Sleep in children with acute lymphoblastic leukemia: an opportunity to improve well- being
Steur, L.M.H.
2021
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Steur, L. M. H. (2021). Sleep in children with acute lymphoblastic leukemia: an opportunity to improve well- being.
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acute lymphoblastic leukemia:
an opportunity to improve well-being
Lindsay Steur
The studies in the second part of this thesis were financially supported by the Dutch Cancer Society (KWF Kankerbestrijding).
The printing of this thesis was supported by Volleman Consultants, Multi Corporation, Pfizer, ChipSoft, Biesbroeck Automation, Phy-X, and PACT.
Cover design & illustrations Ilse Schrauwers | isontwerp.nl Layout Renate Siebes | Proefschrift.nu
Printing Gildeprint
ISBN 978-94-9230-340-0
© 2020 Lindsay Steur
All rights reserved. No part of this thesis may be reproduced, stored or transmitted in any form or by any means, without prior permission of the author, or, when applicable, of the publishers of the scientific papers.
Sleep in children with
acute lymphoblastic leukemia:
an opportunity to improve well-being
ACADeMISCh PRoeFSChRIFT
ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam,
op gezag van de rector magnificus prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie
van de Faculteit der Geneeskunde op vrijdag 15 januari 2021 om 13.45 uur
in de aula van de universiteit, De Boelelaan 1105
door
Lindsay Martina Helena Steur
geboren te Nijmegen
copromotor: dr. R.R.L. Van Litsenburg
Chapter 1 General introduction 7 Chapter 2 The prevalence and risk factors of sleep problems in pediatric
oncology: its effect on quality of life during and after cancer treatment Expert Rev Qual Life Cancer Care. 2016;1:153-171
29
Part I Measuring sleep in children
Chapter 3 Psychometric properties and Dutch norm values of the Children’s Sleep Habits Questionnaire in toddlers
Sleep Med. 2017;34:57-63
73
Chapter 4 Psychometric properties and norm scores of the Sleep Self Report in Dutch children
Health Qual Life Outcomes. 2019;17:15
93
Chapter 5 Actigraphic estimates of sleep and the sleep-wake rhythm, and 6-sulfatoxymelatonin levels in healthy Dutch children
Chronobiol Int. 2020 Mar 4:1-13. [Epub ahead of print]
111
Part II Sleep, sleep-wake rhythms, and cancer-related fatigue in children with acute lymphoblastic leukemia
Chapter 6 High prevalence of parent-reported sleep problems in pediatric patients with acute lymphoblastic leukemia after induction therapy Pediatr Blood Cancer. 2020 Jan 15:e28165
137
Chapter 7 Sleep-wake rhythm disruption is associated with cancer-related fatigue in pediatric acute lymphoblastic leukemia
Sleep. 2020 Jun 15;43(6):zsz320.
161
Chapter 8 The impact of maintenance therapy on sleep-wake rhythms and cancer-related fatigue in pediatric acute lymphoblastic leukemia Support Care Cancer. 2020 Apr 13. [Epub ahead of print]
185
Chapter 9 The longitudinal development of sleep in pediatric acute lymphoblastic leukemia
In preparation
207
Chapter 10 General discussion 231
Chapter 11 English summary 253
Chapter 12 Nederlandse samenvatting 261
appendices Abbreviations List of co-authors List of publications PhD portfolio Dankwoord About the author
273 275 277 279 282 288
General introduction
1 Sleep is essential for normal daily functioning and childhood development. Disturbed sleep
has important negative daytime consequences and is associated with many unfavorable physical and psychosocial health outcomes.1-9 Children with cancer are vulnerable to sleep problems presumably related directly to treatment effects (glucocorticoids, chemotherapeutics), treatment-related toxicities (such as pain, nausea, vomiting, and infectious diseases), environmental factors (such as infusion pump alarms or room entering during hospitalization) psychological factors (among others, distress, anxiety, and fatigue), and social factors (such as changed parenting strategies).10-14 Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer and treatment is long and intensive.15, 16 The potential risk factors of sleep and sleep-wake rhythm disturbances in this population are summarized in Figure 1.1 and are described in this introduction. Children with a chronic illness have an increased risk of acute as well as chronic sleep problems compared to healthy peers.17 Furthermore, disturbed sleep is an additional stressor to families facing childhood cancer. Therefore, attention to and treatment of disturbed sleep(-wake rhythms) in these vulnerable children is of major importance. Interventions aimed at improving sleep and sleep-wake rhythms in children with ALL might provide opportunities to improve
Figure 1.1 | Potential risk factors of sleep(-wake rhythm) disturbances in children with ALL.
ALL = acute lymphoblastic leukemia.
Sleep and sleep-wake
rhythm disturbances
Physical Treatment-
related toxicities
Lower physical activity
ALL treatment
Social
Changed social patterns and family routines
Inability to attend school
Parenting strategies Psychological
Distress
Parental functioning
Anxiety Cancer-related
fatigue
Co-sleeping
their well-being. However, evidence on sleep and sleep-wake rhythms in children with ALL during and shortly after treatment is scarce. Before effective interventions can be designed it is important to provide more insight into sleep and sleep-wake rhythms in this population first. Moreover, in order to recognize sleep disturbances in children, valid and reliable screening tools are essential and culturally appropriate scores in healthy children are mandatory.
Background
acute lymphoblastic leukemia Epidemiology and pathogenesis
Globally 397,000 childhood cancer cases were estimated in 2015.18 In the Netherlands around 600 children are newly diagnosed with cancer annually. ALL is the most common type of childhood cancer, with approximately 130 new diagnoses each year.15, 19 The incidence of ALL is highest in children aged 2–5 years and slightly more boys are affected compared to girls.15, 19, 20 The precise etiology of ALL is unknown but it is known that accumulation of genetic aberrations in a lymphocyte precursor cell ultimately lead to uncontrolled proliferation and block of differentiation of immature lymphoid precursor cells.19 Primary somatic genetic abnormalities are critical in the pathogenesis of leukemia.
However, additional mutations are necessary to ultimately lead to leukemia.21 Treatment and outcome
In the Netherlands pediatric cancer patients are treated according to the Dutch Childhood Oncology Group (DCOG) treatment protocols. Since 2012 children with ALL are treated according the DCOG ALL-11 treatment protocol.16
Over the past decades survival rates of ALL have significantly improved. With the preceding national treatment protocol (DCOG ALL-10) 5-year event free survival was 88.7% (standard risk: 93.1%, medium risk: 88.9%, high risk: 75.3%). The 5-year overall survival was 93.9%
(standard risk: 99.0%, medium risk: 93.2%, high risk: 81.5%).15 With the high survival rates achieved with the ALL-10 treatment protocol, the primary aim of the ALL-11 treatment protocol was to improve overall outcome by: 1. Reducing treatment intensity for specific patient groups (such as patients with a TEL/AML1 translocation, which is associated with a good prognosis and an extremely low relapse rate and for patients with Down syndrome as they are at a higher risk for anthracycline-induced cardiotoxicity); 2. Increase treatment intensity for patients with genetic aberrations that are associated with poor prognosis (IKZF1 deletion); 3. Individualize asparaginase therapy, and 4. Reduce overall toxicity by decreasing the cumulative dose of anthracyclines, omitting cranial irradiation, and total body irradiation.
1 According to the DCOG ALL-11 treatment protocol, the majority of children with ALL receive
two years of chemotherapy treatment. Children with an IKZF1 deletion, receive an additional third year of chemotherapy. Treatment is divided in different phases: Induction (protocol 1A and 1B), central nervous system directed therapy (protocol M), intensification, and maintenance or high risk therapy. Treatment intensity depends on risk group stratification.
Children are stratified to the following risk groups (with increasing treatment intensity) based on response to treatment and cytogenetics: standard risk, medium risk, and high risk. Induction therapy is the same for all patients with ALL (except for patients with Down syndrome who do not receive anthracyclines). Induction therapy lasts for around 3 months and is considered the most intensive phase of therapy. It is aimed to achieve complete remission and acquire normal hematopoiesis. After induction therapy the majority of patients receive central nervous system directed therapy (protocol M), except for those already classified as high risk patients. Protocol M is aimed to prevent central nervous system relapse. Maintenance treatment is given up to two to three years from initial diagnosis and is aimed to eliminate minimal residual disease and hence prevent relapse.
Standard risk maintenance therapy consists of daily oral chemotherapy. Medium risk group patients additionally receive weekly intravenous chemotherapy, cyclic oral dexamethasone treatment (5 days with dexamethasone alternated by 16 days without dexamethasone), and intrathecal chemotherapy (around once per four months). High risk patients are expected to have a poorer prognosis and, therefore, receive intensified treatment regimens including an allogenic stem cell transplantation, if a suitable donor is available.16
Sleep and sleep-wake rhythms Normal sleep and sleep-wake rhythms
Healthy sleep patterns can be established with appropriate sleep hygiene. Sleep hygiene refers to behaviors that promote good nighttime sleep quantity and quality, which encourages full daytime alertness.22, 23 Sleep hygiene recommendations for example include, consistent sleep schedules and pre-sleep routines, relaxing activities before bedtime, calm and quite bedroom, and avoiding electronic devices before bedtime.22, 23 Sleep behaviors are shaped during early childhood and are strongly related to parenting strategies and family structures.11, 24 For example, in order to learn children to fall asleep without delay and without the presence of a parent, consistent limits regarding bedtimes and regular sleep routines are imperative.24 Sleep behaviors change during childhood development. While sleep behaviors are mainly shaped by parents in younger children, autonomy increases across adolescence. Moreover, sleep behaviors increasingly depend on social- and academic demands in adolescents.25
The sleep-wake rhythm is one of the human circadian rhythms that is generated by the cells of the suprachiasmatic nuclei that is located in the anterior hypothalamus.26 To align the
circadian sleep-wake cycle to exact 24-hours it needs to be synchronized daily by external cues, such as scheduled sleep, physical activity, meals, and most importantly, light.26-29 Furthermore, the production of endogenous melatonin by the pineal gland is important.
The timing of all these cues is highly important for the synchronization of the sleep-wake cycle.26 The sleep-wake cycle has previously been described by two interacting processes,
“Process S” and “Process C”. “Process S” reflects sleep pressure which accumulates during waking and dissipates during sleep. “Process C” regulates the timing of sleep, so that when sleep pressure surpasses an upper threshold, sleep is initiated, and when sleep pressure falls below a lower threshold, wake is initiated.30 A developmental delay in sleep-wake cycle occurs across adolescence and is associated with socio-behavioral changes (such as increasing social activities and academic demands).30 However, biological factors such as, lengthening of the intrinsic period (Process C) and slower accumulation of homeostatic sleep pressure (Process S) are suggested to be associated with the sleep- wake cycle delay as well.30
Sleep and sleep-wake rhythm disturbances
Sleep disturbances are common in children and adolescents.31 The types of sleep disturbances change among age groups. For example, nighttime fears and night awakenings are more common in toddlers while daytime sleepiness, insomnia, and delayed sleep phase disorder are most commonly reported in adolescents.24, 25, 31-33
Bedtime problems (including for example night awakenings and bedtime resistance) often arise in toddlers when they test the limits to determine boundaries. Inconsistent bedtime routines and limits that change, as a result of the child’s behavior, may cause or worsen bedtime problems.24 In adolescents, participation in social activities (such as sports, games, socialize with peers), jobs, and higher academic demands can compete with bedtime.25 In combination with early wake times on schooldays this results in insufficient sleep and daytime sleepiness. Furthermore, impaired sleep hygiene (such as use of electronic devices or participation in sport activities before bedtime) in adolescents, may contribute to poor sleep quantity and quality.25 Family and environmental issues can also contribute to the development of sleep disturbances during childhood. Impaired parental psychosocial functioning and limited parenting skills may, for example, hamper regular bedtime routines and consistent limit setting. Furthermore, home environment factors (such as environmental noises, need for bedroom sharing) might disturb sleep.24
The presence of sleep problems in early childhood is a risk factor for chronic sleep problems: one-third of sleep problems will persist into late adolescence.34 It is, therefore, important to pay attention to sleep in young children in order to prevent development of chronic sleep problems.
1 acute lymphoblastic leukemia and sleep(-wake rhythm) disturbances
Sleep disturbances are common during ALL maintenance therapy.2, 11, 35 The etiology of sleep(-wake rhythm) disturbances in children with ALL is probably multifactorial. Children with ALL are vulnerable to sleep(-wake rhythm) disturbances due to many factors (physical, psychological, and social) that are shown in Figure 1.1. These factors are described in this section.
First, ALL most frequently occurs in toddlers and pre-school aged children, a period that is essential for the development of sleep habits. During this early phase of childhood development sleep habits are strongly shaped by parental influences.11, 24 Parents need to be consistent and engage in limit setting to teach their children healthy sleep behaviors.
Changed parenting strategies and more lenient parenting have been described in parents of children with ALL.11, 36 Maintaining regular sleep routines and consistent bedtimes might, therefore, be challenging in this population. Second, treatment for ALL is long and intensive, with frequent chemotherapy administrations and regular medical procedures.15, 19 Furthermore, it includes glucocorticoids, that are known for their effect on sleep outcomes.13, 37, 38 Several factors during ALL therapy can impair sleep hygiene and affect the external cues that are essential for the synchronization of the sleep-wake rhythm. Treatment- related toxicities (such as nausea, vomiting, pain and fever/infectious diseases), hospital visits, and hospital admissions (nighttime awakenings for medication administration, by infusion pump alarms or by room entering of medical staff) may for example influence light exposure, physical activity, social activities, and school attendance.14, 15 Third, the psychosocial impact of ALL treatment to children with ALL and their parents is also bi- directionally related with sleep. Children with ALL, for example, experience treatment- related and procedural-related anxiety, especially during the first part of treatment, which could be important sources of distress and disturb sleep.12 Furthermore, cancer-related fatigue has previously been described in children with ALL.38 Increased daytime napping as a result of cancer-related fatigue may disturb sleep(-wake rhythms). Child sleep is also related to parental psychosocial functioning (such as parental distress, parental quality of life (QoL), and parental sleep), which is impaired in parents of children with ALL.39-42
consequences of disturbed sleep and sleep-wake rhythms
Disturbed sleep has important negative daytime consequences (such as daytime sleepiness, impaired cognitive functioning, and impaired academic achievement) and is associated with many unfavorable physical (such as an increased risk of metabolic syndrome, diabetes mellitus, and childhood obesity) and psychosocial health outcomes (such as impaired QoL, fatigue, and depressive symptoms).1-9 A few consequences (metabolic syndrome, obesity, and cancer-related fatigue) of specific importance to children with ALL are described in this section.
Metabolic syndrome and obesity are common problems in adult survivors of pediatric ALL, with prevalence rates of 34% and 45%, respectively.43 Both metabolic syndrome and obesity are risk factors of cardiovascular diseases and associated mortality. Survivors of childhood cancer are known to have an increased mortality risk secondary to cardiovascular diseases.44 Since sleep(-wake rhythms) may play a role in the pathophysiology of these risk factors this might provide opportunities for prevention. Clock genes within the cells of the suprachiasmathic nuclei, that play a central role in the regulation of circadian rhythms, are also important for several metabolic pathways.45, 46 They control energy homeostasis by their involvement in glucose metabolism, lipid homeostasis, and synthesis of cholesterol.45 Mice with Clock gene deletion, are hyperphagic, obese, have affected feeding rhythms, and develop metabolic syndrome.46 Furthermore, short sleep duration has been related to changes in appetite regulating hormones.47 Leptin, which suppresses appetite, was reduced in patients with short sleep duration, whereas ghrelin, that stimulates appetite, was elevated.47 Sleep(-wake rhythm) disturbances may, therefore, result in metabolic dysregulations.
Cancer-related fatigue is one of the most common side-effects of cancer treatments and severe cancer-related fatigue often persists after treatment has ended.48-51 The prevalence of fatigue in survivors of childhood cancer is comparable to children with an auto-immune disease or with cystic fibrosis.51 However, evidence on the prevalence and development of cancer-related fatigue during treatment is limited. Cancer-related fatigue is a distressing and disabling symptom that impairs school functioning and reduces the ability to participate in social roles and activities.52, 53 Underlying mechanisms are not yet well understood.
The etiology seems multifactorial and a biopsychosocial model including demographic, biological, medical, functional, and behavioral factors contributing to cancer-related fatigue has been suggested.49 Sleep disturbances (behavioral) and circadian rhythm/
sleep-wake rhythm disturbances (biological) are included in this model.49 Sleep(-wake rhythms) could, therefore, play a role in the causality of cancer-related fatigue in children with ALL. A relationship between sleep-wake rhythm disturbances and cancer-related fatigue has been suggested in pediatric oncology populations, however, evidence is limited.37, 54 Such a relationship could advance our knowledge regarding the etiology of cancer-related fatigue and guide the development of interventions to improve well-being of pediatric cancer patients.
How to measure sleep and sleep-wake rhythms?
Sleep is a multidimensional construct that includes both objective as well as subjective aspects. In order to thoroughly evaluate sleep, a combination of measurements provides the most complete information.
To determine subjective aspects of sleep, Patient Reported Outcomes (PROs) can provide information on sleep behaviors and daytime consequences of impaired sleep, such as
1 bedtime routines, sleep anxiety, and daytime sleepiness. Using PROs, child sleep can be
evaluated by different respondents. Child self-reports and parent-reports are most often used. Sometimes children are too young or ill to complete self-reports and, therefore, parent-reports are used instead. However, parent and child perceptions on sleep can be different. Parent- and self-reports can provide complementary information on how sleep is perceived. In clinical practice both their perceptions are important since children are treated in a family context and both patients and their parents are involved in the decision making process. Parent- and self-reports should, therefore, be combined whenever possible.
Objective aspects of sleep, can be determined with instruments such as polysomnography and actigraphy. Polysomnography is considered the gold standard for objective evaluations of sleep. It not only provides quantitative data on sleep but it also determines sleep stages based on electroencephalography registrations. However, it is costly, labor intensive, and it can only measure sleep over a limited time period in a clinical setting. Actigraphy is considered a low cost alternative to polysomnography that can be used in ambulant settings for longer time periods. An actigraph is a non-intrusive device that processes sleep-wake outcomes by the occurrence and intensity of limb movements. Actigraphy has been validated against polysomnography in infants, children and adolescents.55-57 Sleep estimates that can be calculated from actigraphy assessments are (definitions are provided in Table 1.1): Sleep onset latency, total sleep time, sleep efficiency, wake after sleep onset, and the total number of awakenings after sleep onset.58 The total time in bed, defined as the number of minutes spent in bed, can additionally be calculated based on sleep log bed- and wake times.
Table 1.1 | Definitions of actigrahic sleep estimates
Variable Definition
Sleep onset latency The number of minutes between bedtime and the first minute scored as sleep
Total sleep time The number of minutes scored asleep during the time spent in bed Sleep efficiency The ratio between total sleep time and time spent in bed
Wake after sleep onset The number of minutes awake after sleep onset Nighttime awakenings The total number of awakenings after sleep onset
There are different approaches to quantify the sleep-wake rhythm with actigraphic recordings. Two commonly used methods are the cosinor analysis and nonparametric method. Cosinor analysis fits a 24-hour cosine wave to the data and provides the estimated phase and amplitude. This method is parametric and presumes that the activity level variation over the day is best described with a 12:12 hour symmetrical sinusoidal. However, the sleep-wake rhythm, particularly in children, is far from symmetrical and sinusoidal. In
adults and adolescents, for example, there is an asymmetrical distribution of about 8 hours of sleep and 16 hours of wakefulness and in infants periods of sleep and wakefulness are more alternating over 24-hours. To better accommodate the nonsinusoidal asymmetric activity pattern of everyday life, nonparametric methods have been proposed that do not make assumptions about the distribution of the rhythm. Accordingly, the nonparametric methods describe the sleep-wake pattern more accurately than cosinor method and has been proposed as the preferred method of use.59 The following sleep-wake rhythm variables can be calculated with nonparametric methods (definitions are provided in Table 1.2): Interdaily stability, Intradaily variability, L5 counts, M10 counts, and the relative amplitude.60
Table 1.2 | Definitions of sleep-wake rhythm outcomes
Variable Range Definition
Intradaily variability 0–2 An estimate of the 24-hour rest-activity rhythm and reflects the fragmentation of the rhythm, a higher intradaily variability indicates a more fragmented rhythm.
Interdaily stability 0–1 Is an estimate of the stability of the rhythm, and describes the synchronization of the rhythm, wherein 1 signifies a perfect synchronization to the dark-light cycle.
L5 counts 0–∞ Activity counts of the least active 5 hours of the day.
M10 counts 0–∞ Activity counts of the most active 10 hours of the day.
Relative amplitude 0–1 Ratio of the difference and the sum of M10 and L5 counts.
A higher relative amplitude indicates a bigger difference between the least and most active period during the day, hence a better sleep-wake rhythm.
Another method for the evaluation of the circadian rhythm, is the assessment of melatonin levels. Melatonin has been used as an endogenous marker of circadian dysregulations.
Melatonin production is not influenced by external influences other than light, unlike other circadian rhythm markers, and is therefore a powerful biomarker in the assessment of circadian dysregulation.61 Metabolites of melatonin can be easily assessed in blood, saliva, and urinary samples. Melatonin levels show intra-individual stability but inter-individual variability.62 Melatonin is primarily secreted at night, however, obtaining nocturnal samples is inconvenient, especially in (young) children. First morning urine levels of the metabolite 6-sulfatoxymelatonin (aMT6s) highly correlate with total nocturnal plasma melatonin levels and are, therefore, an appealing alternative.61, 63, 64
Several issues and challenges are important to mention when measuring sleep(-wake rhythms). Given the developmental changes in sleep during childhood, measuring developmentally appropriate sleep constructs is important. Furthermore, taking these
1 developmental changes into account age appropriate scores of healthy children should
be used when comparing sleep in children with a (chronic) illness to healthy children.
Finally, it is important that PROs are psychometrically robust to ensure that outcomes are properly assessed. However, sleep instruments that are fully validated are largely lacking in children and adolescents and appropriate norm scores are not always available.65, 66
aimS, deSign and outline
Given the many risk factors of sleep(-wake rhythm) disturbances in patients with ALL and the associated adverse health outcomes, attention to and screening for sleep(-wake rhythm) disturbances is important. Although evidence on sleep in pediatric oncology has rapidly emerged over the past years, there are still a lot of gaps in our understanding of sleep in pediatric oncology populations. In children with ALL, the prevalence and types of sleep problems in the first period after diagnosis is not yet studied and only a single study reported on sleep-wake rhythms and the association with cancer-related fatigue.37 Furthermore, the majority of studies in children with ALL only employed a single sleep assessment, while the above mentioned sleep measurements can provide complementary information and would provide a more comprehensive overview on sleep(-wake rhythms) in this population. Importantly, studies are limited by cross-sectional designs. Longitudinal studies would inform on the course of sleep disturbances during treatment for ALL and whether sleep disturbances persist over time. In order to detect sleep(-wake rhythm) disturbances, valid and reliable sleep measurements with culturally appropriate scores in healthy children are mandatory. Recognizing patients with impaired sleep as early as possible provides the opportunity to start interventions in a timely manner to prevent persistence of sleep(-wake rhythm) disturbances and to improve well-being of these children.
Therefore, the aims of this thesis were to: 1. Further improve the field of pediatric sleep research by determining the psychometric properties of internationally, frequently used, child sleep questionnaires and provide scores of healthy Dutch children for frequently used sleep measures, and 2. Determine the prevalence, predictors, and development of sleep and sleep-wake rhythms in children with ALL during and after treatment.
In Chapter 2 we provide an overview of literature on sleep in children during and after cancer treatment and the effect on QoL. It emphasizes the clinical relevance of this thesis and underlines the paucity of literature on this topic.
Part i – measuring sleep in children Study designs
The data described in Chapter 3 and Chapter 4 was collected as part of two larger Dutch studies (in 2014 and 2015, respectively) aiming at establishing normative data for a set of questionnaires. Online data collection was conducted in cooperation with Taylor Nelson Sofres Netherlands Institute for Public Opinion (TNS NIPO). TNS NIPO is a Dutch market research agency that provides access to respondents in the TNS NIPO base. The TNS NIPO base is a database with a panel of 55,000 respondents who have indicated to be willing to participate in TNS NIPO research on a regular basis. Parents of children aged 2–3 years were invited by e-mail to complete the Children’s Sleep Habits Questionnaire (Chapter 3) and children aged 7–12 to complete the Sleep Self Report (Chapter 4). Samples were stratified based on Dutch population figures regarding key demographics (age, sex, marital status, and education). Additionally, to provide a clinical sample, children referred to an outpatient sleep clinic (of a general hospital) with any kind of sleep problem were also included (Chapter 4) and completed the Sleep Self Report.
The results described in Chapter 5 were based on a cross-sectional study in healthy Dutch children (without sleep disturbances and/or use of sleep medication) aged 2–18 years.
Recruitment took place through the professional and social networks of the research team, from Summer 2017 until Spring 2018. The study assessment consisted of a general survey completed by one of the parents, a 1-week actigraphy assessment with a sleep log, and a single morning urinary sample (for the assessment of the melatonin metabolite, aMT6s).
Outline first part of this thesis
The first part of this thesis focuses on the psychometric properties and scores in healthy children of different sleep(-wake rhythm) measures. In Chapter 3 and Chapter 4 we describe the psychometric properties and scores of the Children’s Sleep Habits Questionnaire in healthy Dutch Toddlers and the Sleep Self Report in healthy Dutch children aged 7–12 years, respectively. Chapter 5 reports on actigraphy derived sleep and sleep-wake rhythm outcomes, and melatonin levels in healthy children Dutch children aged 2–18 years.
Part ii – Sleep, sleep-wake rhythms, and cancer-related fatigue in children with acute lymphoblastic leukemia
Study design
The results described in the second part of the thesis are part of the SLAAP [SLEEP] study (SLeep in children with Acute lymphoblastic leukemia And their Parents), an observational, longitudinal, multicenter study on sleep(-wake rhythms), QoL, and cancer-related fatigue in children with ALL and their parents.
1
Figure 1.2 | Schematic overview of ALL-treatment and SLAAP study assessments. a End of treatment for patients with IKZF-1 deletion, b Additional assessment with dexamethasone for medium risk group patients, c Includes stem cell transplantation for the majority of patients; M = protocol M of ALL-11 treatment protocol, IV = protocol IV of ALL-11 treatment protocol, ALL = acute lymphoblastic leukemia.
Second assessmentb
1‐year after diagnosis InductionStandard risk Maintenance * End of treatment for patients with IKZF‐1 deletion ** Additional assessment with dexamethasone for medium risk group patients *** Include stem cell transplantation for the majority of patients
InductionMedium risk Intensification and Maintenance InductionHigh risk Therapyc
Standard risk Medium risk High risk
M M
3‐years after diagnosisa Diagnosis M
IV
2‐years after diagnosis/ End of treatment First assessmentThird assessmentLast assessment
Figure 2. Schematic overview of ALL‐treatment and SLAAP study assessments
Figure 1.3 | Assessments with and without dexamethasone during maintenance therapy (±1 year after diagnosis) for medium risk group patients. Light blue bars reflect 7-day assessment with dexamethsaone, Dark blue bars reflect 7 day assessment without dexamethasone; DEX = dexamethasone.
Cycle 1 Without DEX Day 6–21With DEX Day 1–5 Cycle 2Cycle 3 With DEX Day 1–5Without DEX Day 6–21Without DEX Day 6–21With DEX Day 1–5 Scenario A
Day during cycle
Treatment cycle Scenario B
1 Participants in the SLAAP study were prospective followed for three years and participated
in four to five assessments (Figure 1.2). The first measurement was planned after induction therapy (around four to five months after diagnosis), during central nervous system directed therapy. The second measurement was around 1 year after diagnosis, during maintenance therapy. In the medium risk group, children are on cyclic dexamethasone treatment in this period. For these children two measurements were planned, one during the period with and one during the period without dexamethasone treatment (Figure 1.3). The last two measurements were at 2 years after diagnosis (end of treatment for the majority of patients) and 3 years after diagnosis (1 year after end of treatment for the majority patients).
Each study assessment consisted of patient- and parent-reported questionnaires (sleep, QoL, cancer-related fatigue, and parental distress) and a 1-week actigraphy assessment with a sleep log. In addition, a first morning void was collected for the assessment of aMT6s, a metabolite of melatonin. Table 1.3 provides an overview of the measurement tools used in the SLAAP study.
Patients were identified through the Dutch Childhood Oncology Group (DCOG) registry that includes all pediatric patients with a diagnosis of cancer in the Netherlands. Patients were eligible if they were: 1. Diagnosed with primary ALL and treated according to the national first-line DCOG treatment protocol ALL-11, open to patients aged 1 to 19 years 2. ≥ 2 years of age at assessment. Furthermore, parents and patients needed to master Dutch sufficiently to complete the questionnaires. Patients were recruited between August 2013 and July 2017 in the following pediatric oncology centers in the Netherlands:
Emma Children’s Hospital/Academic Medical Center and VU University Medical Center Amsterdam, Wilhelmina’s children’s Hospital/ University Medical Center Utrecht, Princess Máxima Center for pediatric oncology Utrecht, Sophia children’s hospital/Erasmus Medical Center Rotterdam, Beatrix Children’s hospital/University Medical Center Groningen, Amalia Children’s hospital/Radboud University Medical Center Nijmegen. Parents and patients of 12 years or older provided informed consent for participation.
Outline second part of this thesis
The second part of this thesis describes outcomes of the SLAAP study and outcomes described in this thesis are shown in Table 1.3. In Chapter 6 we report on the prevalence and predictors of sleep problems after the first, most intensive part of therapy. Chapter 7 describes sleep-wake rhythms, melatonin levels, and cancer-related fatigue during the same treatment phase. The effect of maintenance therapy on sleep-wake rhythms and cancer-related fatigue and the additional burden of dexamethasone treatment on these outcomes is reported in Chapter 8. In Chapter 9 we describe the longitudinal development of sleep (parent- and patient-reported and actigraphy derived) in children with ALL until 3 years after diagnosis. Finally, in Chapter 10 the results of this thesis are discussed and Chapter 11 provides an overall summary of this thesis.
Table 1.3 | Measurement tools used in the SLAAP study and outcomes described in this thesis Main outcomesMeasurement tools used in the SLAAP study Outcomes/domains described in this thesis Chapter(s) outcomes are described in Child outcomes Sleep Parent-reportChildren’s Sleep Habits Questionnaire (2–12 years) (33 items)- Total sleep disturbances - Bedtime resistance - Sleep duration - Night awakenings - Daytime sleepiness - Sleep anxiety - Sleep onset delay
- Chapter 6 and Chapter 9 Parent-reportAdolescents Sleep Habits Questionnaire (13–18 years) (54 items)- Total sleep disturbances - Morning wakening - Daytime sleepiness
- Chapter 6 and Chapter 9 Self-reportSleep Self Report (7–12 years) (26 items)- Total sleep disturbances - Chapter 6 and Chapter 9 Self-report Adolescents Sleep Habits Questionnaire (13–18 years) (50 items)- Total sleep disturbances - Daytime sleepiness- Chapter 6 and Chapter 9 Actigraphy - Actigraphic sleep estimates: sleep onset latency, total sleep time, sleep efficiency, wake after sleep onset, nighttime awakenings (definitions are shown in Table 1.1) - Sleep-wake rhythm outcomes: Intradaily variability, interdaily stability, L5 counts, M10 counts and relative amplitude (definitions are shown in Table 1.2) - Chapter 6 and Chapter 9 - Chapter 7 and Chapter 8
1
Table 1.3 | Measurement tools used in the SLAAP study and outcomes described in this thesis (continued) Main outcomesMeasurement tools used in the SLAAP study Outcomes/domains described in this thesis Chapter(s) outcomes are described in Quality of life Parent- and self-reportPedsQL Generic (21–23 items)Not in this thesisNot in this thesis Parent- and self-report PedsQL Cancer (25–26 items)Not in this thesisNot in this thesis Cancer-related fatigue Parent- and self-reportPedsQL Multidimensional fatigue Scale (18 items)- Total fatigue - General fatigue - Sleep-rest fatigue - Cognitive fatigue
- Chapter 7 and Chapter 8 MelatonineFirst morning urinary sample- 6-sulfatoxymelatonin- Chapter 7 Parental outcomes SleepMedical Outcomes Study Sleep Scale (12 items)- 9-item sleep problem index - Chapter 6 and Chapter 9 DistressThe Distress Thermometer for Parents (35 items)- Overall distress (0–10 thermometer score) - Parenting problems - Chapter 6 and Chapter 9 Quality of lifeShort Form-12 (12 items)Not in this thesisNot in this thesis
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1
The prevalence and risk factors
2of sleep problems in pediatric oncology: its effect on quality of life
during and after cancer treatment
LMH Steur, RHE Kolk, F Mooij, R De Vries, MA Grootenhuis, GJL Kaspers, RRL Van Litsenburg Expert Rev Qual Life Cancer Care. 2016;1:153-171
abstract
This review aims to describe the prevalence, types and risk factors of sleep problems in children undergoing cancer treatment and in childhood cancer survivors. Furthermore, the relation between sleep and quality of life (QoL) was described. In children undergoing treatment sleep problems were more common compared to norms and controls. In survivors results were more inconsistent and in some studies even less sleep problems were reported. In both populations various sleep problems were reported (such as night awakenings, bedtime resistance, and daytime sleepiness).
Several demographic, disease and treatment related factors were associated with sleep outcomes. Impaired sleep was associated with poorer physical, psychosocial, and cancer-related QoL. Sleep was assessed with a variety of measurements, all measuring different sleep constructs, limiting the formulation of generalizable conclusions. Therefore, a standardized way to assess sleep in different age categories in pediatric oncology is mandatory.
2
IntroductIon
Over the last decades significant progress has been made in the treatment of childhood cancer, and the 5-year survival rates of all forms of cancers combined have now reached almost 80%.1 While survival rates improve, quality of life (QoL) and other psychosocial out- comes, such as fatigue, depression symptoms, anxiety, and school performances become more and more important, and increasing attention is being given to these outcomes both during and after treatment for childhood cancer.
Several studies have reported impaired QoL during treatment2-4 and although QoL improved after treatment it still did not reach normal levels.5-8 Several determinants of QoL have already been identified. Amongst others, QoL has been related to treatment type and intensity,2, 8, 9 child age,2, 8-10 and sex3, 8, 10 and parental or family factors such as parental health, parental psychosocial functioning, and socioeconomic status.8, 11-13 Lower burden of treatment, longer time since diagnosis, male sex, younger age and higher family income are all factors that are associated with better QoL. In previous studies, sleep also appeared to be a potential determinant of QoL in children undergoing cancer treatment and in childhood cancer survivors.4, 14 In these studies, impaired sleep was associated with lower QoL. Adequate sleep is needed for normal child development and optimal daily functioning. Sleep disturbances during childhood could negatively affect physical and psychological development in children.15-18 Evidence on sleep in pediatric oncology is currently emerging, but a lot is still unknown. For example, the nature of sleep problems, the extend of sleep problems, risk factors for sleep problems, and the relation between sleep and QoL have to be further investigated. Management of sleep problems may be an important tool to improve QoL in children undergoing cancer treatment and in childhood cancer survivors. In order to design effective intervention studies to elucidate sleep problems and eventually improve QoL, first, more insight has to be obtained in these areas.
Sleep research (in childhood) faces some important challenges. First, sleep changes during childhood development. For example, sleep duration decreases with increasing age;
nighttime fears and night awakenings are more common sleep problems in toddlers, and bedtime resistance and daytime sleepiness are more common problems in adolescents.19, 20 Consequently, what is perceived as normal sleep behavior and how sleep can be measured appropriately continue to change during childhood. Aside from age, cultural aspects determine the boundaries between normal and problematic sleep and what is perceived as normal sleep behavior as well.21, 22 Therefore, sleep data cannot easily be generalized between populations with different cultural backgrounds. Furthermore, in sleep research, various sleep measurements, measuring different constructs of sleep are available. Objective measures (i.e. polysomnography and actigraphy) provide more valuable quantitative information, for example, on sleep efficiency and night awakenings while subjective
measurements (i.e. sleep diaries and questionnaires) provide more qualitative information, such as daytime sleepiness and feeling rested in the morning. Moreover, a great variety of sleep questionnaires can be used in different age groups, measuring developmentally and age appropriate sleep constructs. Although subjective and objective sleep measures provide complementary information about sleep, they are not always combined.23 In order to determine the scope of future sleep research in childhood oncology and to eventually design intervention studies to eliminate sleep problems and to improve QoL, a summary of current knowledge on sleep as determinant of QoL in childhood oncology is desirable. Therefore, this review aims to 1. provide an overview on the prevalence and types of subjectively and objectively reported sleep problems, both in children undergoing cancer treatment and in childhood cancer survivors, 2. describe risk factors (both socio- demographic factors and medical factors) related to reported sleep problems; and 3.
summarize the relation between sleep and QoL.
methods
The following databases were searched for relevant studies: PubMed, Embase.com, Cummulative Index to Nursing and Allied Health Literature (CINAHL) and PsychINFO.
For this search, the following terms were used (with synonyms and closely related words) as thesaurus terms and free text terms “sleep” AND “quality of life” AND
“cancer”/”oncology” AND “children”/”pediatric”. Details regarding the final search strategies for all databases are provided in Supplemental Table S2.1. The search included all articles from the inception of each database till 18 December 2015. Articles were eligible for inclusion if they: 1. reported on sleep (quantitatively measured with questionnaires, actigraphy, and/or polysomnography); 2. concerned patients diagnosed with cancer at the age of 0–21 years currently receiving (palliative) treatment, or childhood cancer survivors of all ages; 3. reported on observational (nonintervention) studies; 4. were published in English or Dutch; 5. were available as full texts; and 6. reported on original research.
Studies reporting on sleep subscales from questionnaires not primarily assessing sleep, such as fatigue or QoL instruments, were also included. The age range of 0–21 years for children undergoing cancer treatment was used to allow for inclusion of studies enrolling adolescents and young adults treated according to childhood treatment protocols.
Studies including both children and adults without separately presenting results for children were excluded. If the study populations also included patients with nonmalignant diseases, at least a quarter of the patients had to be diagnosed with cancer to meet the inclusion criteria. However, all reports on brain tumors (malignant as well as low-grade tumors) were included due to both the malignant course of some low-grade brain tumors and the direct effect of brain tumors on structures involved in the sleep-wake rhythm.
2 The reference lists of the included articles and previously published relevant reviews
were searched for missing papers. In case the full text of a potentially relevant paper was not available, the corresponding author was contacted. All titles and abstracts identified by the search were screened independently by two of the authors for eligible papers meeting the inclusion criteria (LS screened all hits; second screening was done by RL, FM or RK). All selected papers were subsequently reviewed full-text to assess their eligibility.
Inconsistencies between authors were discussed until consensus was obtained.
results
The main search yielded 1079 unique records, after duplicates were removed (Figure 2.1). Twenty-two studies met the inclusion criteria for this review. Another 10 articles were identified from the reference search. Finally, 32 studies were included in this review.
Fourteen studies reported on children undergoing treatment for childhood cancer, and 15 studies reported on childhood cancer survivors. Three studies reported on children undergoing treatment as well as on childhood cancer survivors.
All articles are outlined (aim, design, sample, sleep and QoL measurements, and the main outcomes regarding sleep and the relation between sleep and QoL) in separate tables for children undergoing cancer treatment and for childhood cancer survivors. For both populations, articles were outlined in three tables representing studies applying sleep questionnaires (Table 2.1 for children undergoing treatment and Table 2.5 for survivors), subscales of non-sleep questionnaires (Table 2.2 for children undergoing treatment and Table 2.6 for survivors) and objective sleep measurements (Table 2.4 for children undergoing treatment and Table 2.7 for survivors).
children undergoing cancer treatment Sleep: measured subjectively
Three studies reported on sleep questionnaire outcomes (Table 2.1),4, 24, 25 and five studies reported on a sleep subscale of a non-sleep questionnaire only (Table 2.2).3, 26-29 Questionnaires that were applied to assess sleep are summarized (number of subscales and/or items, age of application in the included studies, and sleep construct that was measured) in Table 2.3. One additional study reported on a sleep questionnaire and a sleep subscale,30 and one study employed an actigraphy measurement and a sleep subscale to assess sleep.31 Seven additional studies reported on actigraphy measurements only (Table 2.4).32-38
Two studies used the Children’s Sleep Habits Questionnaire (CSHQ) in children during maintenance therapy for acute lymphoblastic leukemia (ALL). Zupanec et al.25 reported a
