This study aimed to investigate the prevalence of fatigue and associated factors in pediatric and adult patients and survivors after treatment for pediatric bone sarcoma. This is the first study to examine fatigue in a relatively large and nationwide cohort of pediatric bone sarcoma patients in follow-up. Our results show that children scored significantly worse on all fatigue measures compared to Dutch normative values, while adults did not significantly differ on any fatigue measure. Using a 3-step model approach, we gained insight into the contribution of demographic, medical, and psychosocial characteristics, pain, and lifestyle. Demographic and medical variables explained only a small percentage of fatigue. Across the models, pain and psychological difficulties showed the strongest negative association with fatigue, whereas physical activity showed the strongest positive association.

We found that the prevalence of severe fatigue in children after pediatric bone sarcoma was 6.5% and 1.3% in adults. These prevalence rates should be interpreted in the context of the Princess Máxima Center, where comprehensive supportive care is provided, including structured attention to fatigue, promotion of physical activity, and access to psychosocial care. Within this setting, fatigue remains a clinically relevant outcome. A previous study in a Dutch national cohort of childhood cancer survivors reported a 28.8% prevalence of severe chronic fatigue in bone sarcoma survivors [7]. It is important to note that this study involved a different patient cohort, treated between 1963 and 2001; differences in treatment, supportive care and follow-up, and the use of a different PROM may partly explain the higher prevalence observed. However, moderate fatigue was more common in our study, affecting 45.2% of children and 10.3% of adults. Previous studies in adolescents and adults with bone or soft tissue sarcomas reported similar patterns, with a substantial proportion of patients experiencing moderate or heightened fatigue during or after treatment [8,9,10].

Children in our study reported more fatigue than the norm, while adults did not differ from the norm. In other studies, fatigue varied over time after treatment completion [1, 40]. However, in our regression analyses, time since end of treatment was only associated with cognitive fatigue and not with the other fatigue scores. Therefore, differences in time since treatment completion are unlikely to fully explain the observed differences between pediatric and adult patients. Other explanations may be that children have not yet learned to balance their energy, whereas older patients may be more experienced in managing fatigue. Fauske et al. (2019) described that patients after bone sarcoma had adapted to their difficulties, including fatigue, and reoriented towards a new normal [41]. This may be explained by response shift, which means that an experience, in this case diagnosis and treatment of pediatric bone sarcoma, can change the internal standard of patients, resulting in a different meaning of self-evaluation and experiences [42]. However, it is important to note that in other studies, adults reported more fatigue than younger survivors. For example, a previous study that assessed the development of fatigue after end of treatment across different childhood cancer diagnoses found that older age at assessment was associated with higher fatigue levels [1]. In another study among childhood cancer survivors, the prevalence of chronic fatigue was significantly higher in adult survivors than in adolescent survivors [7].

Medical factors overall contributed little to the explained variance of the fatigue outcomes. The only medical factor that was significantly associated with fatigue was time since end of treatment, with longer time since treatment being associated with less cognitive fatigue. All other medical factors, such as tumor location or recurrence/progression, were not associated with fatigue in this study. In a Dutch cohort study that assessed fatigue after treatment, the only significant treatment related predictor of self-reported fatigue was immunotherapy [1]. However, immunotherapy is not a standard treatment modality for pediatric patients with bone sarcoma yet. In the same cohort, relapse was associated with higher levels of sleep-rest fatigue and general fatigue. We did not find any associations with relapse or recurrence in our study.

Psychological difficulties were associated with worse general fatigue, sleep/rest fatigue, total fatigue, and PROMIS® fatigue. This underscores that fatigue is related to psychological wellbeing, but the direction of the relationship is not clear [43]. Psychological difficulties, such as anxiety, depression, or fear of cancer recurrence, can contribute to increased fatigue, for example by affecting sleep, reducing energy, or decreasing the motivation to exercise [17, 27, 44]. Conversely, fatigue may also negatively affect psychological wellbeing, for example by the limitations in daily and social activities that patients may experience or by increasing anxiety about health and functioning [27, 45].

Another factor that was associated with fatigue was pain, with higher levels of pain being associated with more fatigue. In a study among children and adolescents undergoing active treatment, pain interference was positively correlated with fatigue [46]. Similarly, other studies found that patients with higher levels of pain experienced more or persistent fatigue [28, 47]. In addition, a systematic review of survivors of childhood cancer found that fatigue was consistently associated with pain [48]. This may be explained by the fact that pain can disrupt sleep and reduce physical activity, both of which are associated with fatigue. Previously, we found that 60 of 144 pediatric bone sarcoma patients in our study (42%) reported pain [21]. This highlights the importance of adequate pain management.

Physical activity was found to be associated with less fatigue. Physical activity was measured objectively using an ActiGraph accelerometer, which provides objective data on daily movement [38]. In our previous study on physical activity in the same cohort of pediatric bone sarcoma patients as in the current study, we found that 78% of patients met the World Health Organization’s (WHO) exercise recommendations for moderate-to-vigorous physical activity [49]. Earlier research has shown beneficial effects of movement and exercise on cancer-related fatigue [24, 50]. Given the cross-sectional design of current study, the direction of the association between fatigue and physical activity is not clear. However, the findings are still particularly relevant for pediatric bone sarcoma patients and survivors, as their treatment can affect physical functioning. Therefore, promoting physical activity and exercise is important in this patient group, as it not only may improve their physical functioning and quality of life, but also reduce fatigue [51, 52].

This study has several strengths and limitations. First, this study assessed several dimensions of fatigue in a large nationwide cohort of pediatric and adult survivors of pediatric bone sarcoma during follow-up after treatment. It provides relevant insights in the prevalence of fatigue and associated factors in this patient group. These findings may guide patients and healthcare providers and contribute to optimizing clinical care for this group. However, this study also has several limitations. First, due to the cross-sectional design, no conclusions can be drawn about the direction of the associations found. Also, children were underrepresented in the study (n = 44; 32%), compared with adults (n = 95; 68%). Therefore, findings should be interpreted with caution in relation to pediatric patients. Second, sleep was not assessed in this study. Although some patients wore an ActiGraph during the day, no sleep parameters were collected. Considering the potential relationship between sleep and fatigue, this could provide additional insights [53]. Additionally, only 55% of patients wore the ActiGraph. Therefore, it is unclear whether physical activity levels in this subgroup are representative of the entire patient group, although in terms of medical characteristics, the patients who wore the ActiGraph did not differ from those who did not. Third, information about school and/or work status and broader social context of the patients was not available, while these factors may also be associated with fatigue [7, 14]. Fourth, we did not have information on whether patients had already received interventions for fatigue. It is possible that some patients received support to manage their fatigue, which could maybe explain the lower levels of fatigue observed in our adult group. Fifth, only patients with sufficient Dutch language proficiency were able to complete the PROMs in the KLIK PROM portal, which may have introduced some selection bias. Sixth, PedsQL™MFS and PROMIS® were assessed at different time points (PedsQL™MFS before and PROMIS® after the outpatient visit), which may have influenced the reported fatigue levels, potentially leading to slightly higher or lower scores on the PROMIS®. Finally, it should be noted that the Princess Máxima Center offers extensive psychosocial care and physical rehabilitation, which may differ from care available in other settings. In addition, the Netherlands represents a relatively well-resourced healthcare system with broad access to care. As a result, our findings may not be entirely generalizable to pediatric bone sarcoma patients in other or less-resourced healthcare settings.

Children reported more fatigue than Dutch normative values, which suggests that younger patients after pediatric bone sarcoma are more vulnerable to fatigue during survivorship. Psychological difficulties and pain were associated with more fatigue, while higher levels of physical activity were associated with less fatigue. These findings suggest that psychological well-being, pain management, and physical activity might be targets for reducing fatigue in pediatric bone sarcoma patients and survivors. Conversely, targeting fatigue might improve psychological well-being and physical activity and reduce pain. Therefore, monitoring and screening for fatigue and related factors during treatment and follow-up care may help to identify patients who could benefit from supportive interventions, such as cognitive behavioral therapy, psycho-education, or exercise programs [53,54,55]. Routine monitoring of fatigue using electronic patient-reported outcome systems, such as the KLIK PROM portal, may facilitate timely identification of patients at risk. Multidisciplinary care, including psychological support, pain management and guidance on physical activity, is likely to be beneficial for this population.