Thanks to advances in treatment, long-term survival of childhood, adolescent, and young adult (CAYA) cancers has improved remarkably over the past decades [
]. As a result, the population of CAYA cancer survivors is increasing [
]. However, most survivors experience late effects from cancer and its treatment, such as cardiovascular disease, renal dysfunction, endocrinopathies, impaired cognitive function, poor mental health, and musculoskeletal problems [
Cancer-related fatigue is a well-known problem during the active treatment phase of cancer but can also be a frequent problem for survivors many years after completion of therapy [
]. The National Comprehensive Cancer Network of the USA defined cancer-related fatigue as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” [
]. In survivors of adult cancers, about 30% experience cancer-related fatigue even years after completion of treatment [
]. For CAYA cancer survivors, the literature on the prevalence of cancer-related fatigue (hereafter referred to as fatigue) is contradictory. A number of studies have reported a high prevalence of fatigue in CAYA cancer survivors [
], but other studies have observed prevalence rates or fatigue levels comparable to controls [
]. Fatigue has a negative impact on many aspects of CAYA cancer survivors’ lives, such as personal relationships, school or work, and activities of daily life, and is associated with lower self-reported quality of life [
Clinical practice guidelines (CPG) could help improve consistency of care, evidence-based healthcare delivery, and thus health outcomes and quality of life in survivors [
]. This is especially important as, to date, long-term follow-up (LTFU) for CAYA cancer survivors is not always well organized and few pediatric oncology institutions offer LTFU to adult survivors of CAYA cancers [
]. As many CAYA cancer survivors are followed by healthcare providers outside the pediatric oncology setting [
], CPGs can help to inform healthcare providers, as well as survivors, about cancer- and treatment-related risks such as fatigue.
In survivors of adult cancers, regular screening for fatigue is recommended [
]. For CAYA cancer survivors, different groups in North America and Europe have developed LTFU CPGs to promote early detection of potential late effects [
]. However, these guidelines were developed independently and differ regarding their recommendations. This can cause uncertainty about which CPG to use in clinical practice and could impede the implementation of a CPG for LTFU of CAYA cancer survivors. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) was founded to harmonize CPGs for CAYA cancer survivors [
]. As the psychological late effects group of the IGHG, we aimed to harmonize the recommendations for fatigue surveillance in CAYA cancer survivors diagnosed before the age of 30.
We summarize the harmonized recommendations for fatigue surveillance in CAYA cancer survivors diagnosed before the age of 30 years. The recommendations were developed using scientifically rigorous methods, are based on evidence from published literature, and are supplemented by expert opinion for topics with little or no evidence. The recommendations are intended to standardize and improve the quality of LTFU care for CAYA cancer survivors and to positively influence fatigue outcomes in survivors. The panel also aimed to raise awareness about CAYA cancer survivors’ risk of fatigue among healthcare providers and CAYA cancer survivors and empower survivors to make informed health choices.
We found that the prevalence of fatigue in survivors of CAYA cancers varied widely from 10 to 85%. Several factors explain this variability. First, we included 28 studies from 14 different countries on three continents (America, Europe, and Asia) with different cultural backgrounds. Then, twelve of the 28 included studies used a tool for assessment of fatigue that was neither standardized nor validated. The other 16 studies used seven different measures to determine the prevalence of fatigue. Additionally, the populations of the included studies varied considerably regarding sample size, follow-up time, included primary diagnoses, and age at diagnosis. The use of so many different assessments for fatigue and heterogeneity in study populations likely contributed to the large differences in the prevalence of fatigue in CAYA cancer survivors.
Despite a sizable number of studies that reported risk factors for fatigue in CAYA cancer survivors, the level of evidence for the recommendations is mainly moderate to low. We found no studies that investigated the latency time to develop fatigue and only two studies that investigated the clinical course of fatigue in CAYA cancer survivors. Future studies should focus on high-quality research to investigate the risk of and risk factors for fatigue in CAYA cancer survivors using scientifically validated fatigue measures (preferably PROMIS Pediatric Fatigue Measure or PedsQL MFS) in CAYA cancer survivors and especially in older adult survivors of CAYA cancers. In addition, longitudinal assessment of fatigue in CAYA cancer patients and survivors is needed to identify the change of fatigue patterns over time (Table
Gaps in knowledge and future directions for research
• High-quality research on risk of fatigue and risk factors for fatigue in CAYA cancer survivors using scientifically validated fatigue measurements (PROMIS Pediatric Fatigue, PedsQL Multidimensional Fatigue Scale)
• Longitudinal studies characterizing the course of fatigue in CAYA cancer patients and survivors and indicators for change
• Investigations of the impact of aging and elapsed time from diagnosis on risk for fatigue
• Investigations evaluating the risk for fatigue after CNS/brain irradiation
• Evaluation of the reliability and validity of a 1-item screening tool for fatigue in CAYA cancer survivors (mixed diagnoses) and parents of very young survivors
• Psychometric validation of fatigue measures in adult CAYA cancer survivors
• Determination of clinically significant thresholds for fatigue measures
• High-quality randomized controlled trials with larger samples to assess the effectiveness of fatigue interventions in CAYA cancer survivors.
• Identify the most effective interventions for different age groups (pediatric survivors, adolescent survivors, young adult survivors, adult survivors of CAYA cancers)
• Test safety and effectiveness of pharmacological interventions to reduce fatigue in CAYA cancer survivors
Thirteen different measures to assess fatigue were used in the included studies, and twelve studies used a non-standardized measure. The use of 25 different measures makes a comparison of study results difficult. To increase comparability across studies, as well as to measure the quality of care across countries, we highly recommend that researchers and clinicians use the recommended fatigue measures unless they need a more specific measure to answer their research questions. This recommendation is in line with other research that has proposed that the PROMIS fatigue measures (child and adult versions) should be adopted as standard measures of fatigue impact and severity [
It would be useful to have a psychometrically sound but very brief fatigue assessment to assess fatigue as a secondary outcome and increase the standardization of fatigue surveillance in survivors (Fig.
). This would reduce the burden associated with fatigue surveillance and potentially improve clinician adherence to fatigue surveillance recommendations. In this regard, the psychometric properties of the Fatigue Thermometer (a 1-item screening tool) [
] should be tested in diagnostic groups other than brain tumor survivors (Table
). Other barriers for surveillance of fatigue include not all institutions have a LTFU program or not all survivors have access to a LTFU program, time constraints during the follow-up appointments, providers’ lack of awareness that many CAYA cancer survivors suffer from fatigue, absence of highly effective treatments for fatigue, and previous contradictory evidence about the prevalence of fatigue in CAYA cancer survivors. Additionally, defining clinically meaningful thresholds for fatigue measures would be useful for clinical practice. Health problems such as fatigue, with unspecific and subjective symptoms, are difficult to measure objectively; validated clinically, significant thresholds are important to support health insurance coverage for interventions that remediate fatigue (Table
When no underlying medical condition is identified, the panel recommends referring survivors who endorse fatigue to a specialist in fatigue (Fig.
). However, not many countries have specialists for fatigue. Healthcare professionals might need to refer survivors to more generic specialists, such as psychologists or physiotherapists. If fatigue specialists are not available, healthcare professionals should counsel survivors about fatigue and interventions available to manage fatigue symptoms. Referral to a more generic specialist should be considered if the interventions are not successful in remediating fatigue, survivors find it difficult to adhere to the interventions, or need more support and guidance. Physical activity and adventure-based interventions should be appropriate for the survivor’s age and physical abilities. Survivors with a higher risk of injury due to chronic health problems or deconditioning should be referred to a physiotherapist for supervised training to assure physical activity are safely implemented. Depending on the maturity and cognitive abilities, relaxation and mindfulness interventions can be useful. Cognitive-behavioral interventions need more resources than the more generic interventions but should be considered for severely fatigued survivors or if other interventions are not successful. Pharmacological approaches (erythropoietin, methylphenidate) should not be routinely used to manage fatigue in CAYA cancer patients and survivors [
] and use of supplements such as
, ginseng products, or CoQ10 is not recommended in survivors of adult cancers because of limited effectiveness and evidence [
]. Supplements should therefore not be routinely used in CAYA cancer survivors.
To date, only a few studies have assessed the effectiveness of interventions for fatigue in CAYA cancer patients or survivors in a reasonably large sample [
]. A reason for this might be the lack of information about the mechanisms of fatigue and that, currently, there exists no gold standard intervention for the treatment of fatigue [
]. Other reasons might be that AYA cancer survivors can be difficult to reach due to transitions in care and changes of contact information and usually, studies including AYA cancer survivors have lower response rates than other groups [
]. Furthermore, barriers for screening for CRF might also contribute to the lack of intervention studies. More high-quality randomized controlled trials (RCT) are needed to study the effectiveness of the physical activity, adventure-based, educational, psychosocial, relaxation and mindfulness, cognitive behavioral therapy, and pharmacological interventions in survivors of CAYA cancers (Table
). These studies’ focus should lie on identifying the most effective interventions for different age groups (pediatric survivors, adolescent survivors, young adult survivors, and adult survivors of CAYA cancers). Evidence from intervention studies in survivors of adult cancers is expected to be transferable to young adult cancer survivors and can be used to guide the design of intervention studies for pediatric and adolescent cancer survivors. Validated fatigue measures, such as the PROMIS Pediatric Fatigue Measure or the PedsQL MFS, should be used to assess CRF in RCTs to reduce bias and increase the comparability of results.
To facilitate dissemination and implementation of this CPG, the evidence and recommendations will be presented directly to clinicians through professional societies and conferences.
Strengths of this CPG are the multidisciplinary and international working group involved in the harmonization process, the evidence-based approach, and the transparency in formulating and grading the recommendations. The international collaboration means a reduction of duplication of effort to develop CPGs and brings together knowledge from different research fields and medical disciplines. A limitation of the recommendations is the gap in the literature regarding the risk of fatigue in survivors over time, and interventions to reduce fatigue in CAYA cancer survivors, as well as the great variability of measures used in the included studies. Research to address these gaps in knowledge should be approached in a systematic, comprehensive manner by sufficiently large single-institution studies, or national and international multi-center collaborative projects.
This surveillance guideline, and the international harmonization initiative that underpins it, aims to improve health outcomes by facilitating more consistent LTFU care for CAYA cancer survivors by improving surveillance, detection, and treatment of fatigue in survivors, as well as promoting strategically planned ongoing research that will inform future guideline updates.
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