Pediatric Brain Tumors: A Study To Document Patient Fatigue
Overview
Children and adolescents who undergo treatment for brain tumors experience higher levels of fatigue compared to survivors of other childhood cancers. This study aimed to explore the longitudinal patterns of fatigue in pediatric brain tumor patients and identify risk factors associated with different tumor locations.
The study assessed fatigue 1,235 times in 425 participants using self-reported PedsQL Multidimensional Fatigue Scale measurements, conducted repeatedly from the end of treatment up to eight years later. The analysis employed mixed models to evaluate fatigue progression and its determinants separately for infratentorial (N = 205), supratentorial hemispheric (N = 91), and supratentorial midline tumors (N = 129).
Findings revealed that cognitive fatigue increased over time, whereas sleep-rest fatigue and general fatigue initially decreased but later increased. There was no significant difference in fatigue based on tumor location; however, risk factors varied by location. For infratentorial tumors, radiotherapy was linked to higher fatigue levels. Centralization of care was associated with reduced fatigue for supratentorial midline tumors, while female sex was a risk factor for increased fatigue in supratentorial hemispheric tumors. Additionally, higher parental education correlated with lower fatigue levels across all tumor locations.
The study concludes that the development of fatigue is more influenced by sociodemographic and treatment-related factors rather than tumor location. Healthcare providers should be vigilant about the potential for increasing fatigue in the years following treatment. Special attention and support may be necessary for patients from families with lower educational backgrounds, as they may be more susceptible to prolonged fatigue.
Introduction
Cancer-related fatigue is consistently reported as one of the most prevalent and distressing symptoms among childhood cancer survivors. The International Late Effects of Childhood Cancer Guidelines Harmonization Group recently published recommendations on monitoring fatigue post-treatment, while the National Cancer Institute highlighted the need for priority research on fatigue in both children and adults. These guidelines emphasize regular fatigue screenings and call for longitudinal studies to track fatigue development post-treatment. Additionally, the International Childhood Cancer Outcome project has identified fatigue as a key outcome indicator.
Pediatric brain tumors have been identified as a risk factor for fatigue in various cross-sectional studies. Our previous longitudinal research supported these findings, observing fatigue development up to five years post-treatment. Notably, cognitive fatigue was more pronounced in children with brain tumors compared to those with extracranial solid or hematologic malignancies, whereas sleep-rest fatigue showed no significant difference. Although radiotherapy did not predict long-term fatigue development, further follow-up is necessary to fully understand its impact.
An area that warrants more investigation is the relationship between fatigue and pediatric brain tumor location. Given the link between cognitive issues and tumor location, this is a crucial area for further study. The impact of pediatric brain tumor location on quality of life (QoL) has been debated, with some studies indicating lower QoL in children with infratentorial tumors compared to those with supratentorial tumors, while other studies found no significant differences. One study exploring the relationship between tumor location and fatigue concluded that more research is needed.
Addressing this knowledge gap is essential as tumor location may influence the severity and prevalence of fatigue. Additionally, the long-term effects of radiotherapy on fatigue should be examined. This study aims to: (i) chart the course of fatigue in the first eight years post-treatment for pediatric brain tumors, and (ii) identify risk factors for fatigue based on different tumor locations.
Method
The study participants were treated or monitored at the Princess Máxima Center for Pediatric Oncology in Utrecht, the national childhood cancer center of the Netherlands since 2018. Centralizing pediatric oncology care at this center has resulted in a specialized medical team with a mission to enhance quality of life (QoL), including systematic psychosocial support. Additionally, the center has a team dedicated to supportive care and physical exercise for healthy child development, along with a multidisciplinary team for both clinical care and outpatient follow-ups. Psychosocial screenings and QoL and fatigue monitoring are standard care practices.
High-quality evidence supports including systematic psychosocial assessments in standard care for young cancer patients. Consequently, 18 Dutch-speaking families were invited to participate in the KLIK program, which monitors patient-reported outcomes, including repeated assessments of fatigue. The KLIK program, used in national pediatric cancer clinics before centralization, involves completing questionnaires at home before outpatient visits, with email reminders and phone follow-ups if necessary.
The Dutch self-report version of the PedsQL Multidimensional Fatigue Scale (MFS) is used to assess fatigue in patients aged eight and older, with assessments occurring at least three months apart post-treatment. The MFS, validated in Dutch with good psychometric properties and national references for healthy populations, includes subscales for cognitive fatigue, sleep/rest fatigue, and general fatigue, scored on a 0–100 scale where higher scores indicate less fatigue.
Participants could engage in KLIK without participating in research, with data extracted only from those who gave informed consent. Medical variables were gathered from the Dutch Childhood Oncology Group and hospital records, including age at assessment and diagnosis, sex, treatment type, treatment period, relapse, and tumor location. Parental socioeconomic status was measured via self-reported education level, categorized as low, middle, or high. The study received ethical approval from the Rotterdam committee (no. MEC-2016-739).
Linear mixed models were used to estimate growth curves for different fatigue subscales, including data from the first eight years post-treatment. Time since end of treatment was the main variable, with polynomial time variables included based on significance. The models accounted for within-subject dependency through random intercepts, and random slopes were added if needed, evaluated by likelihood ratio tests. Interaction between tumor location groups (IT, supratentorial hemispheric [SH], supratentorial midline [SM]) and time variables was included to determine differences. Potential fatigue risk factors were added to the model stratified by tumor location, with variables coded dichotomously or trichotomously based on relevance.
Growth curves combined all tumor locations, calculating mean values and standard deviations based on residual errors. Analyses were performed using SPSS version 26.
Inclusion Criteria
Eligibility for the study required participants to have been diagnosed with a pediatric brain tumor and to be older than eight years at assessment.
Exclusion Criteria
Exclusions were made for those with central nervous system tumors in the spinal region or multiple primary tumor sites.
Result
The study analyzed questionnaire data from 425 participants, resulting in 1,235 total observations with a median of 2 (range 1-10) assessments per participant. Of these assessments, 31.6% were conducted within 2 years post-treatment, 30.5% within 2-4 years, 20.9% within 4-6 years, and 17.0% within 6-8 years. The sample was predominantly male (53.7%), and nearly half were diagnosed post-centralization of care (50.2%). Most participants underwent brain surgery (82.5%), followed by chemotherapy (49.5%) and radiotherapy (44.3%). A combination of surgery, radiotherapy, and chemotherapy was more common in those with SM tumor location (62%) compared to IT (45%) and SH (35%). Only 2.1% received targeted therapy. The most frequent tumor location was IT (51.3%), and SH was the least common (19.2%).
Regarding the longitudinal development of fatigue, a linear model with a random intercept best depicted cognitive fatigue, showing a slight but consistent increase over time. A quadratic model without random slopes best described sleep-rest fatigue and general fatigue, which initially decreased post-treatment and then increased. No significant differences in fatigue progression were observed across tumor locations.
Multivariable analysis results, stratified by tumor location, are detailed in Table 2. Fatigue score changes are presented as unstandardized estimates for raw score comparison. For SH tumor location, higher parental education was linked to lower cognitive fatigue (9.90, p = .019), while female sex correlated with increased cognitive (−9.44, p = .39), sleep-rest (−6.46, p = .025), and general fatigue (−9.99, p = .003). Older age at diagnosis was associated with higher sleep-rest fatigue (−19.25, p = .025), and relapse with increased sleep-rest fatigue (−9.94, p = .13). Due to the low number of patients receiving targeted therapy, it was excluded from the SH univariable models.
For SM tumor location, higher parental education was linked to reduced fatigue across all subscales (cognitive 11.69, p = .004; sleep-rest 5.94, p = .049; general 8.12, p = .014). Post-centralization diagnosis was associated with less sleep-rest fatigue (15.24, p > .001) and general fatigue (9.72, p = .027). Older age at diagnosis was also linked to higher sleep-rest fatigue (15.97, p = .027).
In the IT tumor group, radiotherapy was associated with increased cognitive (−10.95, p = .008) and general fatigue (−8.27, p = .002). Higher parental education was associated with lower cognitive (8.09, p = .014) and general fatigue (7.13, p = .009), while brain surgery correlated with reduced general fatigue (13.60, p > .001).
Conclusion
Fatigue is a persistent issue that requires continuous follow-up care after treatment for pediatric brain tumors. In this study, we examined the progression of fatigue over eight years in 425 children and adolescents who were treated for brain tumors. Using 1235 assessments from the self-report version of the MFS, we analyzed the changes in fatigue over time, categorized by tumor location. Cognitive fatigue showed a steady decline, while sleep-rest fatigue and general fatigue initially improved but later worsened. These findings align with previous reports on fatigue in pediatric brain tumor patients, though this study extends the follow-up period.
Our research aimed to investigate the impact of various risk factors, focusing on different tumor locations. The distribution of tumor locations was consistent with previous reports. Unlike Varni et al., who found no significant difference in fatigue based on tumor location, our larger sample allowed for a more detailed analysis. Stratifying participants by tumor location, we found that radiotherapy was significantly associated with cognitive and general fatigue, particularly for tumors in the IT location. This association was not evident in previous studies, possibly due to the combined analysis of all tumor locations or the extended time required for these effects to manifest.
Additionally, the study explored the impact of treatment protocols, such as proton versus photon radiotherapy, though a direct comparison was not feasible. Patients who did not undergo brain surgery reported higher fatigue levels, suggesting that more neurotoxic treatments might be employed when surgery is not an option. IT tumors, often treated with more intensive protocols like those for medulloblastoma, are associated with long-term neurocognitive effects and conditions like cerebellar mutism syndrome and hypothalamic-pituitary insufficiency, all of which contribute to fatigue.
Older age at diagnosis was linked to increased sleep-rest fatigue, possibly due to older children being more emotionally affected by their diagnosis. Centralization of care, involving specialized teams and systematic attention to fatigue and sleep patterns, was associated with reduced fatigue in patients with SM tumors. Higher parental education was correlated with less cognitive and sleep-rest fatigue, indicating that children from lower educational backgrounds might need additional support.
Female sex was linked to higher sleep-rest and general fatigue in SH tumors, a novel finding that suggests a need for further investigation. Targeted therapy, previously associated with increased fatigue, did not show a significant impact in this study’s multivariable analysis, likely due to the small number of participants receiving this treatment.
The results underscore the importance of long-term monitoring and proactive support for pediatric brain tumor survivors. Healthcare providers should be aware that fatigue may take years to develop post-treatment, necessitating ongoing adaptation of patient and parent information and support strategies. The study highlights the need for further research on fatigue during treatment to better predict long-term outcomes.
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