Abstract: We included 30 studies (18,682 participants in total). Eighteen studies contributed to the main objective and 22 studies contributed to the secondary objectives. We found substantial differences between studies in cancer diagnosis, cancer treatment, age of participants, questionnaires used to assess fatigue, and sample size. All included studies scored at least one 'Risk of bias' item as unclear or high risk. We identified both clinical and statistical heterogeneity and therefore could not pool results, so we present them descriptively. Eighteen studies (describing 14,573 survivors) reported the prevalence of severe fatigue, which ranged from 0% to 61.7%. In a subgroup of three studies including children aged up to 18 years at fatigue assessment (268 survivors), prevalence rates ranged from 6.7% to 12.5%. In comparison, in a subgroup of 12 studies including participants aged 16 and over (13,952 survivors), prevalence rates ranged from 4.4% to 61.7%. The prevalence of severe fatigue in a subgroup of survivors of haematological cancer was presented in seven studies and ranged from 1.8% to 35.9% (1907 survivors). Prevalence of severe fatigue in brain cancer survivors was presented in two studies (252 survivors) and was 14.6% and 21.1% respectively. One study presented a prevalence for bone cancer survivors of 0.0% (17 survivors). Four studies provided prevalence rates of severe fatigue in control groups of siblings or population-based controls, which ranged from 3.1% to 10.3%. In these four studies, survivors were more often fatigued than controls, but this difference was statistically significant in only two studies. Studies assessing risk and associated factors for fatigue were heterogeneous, and definitions of the factors under study were often inconsistent, with results therefore presented descriptively. They found that depression might be associated with fatigue. In contrast, age at diagnosis and education level did not seem to be associated with fatigue. We were unable to calculate any overall risk estimate for any of the reported risks and associated factors, because we could not conduct meta-analysis. One study provided information about the course of fatigue over time, and found that over the course of 2.7 years, 32 of the 102 participants (31.4%) reported persistent severe fatigue. It is unclear how many childhood cancer survivors suffer from severe fatigue. This review encountered several difficulties. We found statistical and clinical heterogeneity and great variation in the reporting of possible risk and associated factors. The evidence in this review is therefore weak, and the exact prevalence of severe fatigue after treatment for childhood cancer remains to be determined. This is also the case for the course of severe fatigue following treatment and the strength of the relationship between fatigue and associated and risk factors. Despite these limitations, our review does provide a comprehensive overview of the existing literature about severe fatigue after treatment for childhood cancer.

Plain-language summary: The evidence is up to date to March 2019. We include 30 studies, describing 18,682 participants after treatment for childhood cancer. We found a lot of variation between studies in cancer diagnosis, cancer treatment, age of participants, the questionnaires used to assess fatigue, and the size of the study. Eighteen studies reported a prevalence of severe fatigue, which ranged from 0% to 61.7%. Four studies reported a prevalence of severe fatigue in the patient's brothers and sisters or in population-based controls. Prevalence rates in these control groups ranged from 3.1% to 10.3%. In these four studies, survivors were more often fatigued than controls. This difference was only significant in two studies. When we looked at the prevalence of severe fatigue in survivors of lymphoma and leukaemia (types of blood cancers), we found that they ranged from 1.8% to 35.9%. Two studies reported on severe fatigue in brain cancer survivors, with rates of 21.13% and 14.6%. One study in bone cancer survivors reported no cases of severe fatigue. For survivors aged 18 and younger, prevalence rates ranged from 6.7% to 12.5%. By contrast, in studies including participants aged 16 years and over (but mostly over 18), prevalence rates ranged from 4.4% to 61.7%. Twenty-two studies assessed one or more possible risk factors for fatigue. Our review shows that depression might increase fatigue. The age at cancer diagnosis and the education level of the survivor did not seem to influence fatigue. Only one study provided information about the course of fatigue over time, and found that over the course of 2.7 years 32 of the 102 participants (31.4%) reported persistent severe fatigue. All included studies had problems with the quality of the evidence, and we found many differences between studies for several characteristics. The evidence to address our review question is therefore weak. The occurrence of severe fatigue after treatment for childhood cancer remains uncertain. This is also the case for the course of severe fatigue after completion of cancer treatment and the risk factors that might be responsible for developing fatigue.