i; 1= s « X timates of the prevalence of sleep disruption in HCT patients 1645

1581 ■ 2 "Û -2 "Û 5 ra -a -5: ra -a „ o -Q vary widely. At 1 year post-HCT, 14% of patients receiving 1646

1582 c S <" <u c 2 & h tt M h ra ^ allogeneic transplant with reduced-intensity conditioning 1647

1583 •S § & ^ 15 F £ & S. JH £ "JJ % ju £ ¡5 ■Î3 and 26% of patients receiving autologous transplantation 1648

1584 reported sleep disruption [39]. A mean of 2 years after 1649

1585 v " 'v ° <u <" in .s "g -g .2 .s "g c .g transplant (range, 1 to 3 years), 20% of patients reported 1650

1586 is « S 1 is « 1 QJ sleep disruption [56]. In contrast, 2 to 5 years after trans- 1651

1587 CJ o e e SJ o " on H -5 c on H a plant, 49% of patients reported none or slight, 43% reported 1652

1588 • • • • moderate, and 8% reported severe sleep disruption [46]. Five 1653

1589 3s or more years after transplant, 44%, 42%, and 14% of patients 1654

1590 reported none or slight, moderate, and severe sleep disrup- 1655

1591 tion, respectively [46]. A mean of 10 years after transplant, 1656

1592 'jz "Û 14% reported moderate or severe sleep disruption [52]. An 1657

1593 IT "jT & o average of 13 years after transplant (range, 10 to 18), 81% of 1658

1594 <U m patients reported they were not bothered or only mildly 1659

1595 U rt C -r-ro bothered by sleep disruption, whereas 19% reported they 1660

1596 S « g u were moderately or severely bothered [57]. In summary, the 1661

1597 g c s . . u û a overall prevalence of any sleep problems after the acute 1662

1598 transplant period (ie, after 100 days) ranges from 14% to 51%, 1663

1599 JZ £o JZ with the prevalence of moderate problems ranging from 14% 1664

1600 to 43% and severe problems ranging from 8% to 14%. Vari- 1665

1601 ability in prevalence rates likely stems from sample bias due 1666

1602 <U <D ^ to small sample sizes in this literature. 1667

1603 U • — C to 1668

1604 u ~ ^ SOCIODEMOGRAPHIC AND CLINICAL PREDICTORS OF 1669

1605 ™ .M ™ C 3 C m O .-M O OJ SLEEP DISRUPTION AND DISORDERS 1670

1606 2 Z o A clinically relevant question is how to identify HCT pa- 1671

1607 tients at risk for sleep disruption and disorders. Risk factors 1672

1608 for insomnia among cancer patients include female gender, 1673

1609 <u <u -a -a anxiety, surgical treatment, and maladaptive beliefs about 1674

1610 sleep [58]. Among HCT patients, 1 small study observed that 1675

1611 ■6 "6 a a conditioning with busulfan and cyclophosphamide was a 1676

1612 -2 .2 risk factor for insomnia [44]. Risk factors for OSA in the 1677

1613 < < general population include obesity, type 2 diabetes, 1678

1614 congestive heart failure, kidney disease, and treatment- 1679

1615 refractory hypertension [17]. 1680

1616 <u £ Some of the risk factors that lead to sleep disruption and 1681

1617 m 'M disorders may be more prevalent after HCT (eg, diabetes, 1682

1618 £ ¿3 hypertension). Risk factors for RLS in the general population 1683

1619 IS u re include female gender, pregnancy, low blood ferritin, high 1684

1620 'M ™ alcohol intake, poor renal function, high blood glucose levels, 1685

1621 and obesity [42]. Although HCT patients are more likely to 1686

have high (rather than low) blood ferritin, they may experience high blood glucose levels and weight gain because of treatment with corticosteroids. In addition, several autoimmune diseases are risk factors for RLS (eg, rheumatoid arthritis, multiple sclerosis, Crohn's disease), suggesting that high levels of inflammation may play a role [42]. These findings have relevance for GVHD as a potential risk factor for RLS, although data are lacking. Thus, in general, risk factors for clinical sleep disorders include female gender, obesity, comorbidities such as diabetes and poor renal function, anxiety, and maladaptive beliefs about sleep.

Regarding sleep disruption outside the context of a diagnosed sleep disorder, evidence suggests that women are more likely to endorse sleep problems than men [44]. Evidence also suggests that sleep disruption is more severe in older patients [44,59]. Systemic inflammation has been associated with worse sleep, although the sample was small and primarily consisted of autologous HCT recipients [60]. Regarding transplant type, allogeneic recipients tend to report better sleep than autologous recipients before transplant and 3 years later [33] but worse sleep during the acute transplant period [4,28,37]. Among allogeneic recipients, significant associations between GVHD and sleep disruption have not been found [47]; however, literature examining this relationship is sparse. Other clinical variables, such as bone marrow versus peripheral blood stem cell transplantation, have not shown significant differences in the prevalence of sleep problems [61]. Nevertheless, comparisons by GVHD and type of hematopoietic stem cell collection are likely underpowered because of small sample sizes. Regarding psychosocial risk factors, research is scarce, but available studies suggest that divorced HCT recipients have higher rates of sleep problems than unmarried patients [29] and unemployed recipients report worse sleep than recipients who are working at the time of assessment [29,49]. In addition, distress, depression, and anxiety are associated with worse sleep [29]. Thus, available evidence suggests that risk factors for sleep disruption outside the context of a diagnosed sleep disorder are older age, female gender, divorce, unemployment, distress, and autologous transplant. Additional research is needed to confirm these findings in larger samples.

TREATMENT OF SLEEP DISRUPTION AND DISORDERS

Treatments for sleep disorders are varied and depend on the underlying cause. Regarding insomnia, the National Institutes of Health Consensus and the American Academy of Sleep Medicine recommend cognitive behavioral therapy for insomnia (CBT-I) as the standard treatment [18]. Extensive research has shown that CBT-I can be as effective as some pharmacologic agents in the treatment of insomnia in the general population [62]. There have been no studies to date on the effectiveness of CBT-I specifically in patients undergoing HCT. Nevertheless, numerous well-designed studies in cancer patients have shown that CBT-I can indeed be effective in improving objectively (eg, actigraphy) and subjectively measured (eg, self-reported insomnia severity and sleep diaries) sleep disruption during and after treatment [63].

Therapeutic effects of CBT-I have been found to last for up to 12 months in cancer survivors [63]. The American Academy of Sleep Medicine recommends that when pharmacotherapy is used for insomnia, short- or intermediate-acting benzodiazepine receptor agonists or ramelteon (Rozerem), a melatonin receptor agonist, be prescribed [16]. Examples of

medications in various drug classes, along with indications, contraindications, and long-term efficacy from randomized placebo-controlled trials in patients with primary insomnia, are listed in Table 3. The choice of medications within a class Q3 of drugs should depend on patients' symptomatology (eg, delayed sleep onset versus difficulty maintaining sleep), patients' preferences regarding use of a controlled substance, and contraindications of the medication. It should be noted that no studies have examined pharmacotherapy for insomnia specifically in the context of HCT.

The first-line treatment for OSA is positive airway pressure, which pneumatically splits the upper airway through a device worn on the nose and/or mouth during sleep [17]. Additional therapies for OSA include surgery, oral appliances, implanted upper airway stimulation devices, and behavioral strategies to lose weight, exercise, adjust sleep position, and avoid alcohol and sedatives at bedtime [17]. No studies have examined treatments for OSA among patients treated with HCT.

The first-line treatment for RLS includes the dopamine agonists pramipexole and ropinirole [18]. Additional medication options include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin, enacarbil, and cabergoline. Although no treatment studies for RLS have been conducted specifically among HCT recipients, pregabalin shows promise for treating RLS secondary to neuropathy and/or neuropathic pain [64]. Also, some data suggest that some antidepressants may contribute to increased risk of RLS, including citalopram, paroxetine, amitriptyline, mirtaza-pine, and tramadol, although evidence is mixed [18]. Thus, avoidance or discontinuation of use of these medications should be considered in patients with RLS.

To our knowledge, only 1 behavioral intervention study has been conducted in HCT recipients with the primary aim of improving sleep disruption outside the context of a diagnosed sleep disorder [65]. In addition, 5 behavioral intervention studies have examined sleep disruption as a secondary outcome [66-70]. All 6 studies were randomized trials of psychoeducation, stress management, aerobic exercise, and resistance training alone or in combination during the inpatient period; 1 study also followed patients for 6 months post-HCT [66]. Samples consisted of patients receiving allogeneic HCT [67,69], autologous HCT [70], tandem autologous HCT [65], and either allogeneic or autologous HCT [66,67]. All reported null results for sleep disruption compared with usual care. Sample sizes ranged from 42 to 700. Thus, available data suggest that sleep disruption does not improve with exercise or stress management during the inpatient period. Additional studies focusing on long-term transplant survivors are needed.

DISCUSSION

Sleep disruption is a common problem among HCT recipients. In addition to being distressing in its own right, sleep disruption may affect other clinically important outcomes. For example, previous research in patients undergoing standard-dose chemotherapy suggests that sleep disruption occurs first in a cascade of symptoms, contributing to increases in fatigue and in turn depression [71]. In addition, preliminary research suggests that sleep disruption may negatively impact immune response and reconstitution [72], although this has not been demonstrated in the context of HCT. Taken together, these studies argue for early intervention to manage sleep disruption and disorders in HCT recipients.

Table 3

Medications Recommended for Treatment of Insomnia by the American Academy of Sleep Medicine [16]

Drug Class

Agent(s)

FDA-Approved for Sleep Onset [79]

FDA-Approved for Sleep Maintenance [79]

Controlled Substance

Generic Available

Relevant Contraindications Include [79]

RCT-Demonstrated Efficacy for Insomnia up to

Relevant Drug Interactions

Ö H ö

ttí ttí

Short/intermediate Eszopiclone

acting benzodiazepine (Lunesta) receptor agonists

Temazepam (Restoril)

Triazolam (Halcion)

Zaleplon (Sonata)

Zolpidem (Ambien)

Zolpidem (Ambien CR)

Zolpidem (Intermezzo)

Impaired motor/cognitive 6 mo

performance with higher dosage in elderly

Oversedation, confusion, 8 wk

ataxia with higher dosage in elderly

Compromised respiratory 5 wk

function, renal or hepatic impairment, pulmonary insufficiency

Conditions affecting 4 wk

metabolism or hemodynamic responses or compromised respiratory function

Compromised respiratory 8 mo

function, conditions affecting metabolism or hemodynamic responses, renal or hepatic impairment, risk of impaired motor/cognitive performance in elderly

Compromised respiratory 6 mo

function, conditions affecting metabolism or hemodynamic responses, renal or hepatic impairment, risk of impaired motor/cognitive performance in elderly

Compromised respiratory 4 wk

function, risk of impaired motor/cognitive performance in elderly

CNS depressants, rifampicin, ketoconazole

CNS depressants, hypnotics, diphenhydramine

Ketoconazole, itraconazole, nefazodone, HIV protease inhibitors, medications that impair the oxidative metabolism mediated by CYP3A4 Promethazine; rifampin; CYP3A4 inducers; CYP3A4 inhibitors; cimetidine; additive CNS depression with other psychotropic medications, anticonvulsants, antihistamines, narcotic analgesics, anesthetics, ethanol, and other CNS depressants CNS depressants; other sedative-hypnotics; imipramine; chlorpromazine; alcohol; sertraline; CYP3A4 inhibitors; rifampin; fluoxetine; ketoconazole

CNS depressants; other sedative-hypnotics; imipramine; chlorpromazine; alcohol; sertraline; CYP3A4 inhibitors; rifampin; fluoxetine; ketoconazole

CNS depressants; imipramine; chlorpromazine; rifampin; ketoconazole

Melatonin receptor agonist

Ramelteon (Rozerem)

Intermediate/long acting Clonazepam benzodiazepine (Klonopin)

receptor agonist

Hepatic impairment, may affect 6 mo reproductive hormones

Renal or hepatic impairment, None

respiratory diseases, elderly patients, glaucoma

CYP inducers, CYP1A2 inhibitors, CYP3A4 inhibitors, CYP2C9 inhibitors; donepezil; doxepin; zolpidem; CNS depressants; alcohol CYP450 inducers; propantheline; CYP3A inhibitors; alcohol; narcotics; barbiturates; hypnotics; antianxiety agents; phenothiazines; thioxanthene; butyrophenone antipsychotics; MAOIs; TCAs; anticonvulsant drugs; CNS depressants; valproic acid

(continued on next page)

00000000000099999999999999999999999999999999999999999999999999999 11000000000099999999998888888888777777777766666666665555555555444

Table 3

(continued )

Drug Class

Agent(s)

FDA-Approved for Sleep Onset [79]

FDA-Approved for Sleep Maintenance [79]

Controlled Substance

Generic Available

Relevant Contraindications Include [79]

RCT-Demonstrated Efficacy for Insomnia up to

Relevant Drug Interactions

Ö H ö

tö tö

Sedating low-dose antidepressant

Estazolam (ProSom, Eurodin)

Flurazepam (Dalmane)

Lorazepam (Ativan)

Amitriptyline

Doxepin (Silenor) 3-6 mg

Mirtazapine (Remeron)

Trazodone (Oleptro)

Renal or hepatic impairment, compromised respiratory function, depression

Depression, hepatic or renal impairment, pulmonary insufficiency

Compromised respiratory function, impaired renal or hepatic function, elderly Liver dysfunction

Compromised respiratory function

Neutropenia and hyponatremia reported, renal or hepatic impairment, conditions affecting metabolism or hemodynamic responses, elderly, may cause orthostatic hypotension

Hypotension and syncope reported, elderly, renal or hepatic impairment, hyponatremia may

CNS-acting drugs; anticonvulsants; antihistamines; alcohol; barbiturates; MAOIs; narcotics; phenothiazines; psychotropic medications; CNS depressants; smoking; CYP3A inhibitors; CYP3A inducers CNS depressants; alcohol

CNS depressants; clozapine; valproate; probenecid; theophylline; aminophylline

Guanethidine; CNS depressants; CYP2D6 inhibitors; TCAs; SSRIs; "caution with thyroid drugs"; disulfiram; ethchlorvynol; anticholinergics; sympathomimetics; neuroleptics; cimetidine Alcohol; CNS depressants; sedating antihistamines; CYP2C19 inhibitors; CYP2D6 inhibitors; CYP1A2 inhibitors; CYP2C9 inhibitors; cimetidine; tolazamide; sertraline MAOIs; serotonergic drugs; drugs affecting hepatic metabolism; CYP enzyme inducers; drugs metabolized by or inducers of cytochrome P450; antihypertensives known to cause hyponatremia; phenytoin; carbamazepine; hepatic metabolism inducers; cimetidine; ketoconazole; cimetidine; alcohol; diazepam; CYP3A4 inhibitors; HIV protease inhibitors; azole antifungals; erythromycin; nefazodone; warfarin Serotonergic drugs; drugs which impair serotonin metabolism; antipsychotics; dopamine agonists; serotonin precursors; CYP3A4 inhibitors; Carbamazepine; MAOIs; alcohol; barbiturates; CNS depressants; warfarin; antihypertensives; NSAIDs; aspirin; drugs that affect coagulation or bleeding; diuretics; drugs that prolong QT interval

to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to ooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo

I—'I—' »—' »—'I—'I—'I—'I—'I—'I—'I—'I—'I—» I—» I—'I—» I—» I—» I—» I—» I—» I—» I—'I—» I—» I—» I—'I—'I—'I—» I—'I—» I—» I—'i—» I—» I—» I—' »—' »—'i—» I—'OOOOOOOOOOOOOOOOOOOOOOO

-*i—'I—'I—'OOOOOOOOOO

ö H ö

Trimipramine (Surmontil)

Liver dysfunction, elderly

Other prescription drugs

Gabapentin (Neurontin) Olanzapine (Zyprexa)

Yes Yes

Tiagabine (Gabitril)

Quetiapine (Seroquel)

Liver dysfunction, hepatic impairment

Hepatic impairment; prostatic hypertrophy; may cause orthostatic hypotension; leukopenia, neutropenia, and agranulocytosis reported; may cause cognitive and motor impairment

Incapacitating weakness reported

None None

1 night

May induce orthostatic hypotension; leukopenia, neutropenia, and agranulocytosis reported; may impair physical/ mental abilities

Serotonergic drugs; drugs which impair serotonin metabolism; caution on patients on thyroid medication; guanethidine; cimetidine; alcohol; catecholamines; anticholinergics; sympathomimetic amines; local decongestants; local anesthetics containing epinephrine; atropine; CYP2D6 inhibitors; SSRIs; TCAs

Maalox; naproxen sodium; hydrocodone

Diazepam; alcohol; carbamazepine; omeprazole; rifampin; CYP1A2 inducers; fluoxetine; fluvoxamine; other centrally-acting drugs; potentially hepatotoxic drugs; antihypertensives; levodopa; dopamine agonists; anticholinergic drugs; parenteral benzodiazepines Valproate; carbamazepine; phenytoin; phenobarbital; ethanol; triazolam; drugs that lower seizure threshold (antidepressants, antipsychotics, stimulants, narcotics); drugs that induce or inhibit hepatic metabolizing enzymes; highly protein-bound drugs Centrally-acting drugs; alcohol; CYP3A4 inhibitors; CYP3A4 inducers; antihypertensives; levodopa; dopamine agonists; drugs known to cause electrolye imbalance; drugs known to prolong QTc interval (eg, antiarrhythmics, antipsychotics, antibiotics); anticholinergic medications

FDA indicates U.S. Food and Drug Administration; RCT, randomized controlled trial; CNS, central nervous system; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to 654UJtoi—>098 —I 6 5 4 UJ to—>098 —I 6 5 4 UJ to—>098 —I 6 5 4 UJ to—>098 —I 6 5 4 UJ to—>098 —I 6 5 4 UJ to—>098 —I 6 5 4 UJ to

Effective management of sleep disruption may be difficult in the inpatient setting due to environmental factors that can interrupt sleep. Environmental interventions to improve sleep among inpatients may be more effective than patient-based interventions (eg, minimizing of nighttime vital signs monitoring). A study conducted by Sharda et al. [73] suggests that vital sign monitoring might not be necessary for HCT patients with low-risk profiles (ie, lack of daytime fever and central nervous system complaints) and may lead to improved sleep and health. In contrast, use of a hypnotic (zolpidem) has been associated with increased inpatient falls [74].

Regarding outpatient sleep management, several phar-macologic and behavioral management options are available. National Comprehensive Cancer Network Survivorship guidelines recommend screening for sleep disruption at regular intervals, particularly when there has been a change in clinical status or treatment [75]. Insomnia causing decreased daytime functioning, worse quality of life, worsening of complaints, or distress to the patient should be treated with CBT, sleep hygiene education, medication, and/ or referral to a sleep specialist [75]. In light of the strong evidence base for CBT-I in cancer patients, we believe it should be considered as a first choice for treatment of chronic sleep disruption in HCT recipients. CBT-I lacks side effects, medication interactions, and potential for abuse. In addition, it may be more acceptable than pharmacologic treatment for HCT recipients who would prefer to avoid additional medication. Referral to a clinical psychologist board certified in behavioral sleep medicine is recommended for patients interested in CBT-I. For patients who are unwilling or unable to engage in CBT-I or for whom it is not effective or feasible, pharmacologic treatment is a viable alternative. Previous research has found that sleep medications commonly prescribed to cancer patients are lorazepam (31.4%) and zolpidem (29.4%) [76], although, as noted previously, no evidence exists for their effectiveness in HCT recipients. Patients with OSA should be referred to a sleep medicine physician, whereas patients with RLS should be treated with medication and/or referred to a sleep medicine physician [75]. Because of the specialized needs of HCT patients, it is advisable that patients with sleep disorders be managed by an interdisciplinary team consisting of the transplant physician, sleep medicine physician, and/or clinical psychologist.

Additional research is clearly needed regarding sleep disruption in HCT recipients. Longitudinal studies should be conducted to determine prevalence, chronicity, and natural course of sleep disruption and disorders secondary to HCT using well-validated objective and self-report measures of sleep as well as clinical diagnostic criteria. The prevalence of sleep disruption and disorders in HCT recipients should be compared with population normative data, because they are also common among individuals without cancer. Future studies should also aim to identify genetic, sociodemo-graphic, and clinical risk factors for sleep disruption and disorders secondary to HCT. Well-designed randomized controlled trials are needed to test the efficacy of behavioral and pharmaceutical management of sleep problems in HCT recipients.

In summary, sleep disruption is a common, distressing, and under-recognized problem among HCT recipients. Clinical efforts to proactively manage sleep disruption and disorders have the potential to improve overall quality of life in this population. Until more research is conducted with a

specific focus on HCT recipients, strategies to manage sleep disruption and disorders should be adapted from the current evidence base in cancer patients and the general population.

ACKNOWLEDGMENTS

Financial disclosure: Supported by National Cancer Insti- qi tute grant K07 CA138499 (to H.S.L.J.), National Cancer Institute grant K07 CA132916 (to O. P.), and the Stanford Cancer Q13 Institute Seed Award (to O. P.).

Conflict of interest statement: ■■■. Q4

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