Health-related quality of life and its determinants during and after treatment for paediatric acute lymphoblastic leukaemia: a national, prospective, longitudinal study in the Netherlands.

OBJECTIVES: Health-related quality of life (HRQoL) is impaired in paediatric patients with acute lymphoblastic leukaemia (ALL). Over the past decades, ALL treatment has successfully been adjusted to the risk of relapse, which is now reflected by the stratification of patients into three risk groups who receive treatment of differing intensities. This study is the first to evaluate the longitudinal course of HRQoL in light of these adjustments and identify determinants of HRQoL. DESIGN: Two prospective, national cohort studies (add-on studies within the two most recent treatment protocols for children with ALL (ALL-10 and ALL-11)). SETTING: Dutch paediatric oncology hospitals between October 2006 and October 2009 (ALL-10) and between August 2013 and July 2017 (ALL-11). PARTICIPANTS: Patients with ALL (2-18 years) are treated according to the ALL-10 or ALL-11 treatment protocol. Patients treated according to the ALL-10 protocol only completed a cancer-specific QoL measure and patients treated according to the ALL-11 protocol completed both a cancer-specific and generic QoL measure (see below). OUTCOME MEASURES: HRQoL, assessed with parent-proxy questionnaires (PedsQL Generic and Cancer module) within the first 5 months (T0), at 1 year (T1), 2 years (T2) and 3 years (T3) after diagnosis. The proportion of patients with clinically relevant generic HRQoL impairment was compared with healthy norm values. Multivariable mixed model analyses were used to evaluate the development of HRQoL over time and its medical and sociodemographic determinants (collected on enrolment). RESULTS: Of the ALL-10 cohort, 132 families participated and of the ALL-11 cohort, 136 families participated (268 total). Thus, cancer-specific HRQoL assessments were available for 268 patients (median age 5.3 years (IQR 6.15), 56.0% boys, 69.0% medium-risk ALL), and generic HRQoL assessments for 136 patients (median age 4.8 years (IQR 6.13), 60.3% boys, 75.0% medium-risk ALL). Generic HRQoL improved between timepoints T0 and T3 (total score B 16.1, 95% CI 12.2 to 20.1, p<0.001), but did not restore to normal 1 year after the end of treatment: 28.0% of children remained impaired compared with 16% in the general population (p=0.003). Cancer-specific HRQoL generally improved from T0 to T2 (Pain B 11.3, 95% CI 7.1 to 15.5; Nausea B 11.7, 8.4 to 15.1; Procedural Anxiety B 19.1, 14.8 to 23.4; Treatment Anxiety B 12.8, 9.5 to 16.0; Worry B 3.5, 0.6 to 6.3; Communication B 8.5, 5.0 to 11.9; all p<0.001 except for Worry (p=0.02)), while Physical Appearance and Cognitive Functioning remained stable. Higher treatment intensity and experiencing pain or simultaneous chronic illness were associated with lower HRQoL over time for multiple subscales. CONCLUSIONS: HRQoL impairment is prevalent during and after ALL treatment. Patients with standard-risk ALL and reduced treatment intensity have better HRQoL than patients in higher risk groups. Systematic monitoring of HRQoL is of utmost importance in order to provide timely psychosocial interventions and supportive care.

Fatigue trajectories during pediatric ALL therapy are associated with fatigue after treatment: a national longitudinal cohort study.

OBJECTIVE: Fatigue is one of the most prevalent and distressing symptoms reported by survivors of childhood cancer. There is currently a lack of longitudinal studies on cancer-related fatigue, and especially on the relationship between the course of fatigue during treatment and fatigue at follow-up. The purpose of the current study was therefore to investigate if the course of fatigue during treatment, treatment intensity, serious adverse events, sex, or age at diagnosis are associated with cancer-related fatigue after treatment. METHODS: Participants were 92 children and adolescents diagnosed with acute lymphoblastic leukemia (mean age at diagnosis was 6.26 years). Fatigue was measured with PedsQL multidimensional fatigue scale proxy reports 5 months after diagnosis, 12 months after diagnosis, 24 months after diagnosis, and at follow-up 12 months after end of treatment. The effect of patient and treatment characteristics on fatigue reported at follow-up was tested through logistic regression analyses. RESULTS: The course of fatigue during treatment significantly predicted fatigue reported at follow-up for general fatigue (p = .038, OR = 9.20), sleep/rest fatigue (p = .011, OR = 15.48), and cognitive fatigue (p < .001, OR = 10.78). None of the other variables were associated with fatigue at follow-up for any of the subscales. CONCLUSIONS: The findings demonstrate that fatigue reported during treatment can predict fatigue at follow-up. These results stress the need for longitudinal assessments. Healthcare professionals need to be aware that pediatric patients who are fatigued during treatment need to receive additional attention and timely interventions since cancer-related fatigue will not resolve by itself in the first year after end of treatment.

Parental functioning during maintenance treatment for childhood acute lymphoblastic leukemia: Effects of treatment intensity and dexamethasone pulses.

BACKGROUND: During maintenance treatment, Dutch pediatric patients with medium-risk (MR) acute lymphoblastic leukemia (ALL) receive intravenous chemotherapy and cyclic dexamethasone. Dexamethasone affects child's sleep and behavior. Standard-risk (SR) patients only receive oral chemotherapy, without dexamethasone. Effects of stratified therapy on parents are not well known. This study compares parental sleep, distress and quality of life (QoL) with the general population, between MR and SR groups, and on- and off-dexamethasone (MR group). PROCEDURE: One year after diagnosis, parents of MR patients completed the Medical Outcomes Study (MOS) sleep, distress thermometer for parents and Short Form-12 (SF-12) twice; once on-dexamethasone and once off-dexamethasone. SR parents completed one measurement. Sleep problems, distress and QoL scores (off-dexamethasone) were compared to reference values and between MR and SR. Score differences on- and off-dexamethasone were assessed by multilevel regression analysis. RESULTS: Parents (80% mothers) of 121 patients (57% males; 75% MR, 25% SR) completed 191 measurements. Compared to reference values, parents reported more sleep disturbances, higher distress, and lower mental QoL. Additionally, MR parents reported clinical distress (score ≥ 4), whereas SR parents (on average) did not (mean 4.8 ± 2.4 vs 3.5 ± 2.4, P = .02). Within the MR group, outcomes did not significantly differ on- and off-dexamethasone. CONCLUSIONS: Parents of ALL patients report sleep problems, high distress, and QoL impairment. Within the MR group, parental functioning did not differ on- and off-dexamethasone. However, MR parents reported clinical distress more often than SR parents, possibly reflecting differences in prognostic estimates and treatment burden. This perhaps includes the overall strain of cyclic dexamethasone. This study highlights the need for psychosocial support throughout treatment, regardless of risk stratification.

High prevalence of parent-reported sleep problems in pediatric patients with acute lymphoblastic leukemia after induction therapy.

OBJECTIVE: To assess sleep problems (prevalence and predictors) in pediatric patients with acute lymphoblastic leukemia (ALL) after the most intensive phase of therapy (induction). METHODS: Patients (≥2 years) treated according to the Dutch ALL-11 protocol were included. Sleep was measured using parent-reports and self-reports (Children's Sleep Habits Questionnaire; CSHQ) and actigraphy. Parental sleep (Medical Outcome Study Sleep Scale) and distress and parenting problems (Distress Thermometer for Parents) were assessed with questionnaires. Z-scores were calculated for total CSHQ scores using age-appropriate scores of healthy Dutch children. The prevalence of sleep problems (defined as a Z-score > 1) in patients with ALL was compared to healthy children (chi-square tests). Actigraphic sleep estimates were collected in healthy Dutch children (n = 86, 2-18 years) for comparison with patients (linear regression). Determinants of parent-reported child sleep (total CSHQ Z-score) were identified with regression models. RESULTS: Responses were collected for 124 patients (response rate 67%), comprising 123 parent-reports, 34 self-reports, and 69 actigraphy assessments. Parents reported sleep problems in 38.0% of the patients compared to 15.2% in healthy children (P < .001). Patients reported fewer sleep problems themselves: 12.1% compared to 15.8% in healthy children (P = .33). Total time in bed (B (95% CI): 22.89 (9.55-36.22)) and total sleep time (B (95% CI):16.30 (1.40-31.19)), as derived from actigraphy, were significantly longer in patients. More parent-reported child sleep problems were predicted by parenting problems, more parental sleep problems, bedroom sharing, and child's sleep medication use (explained variance: 27.4%). CONCLUSIONS: Systematic monitoring of child and parental sleep and implementation of effective interventions may be a gateway to improve quality of survival in pediatric ALL.

Sleep-wake rhythm disruption is associated with cancer-related fatigue in pediatric acute lymphoblastic leukemia.

STUDY OBJECTIVES: To compare sleep-wake rhythms, melatonin, and cancer-related fatigue in pediatric patients with acute lymphoblastic leukemia (ALL) to healthy children and to assess the association between sleep-wake outcomes and cancer-related fatigue. METHODS: A national cohort of ALL patients (2-18 years) was included. Sleep-wake rhythms were measured using actigraphy and generated the following variables: Interdaily stability (IS): higher IS reflects higher stability; intradaily variability (IV): lower IV indicates less fragmentation; L5 and M10 counts: activity counts during the five least and 10 most active hours, respectively; and relative amplitude (RA): the ratio of L5 and M10 counts (higher RA reflects a more robust rhythm). The melatonin metabolite, 6-sulfatoxymelatonin (aMT6s), was assessed in urine. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Using regression models sleep-wake rhythms, aMT6s, and cancer-related fatigue were compared to healthy children and associations between sleep-wake outcomes and cancer-related fatigue were assessed in ALL patients. RESULTS: In total, 126 patients participated (response rate: 67%). IS, RA, and M10 counts were lower in patients compared to healthy children (p < 0.001). aMT6s levels were comparable to healthy children (p = 0.425). Patients with ALL were more fatigued compared to healthy children (p < 0.001). Lower IS, RA and M10 counts and higher IV were significantly associated with more parent-reported cancer-related fatigue. Associations between sleep-wake rhythms and self-reported cancer-related fatigue were not statistically significant. CONCLUSIONS: Sleep-wake rhythm impairment is associated with more cancer-related fatigue in pediatric ALL patients. Interventions aimed to improve sleep hygiene and encourage physical activity may reduce cancer-related fatigue.

Determinants of health-related quality of life proxy rating disagreement between caregivers of children with cancer.

PURPOSE: Proxy reports of health-related quality of life (HRQoL) are commonly used in pediatric oncology. However, it is not known if caregivers' reports differ. This study therefore aims to compare paternal and maternal proxy reports, and explore determinants of couple disagreement (sociodemographic and medical characteristics, and parental QoL and distress). METHODS: Both parents completed the PedsQL generic (child's HRQoL), Short Form-12 (own QoL) and Distress Thermometer for Parents. To assess agreement in child HRQoL, intra-class correlation coefficients (ICCs) were calculated. Differences between fathers/mothers were assessed with paired t tests. Systematic disagreement patterns were visualized with Bland-Altman plots. Characteristics of parental couples with a mean proxy difference in the highest quartile (highest proxy score minus lowest proxy score) were explored with multiple logistic regression analysis. RESULTS: Parents of 120 children with cancer (87% post-treatment, mean age 11.0 ± 5.7 years) participated. No significant differences were found between paternal and maternal proxy scores, and agreement was good on all scales (ICCs 0.65-0.83). Bland-Altman plots revealed no systematic disagreement patterns, but there was a wide range in magnitude of the differences, and differences went in both directions. Couples with a mean proxy difference (irrespective of which direction) in the highest quartile (± 20 points) were more likely to have a child in active treatment, with retinoblastoma or relapsed disease, and to diverge in their own QoL. CONCLUSIONS: If proxy reports of only one parent are available, clinicians may reasonably assume that paternal and maternal reports are interchangeable. However, if in doubt, respondent's sex is not of major importance, but clinicians should be aware of patient's and family's characteristics.

Concurrence of sleep problems and distress: prevalence and determinants in parents of children with cancer.

Background: Parents of children with cancer are at risk for sleep problems. If these problems persist, an important perpetuating factor might be ongoing parental distress. Objective: The aim of this study is to assess the prevalence of sleep problems and the concurrence with distress in parents of children treated for cancer, and to identify predictors of this symptom clustering. Method: Parents completed the Medical Outcomes Study (MOS) Sleep Scale and Distress Thermometer for Parents (DT-P). Clinically relevant sleep problems were defined as a score >1SD above the norm and clinical distress as a thermometer score above the established cut-off of 4. Four parent categories were constructed: neither sleep problems nor distress; no distress but sleep problems; no sleep problems but distress; both sleep problems and distress. Predictive determinants (sociodemographic, medical, psychosocial) for each category were assessed with multilevel multinomial logistic regression. Results: Parents (202 mothers and 150 fathers) of 231 children with different cancers participated. Mean time since diagnosis was 3.3 ± 1.4 years (90% off-treatment). The prevalence of sleep problems was 37%. Fifty percent of parents reported neither sleep problems nor distress, 9% had only sleep problems, 13% only distress, and 28% reported both. Compared to parents without sleep problems or distress, parents who reported both were more likely to report parenting problems (OR 4.4, [2.2-9.1]), chronic illness (OR 2.8, [1.2-6.5]), insufficient social support (OR 3.7, [1.5-9.1]), pre-existent sleep problems (OR 6.2, [2.0-18.6]) and be female (OR 1.8, [1.1-4.2]). Conclusions: Sleep problems are common in parents of children treated for cancer, and occur mostly in the presence of clinical distress. Future research must show which interventions are most effective in this group: mainly targeted at sleep improvement or with prominent roles for stress management or trauma processing.

Antecedentes: Los padres de niños con cáncer corren el riesgo de tener problemas para dormir. Si estos problemas persisten, podría ser un factor perpetuador importante malestar en los padres.Método: Los padres completaron el Estudio de Resultados Médicos (MOS, sus siglas en inglés), la escala de sueño y el termómetro de distrés para padres (DT-P, sus siglas en inglés). Los problemas de sueño clínicamente relevantes se definieron como una puntuación> 1 SD por encima de la norma y el malestar clínico como una puntuación de termómetro por encima del límite establecido de 4. Se construyeron cuatro categorías de padres: sin problemas de sueño ni malestar; sin malestar y con problemas de sueño; sin problemas de sueño y con malestar, tanto problemas de sueño como de malestar. Los determinantes predictivos (sociodemográficos, médicos, psicosociales) para cada categoría se evaluaron con regresión logística multinomial multinivel.Resultados: Participaron padres (202 madres y 150 padres) de 231 niños con diferentes tipos de cáncer. El tiempo medio desde el diagnóstico fue de 3,3 ± 1,4 años (90% sin tratamiento). La prevalencia de problemas de sueño fue del 37%. El cincuenta por ciento de los padres no reportaron problemas de sueño ni malestar, el 9% solo tuvo problemas de sueño, el 13% solo sufrió malestar y el 28% informó de ambos. En comparación con los padres sin problemas de sueño o malestar, los padres que informaron ambos problemas, tenían más probabilidades de reportar problemas de crianza (OR 4.4, [2.2-9.1]), enfermedades crónicas (OR 2.8, [1.2-6.5]), apoyo social insuficiente (OR 3.7), [1.5-9.1]), problemas de sueño preexistentes (OR 6.2, [2.0-18.6]) y ser mujer (OR 1.8, [1.1-4.2]).Conclusiones: Los problemas del sueño son comunes en los padres de niños tratados por cáncer, y ocurren principalmente en presencia de malestar clínico. Las investigaciones futuras deben mostrar qué intervenciones son más efectivas en este grupo: principalmente dirigidas a mejorar el sueño o con roles prominentes para el manejo del estrés o el procesamiento de traumas.

Longitudinal development of cancer-related fatigue and physical activity in childhood cancer patients.

PURPOSE: Cancer-related fatigue is one of the most distressing side effects of childhood cancer treatment. Physical activity can decrease fatigue and has positive effects on other health outcomes. Most research on physical activity pertains to adults, and the few studies that focus on children have limited follow-up time. This study evaluates cancer-related fatigue in children and its association with physical activity over a one-year time period. METHODS: Sixty-eight children with cancer (7-18 years) were recruited during or within the first year after treatment. Physical activity (Actical activity monitor) and cancer-related fatigue (Pediatric Quality-of-Life Questionnaire Multidimensional Fatigue Scale (PedsQL-MFS), self- and parent- reports) were assessed at baseline, 4 months, and 12 months. PedsQL-MFS scores were compared with Dutch norms. Longitudinal association of cancer-related fatigue with physical activity was evaluated (No. NTR 1531). RESULTS: Generally, PedsQL-MFS scores were worse than norms at baseline and 4 months, and recovered by 12 months except for the parent-proxy scores in adolescents. Younger children (≤12 years) self-reported comparable or better scores than norms. Physical activity generally improved over time, but patients mostly remained sedentary. During follow-up, increased physical activity was associated with less cancer-related fatigue. CONCLUSION: Cancer-related fatigue in children improves over time, and increased physical activity is associated with less cancer-related fatigue. Given the sedentary lifestyle of this population, the positive effect of physical activity on cancer-related fatigue, and the many other health benefits of an active lifestyle, it is important to stimulate physical activity in childhood cancer patients and survivors.