Cancer-related fatigue (CRF) is the most common persistent and distressing symptom reported by cancer survivors in the months and years after the successful treatment of cancer. Fatigue presents as a sensation ranging from tiredness to exhaustion that affects the survivor's physical, emotional, and/or cognitive functioning. The majority of reports estimate that approximately one-third of survivors experience fatigue. The growing number of survivors makes this an important area of scientific development. Fatigue is often unrecognized and undertreated by health care professionals, in part because of a lack of knowledge of mechanism-targeted interventions.
State of the Art: Europe
In Europe, cancer patients are warned and indeed expected to become fatigued during treatment. However, the majority of patients do not expect long-term fatigue after treatment and are not routinely warned of the possibility of such problems occurring. Although CRF may occur only in approximately one-third of survivors, the figures may vary with individual studies.[2, 3] The absolute number of cancer survivors is increasing all the time. The majority of studies regarding CRF have been conducted in women with breast cancer, with a small number taking place in patients with lymphoma. To the best of our knowledge, outside of these 2 diagnostic groups, there have been comparatively fewer studies conducted.
The European Association for Palliative Care (EAPC) has produced a working definition of CRF, describing it as “a subjective feeling of tiredness, weakness or lack of energy.” A lack of consensus concerning the definition among researchers has led to the development of a myriad of tools to assess CRF, and has meant there is no universally agreed upon definition. In Europe, data from patients experiencing fatigue during treatment have come from the 3 fatigue subscale items regarding tiredness, weakness, and lack of energy from the 30 items on the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life (QOL) (EORTC QLQ 30) questionnaire. In addition, in survivors of a working age, an important area to assess is the impact of fatigue on vocational functioning.
There are no European guidelines for monitoring CRF in survivors of cancer. Because many countries in Europe have their own language(s), it is difficult for researchers to achieve pan-European consensus regarding definitions and questionnaires. This is complicated further by health policies that are different for each country. However, CRF is recognized as a long-term sequel of treatment in survivorship strategies identified by the United Kingdom National Health Service and by the EORTC.
A barrier to developing a coherent strategy for the treatment of CRF in patients with cancer is the lack of understanding of the multiple factors causing CRF in this group. There is evidence to suggest that CRF is associated with increased levels of inflammatory cytokines and that individuals are more susceptible to CRF because of genetic polymorphisms. However, these studies have been conducted mainly in women with breast cancer and the results will need to be replicated in other tumor groups. Cytokine levels must be measured longitudinally and examined for associations with the subjective measurement of CRF. Cytokine changes may be secondary to disturbances in the hypothalamic-adrenal-pituitary axis (HPA). Results provide preliminary evidence of alterations in HPA axis regulation of cortisol among survivors of breast cancer. However, HPA axis dysregulation has been observed less consistently than have alterations in the immunologic milieu. There also may be changes in muscle metabolism and structure underpinning CRF. Any such changes are likely to be more pronounced in patients with advanced cancer, but a similar process driven by autoimmune or generalized proinflammatory processes may be underway in survivors. One caveat is that muscle wasting is also a part of the natural aging process.
There may be an overlap between CRF and the chronic fatigue syndrome and research conducted in this group of patients may provide insight and direction for future studies.[14, 15] In both groups, the fatigue is chronic in duration (ie, with a duration of > 1 month and temporarily separate from the initial “insult.” In the case of chronic fatigue syndrome, there is a set of diagnostic criteria that have been widely recognized and adopted by the clinical and research community. A similar set of diagnostic criteria for CRF syndrome has been developed in the United States by Cella et al. These criteria have not been widely adopted in Europe. It may be possible to screen for this syndrome using questionnaire cutoff scores.
State of the Art: United States
In the United States, CRF has been well documented in association with cancer diagnosis and treatment. Steadily increasing trends toward the use of multimodal cancer treatments have prompted an even greater interest in CRF and other symptom research in cancer.
Over the last 35 years, oncology researchers in the United States have developed screening, assessment, treatment, and evaluation methods for CRF in patients with cancer. As cancer has evolved into a chronic disease, the focus has been extended to improving functional status and QOL for survivors. There are many challenges to providing state-of-the-art supportive care for CRF to survivors of cancer in the United States.
Although to the best of our knowledge there is no a good consensus regarding the definition of CRF, the most widely used is the National Comprehensive Cancer Network (NCCN)'s definition that CRF is “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.” Functioning has been defined by the World Health Organization to refer to all body functions, activities, and participation in various roles. There has been a call to link the definition to the measurement of CRF and to reconcile differences across self-reported measures.[7, 22] Most instruments used by researchers rely on perception alone; a few add items that reflect the consequences of fatigue for physical, role, social, and vocational functioning to the perceptions or, less commonly, use a case definition (International Classification of Diseases, 10th revision) approach. To facilitate larger and more diverse studies, there is a need to achieve consensus on domains of measurement and to harmonize measures. The Patient-Reported Outcomes Measurement Information System (PROMIS) Network funded by the National Institutes of Health has developed a set of standardized self-report measures of symptoms for CRF and other health domains, including physical functioning, to meet this need.
Although a majority of survivors speak English as their primary language, communication can be a significant barrier and limit access to care for approximately 20% of the population who speak a language other than English at home. In addition, according to the National Assessment of Adult Literacy, only 12% of those living in the United States have proficient health literacy and 14% of the US population has below basic health literacy. Low literacy in the United States is different from that in Europe because it impacts employment and the ability to obtain health insurance coverage. Communication barriers amplify the challenges of screening and managing CRF in survivors. To optimize the screening and management of CRF in the United States, measures are needed that are sensitive to low health literacy and translated with demonstrated measurement invariance across language and culture.
Another challenge to providing quality supportive care services for CRF to cancer survivors in the United States is the health care reimbursement system. Private medical insurance is usually obtained through employment and the management of CRF may only be partially reimbursed. The American Society of Clinical Oncology developed a policy statement to integrate the elimination of cancer health disparities into the society's mission and activities. This effort falls short of ensuring that CRF will be screened and managed in patients with cancer. If patients undergoing multimodal cancer treatment are unable to function at the level needed to maintain employment and/or lack medical insurance, they may experience barriers in accessing supportive care or rehabilitation services that require self-payment.
National and private organizations in the United States have developed symptom management guidelines for oncology clinicians to use to educate and manage cancer patients and their families.[20, 27] These evidenced-based practice guidelines are updated regularly to reflect current information on methods with which to screen, assess, and select interventions for CRF. The majority of study participants have been receiving active treatment for cancer[20, 27] and evidence is lacking regarding the effectiveness of many CRF interventions in survivors of many types of cancer. Translational research is needed to test research techniques designed to improve the capacity of clinicians to screen, assess, and deliver effective interventions to lower CRF and improve function in survivors.
Intervention Studies: Europe
There have been 3 complementary Cochrane systematic reviews conducted by European research groups focusing on the treatment of CRF at all stages of cancer. These reviews have examined the role of pharmacologic agents, exercise, and psychological interventions in modifying CRF, but rarely included functional outcomes. Although not limited to European trials, these reviews only examined randomized controlled trials; the vast majority of the trials were conducted during treatment. Specific implications of the findings for cancer survivors will now be discussed.
Psychostimulant drugs such as methylphenidate have been shown to be effective in patients undergoing chemotherapy, but concerns exist about their side effect profile and possible addiction in survivors. Overall, there is insufficient evidence to recommend their adoption in routine use in European practice in cancer survivors. They are used very infrequently in clinical practice.
Exercise studies have involved a mixture of resistance and cardiovascular training. The trials differed extensively in terms of frequency, intensity, and duration of the interventions. The majority of studies were conducted in women with breast cancer. A meta-analysis of all fatigue data was conducted, the findings of which were that exercise was statistically more effective on a range of fatigue questionnaire scores than the control intervention at the end of the intervention period. This conclusion suggests that the mode of exercise is important, but there remain problems with the quality of studies and the outcome measures used.
A recent meta-analysis examining the role of exercise in cancer survivors was published in the British Medical Journal. The results demonstrated an improvement in fatigue and physical functions; the reduction in fatigue was significant but small. Overall, the effect size of exercise was small and was less than that of the meta-analysis effect size noted in the psychostimulant drug studies. This is perhaps one of the reasons limiting the universal recommendation of exercise for CRF in cancer survivors.
Although an intervention that can be delivered and promoted by classes and subsidized gym memberships might appear to be the most appropriate for the survivor, it is unclear what the optimum dose, type, or frequency of exercise needs to be. This may explain why there is an overall suggestion for the use of exercise in national strategies, but these suggestions lack the details required for adoption into European practice.
Psychosocial interventions include psychological, educational, and support group studies. There is a wide variation in study size, design, and quality. These studies were a heterogeneous category that included cognitive behavioral therapy, supportive therapies, and psychoeducation. Only 5 intervention studies included in the review specifically examined the effect on CRF. In general, during these interventions patients were educated about fatigue and taught self-care or coping techniques, energy conservation, and activity management. This may be an effective treatment approach but is clearly resource-intensive and needs to be directed at those individuals who are most fatigued. Interventions aimed at severely fatigued survivors can realize large effects.
The vast majority of psychoeducational interventions aimed at improving psychological distress, mood, and other symptoms such as sleep disturbances failed to improve CRF as a secondary outcome. This suggests that any psychologically based intervention to treat CRF in survivors must focus on fatigue and not treat it as a secondary outcome. These interventions have time and resource implications in terms of training and standardization of delivery of the intervention. The lack of specifically identifiable components has meant that this is not offered routinely in European practices.
The overall aim of these reviews was to provide implications for future research and practice. These conclusions (limited by the absolute numbers and quality of studies) have not been widely adopted by European clinicians. In practice, this means these interventions are being undertaken in an inconsistent, non–evidence-based manner or they are not being attempted at all.
Intervention Studies: United States
Although there have been more than 170 empiric studies of pharmacologic and nonpharmacologic interventions to reduce or manage CRF, and several meta-analyses or systematic reviews,[27-30, 34-36] many of the interventions in fatigue have not been tested in cancer survivors who have concluded active treatment. To the best of our knowledge, few of the studies have included functioning as a primary or secondary outcome. Similarly, although guidelines for the management of cancer-related fatigue have been disseminated by the NCCN and the Oncology Nursing Society, they are not tailored to the posttreatment phase.
Randomized trails support the benefits of several different exercise modalities in the management of fatigue after cancer treatment in patients with breast cancer or solid tumors, or those undergoing hematopoietic stem cell transplantation, although effect sizes are generally small. Exercise may also produce favorable effects on sleep, mood, muscle strength, cardiorespiratory fitness, body composition, and the neuroendocrine milieu. These effects also may contribute to the observed improvement in fatigue outcomes noted in survivors. Studies are needed to define the type, intensity, and duration of physical exercise that is most beneficial in reducing fatigue after treatment and will set the stage to provide the rationale for exercise prescriptions to cancer survivors. A recent systematic review concluded that structured rehabilitation results in statistically significant and sustained improvements in fatigue, particularly in patients who have completed treatment and are in the survivorship phase. Despite these promising results, rehabilitation services are not systematically offered to cancer survivors in the United States after the completion of cancer treatment due to lack of specialized programs for cancer survivors and reimbursement of fees.
There is also preliminary evidence from open-label and/or uncontrolled studies to support the efficacy of integrative medicine approaches to the treatment of fatigue, including yoga, relaxation, mindfulness-based stress reduction, acupuncture, medical Qigong, massage, healing touch, Reiki, and combined modality interventions that include aromatherapy, lavender foot soaks, and reflexology.[34, 40] However, the studies examining these interventions have tended to have small and/or heterogeneous samples, making it difficult to draw firm conclusions regarding the efficacy of these interventions in survivor populations.
Our bibliometric analysis of the literature comparing the fatigue trials published by European researchers with those conducted by investigators in the United States and Canada revealed that our current knowledge about the effectiveness of CRF interventions is supported by a generally balanced representation of studies conducted in Europe compared with the United States and Canada. However, some trends were noted. For example, a majority of the randomized trials of exercise, sleep, energy conservation, activity management, psychostimulant drugs, and antidepressants to treat CRF have been conducted by US investigators. Most of the randomized trials of structured rehabilitation interventions have been tested by European researchers. One reason may be the more prohibitive drug trial regulations in Europe than in the United States.
Psychoeducational and psychosocial support interventions, acupuncture, and levocarnitine supplementation have been tested by both US and European researchers, although predominantly in patients receiving active anticancer treatment or those at the end of life. A majority of the systematic reviews have been conducted by European researchers, whereas the 2 guidelines for the management of CRF were developed by US-based investigator teams.
In summary, a wide range of pharmacologic and nonpharmacologic interventions for fatigue have been studied, although many potentially promising interventions have been tested in only uncontrolled or pilot studies. With the exception of exercise and rehabilitation, to our knowledge relatively few studies have been conducted in samples comprised exclusively of cancer survivors who are posttreatment.
Future Directions: European Perspective
There is overlap between Europe and the United States with regard to future areas of focus related to CRF. An overall aim will be to design international and transcontinental studies. European researchers and clinicians need to reach consensus on the clinical phenotype(s) of CRF in survivors, accommodating the variability in their presenting features. We also need to link the symptom of fatigue to its impact on functioning. It is not possible to intervene for all patients and the evidence[1, 5] suggests those with the most severe fatigue are the ones most likely to respond to an intervention. This should be linked to the further intervention of biological markers.
European researchers now need to develop trials specifically for examining interventions in fatigued survivors. These may be exercise-based with a brief cognitive intervention, but also may be directed toward the modulation of the prolonged inflammatory response observed in this group. Whatever intervention is used, the inclusion of biomarkers as surrogate endpoints, together with the measurement of CRF and physical functioning as primary and secondary endpoints, will contribute to our knowledge of the etiology of CRF and the mechanism of action underlying effective interventions.
Future Directions: United States Perspective
Variations in the conceptual definitions of CRF give rise to different requirements for adequate measurement. The European and US conceptual definitions differ; the European definition includes sensation only whereas the US definition includes both sensation and functional impact. These differences result in a lack of comparability of CRF measures and limit the ability to collaborate and replicate research findings and extend the theory base. However, studies examining the experience of CRF using qualitative methods conducted in Europe, the United States, and other countries reveal fairly consistent observations cross culturally. CRF is highly prevalent, experienced as distressing and unpredictable, amplifies symptoms and mood disturbances, and is problematic for patients to self-manage. There is a need for expert consensus on the key construct that should be measured in different types of CRF research including domains of self-reported CRF, use of case definition, and other behavioral or biological constructs. Such consensus on measurement will support investigators in leveraging data resources such as cancer registries and nationally representative panels and facilitate larger, more diverse samples for observational studies. Despite a robust scientific literature of behavioral correlates for CRF, there is limited understanding of its biology. Research is needed to extend our understanding of biological mechanisms underlying CRF in survivors to include the role of proinflammatory cytokines and HPA axis dysfunction,[11, 42] as well as other theoretically plausible mechanisms such as disrupted circadian rhythms, disturbed sleep, and dysregulated monoamine pathways that control dopamine, serotonin, and norepinephrine. Ultimately, an integrated understanding of these pathways is essential to complete our understanding of CRF.
Another important trend in symptom research is the examination of profiles of gene polymorphisms, which are mutations and/or common variations associated with gene function; gene expression, the evidence of activation and de activation of genes; and protein concentration, such as cytokines, to better understand the genetic basis of CRF.[43, 44] A clearer understanding of the biology and genetics of CRF will enable the identification of new pharmacologic targets for CRF intervention.
Rigorously designed and adequately powered randomized controlled trails are urgently needed to test therapies for fatigue that have demonstrated therapeutic effects in preliminary studies in cancer survivors. Harmonized definitions of fatigue and the use of instruments with demonstrated measurement invariance across languages and cultures will permit pooling of data, including from those from non-cancer comparison groups. Additional research in large, heterogeneous samples is needed to isolate the components of an intervention, such as exercise, that account for observed improvements in fatigue outcomes. Comparative effectiveness studies are also needed to determine how transferable findings will be across languages, clinical settings, and cultures.
Given the lack of international investigator teams and consortia, we identified a current opportunity to strengthen collaboration between fatigue researchers in the United States and Europe in testing interventions for fatigued cancer survivors. Several substantive and methodological challenges will need to be addressed to set the stage for such collaborations, including international consensus on the defining features of fatigue in cancer survivors; harmonized measurement of fatigue outcomes using instruments that have demonstrated measurement equivalence across languages and cultures; and interventions, such as including exercise, rehabilitation, and psychoeducational interventions that have been manualized to permit intervention fidelity across diverse contexts. Study designs and sampling frames will need to be controlled for the possible effects of regional, cultural, and economically related differences in cancer treatment approaches and care delivery patterns and variability in selection biases for study participation and follow-up.