The NCCN Cancer-Related Fatigue (CRF) Scientific Research Committee was convened in September 2009 to accomplish 3 objectives: 1) review the current methods to measure and interventions to treat CRF; 2) recommend a CRF measure or develop a new measure for a future research project; and 3) discuss how to proceed with a CRF research project to parallel the NCCN Oncology Outcomes Database. This report summarizes the committee's work and will guide the planned CRF research project.
Definition of CRF
One reason for the slow progress in developing effective interventions to reduce CRF is the lack of consensus on a conceptual definition and its measurement in clinical research. Compared with other cancer-related symptoms, such as pain and nausea, for which conceptual definitions are more inherent and measurement strategies more established, agreeing on the definition and measurement of CRF has been a major limitation to progress in developing effective treatments.1 Currently, each study must define CRF and indicate which conceptual model underlies the assessment of CRF for that study.
NCCN currently defines CRF 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.”2 The unique characteristics of fatigue in this population have led some to propose diagnostic criteria for the “syndrome of cancer-fatigue.”3,4 According to the International Classification of Disease, 10th edition, the diagnosis of CRF is based on 4 criteria, including indicators of symptom presence for 2 or more weeks, significant distress or impairment, consequence of cancer or its treatment, and absence of comorbid psychiatric disorders.3 However, the committee developed the consensus to view CRF as a subjective changing experience not a diagnosis.
Factors Contributing to CRF
Fatigue is commonly experienced by individuals who have been diagnosed with cancer, and the management of fatigue in this population is complex because many factors may contribute to the symptom. The committee developed Figure 1 to provide a framework for considering treatable contributing factors. The treatment and resolution of these factors may reduce, or even resolve, the symptom of fatigue.
Most studies of CRF have used self-report questionnaires that focus on one or more dimensions of fatigue. However, studies suggest that fatigue does not exist in isolation but rather in a cluster of symptoms, including difficulty sleeping, depression, and pain. A 36-item self-report biopsychosocial screening form was used to query patients about their concerns regarding problems such as fatigue, pain, nausea/vomiting, transportation, finances, and concerns about end of life.5 Among more than 2000 patients with various cancers who completed this form at their initial consultation at a comprehensive cancer center, fatigue was the most common problem reported (42%). Other common problems were difficulty sleeping (33%), pain (29%), and feeling “down, depressed, or blue” (27%). Pearson correlation confirmed the correlation among fatigue, difficulty sleeping, and depression (P < .05; Karen L. Clark, MS, unpublished data).
Treatable contributing factors to cancer-related fatigue.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0101
Treatable contributing factors to cancer-related fatigue.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0101
Treatable contributing factors to cancer-related fatigue.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0101
Among 215 patients with breast cancer undergoing chemotherapy or radiation therapy, So et al.6 found that 88% reported fatigue, 77% pain, 36% depression, and 21% anxiety (all P < .01), with significant correlations among these supporting the existence of a symptom cluster. Gaston-Johansson et al.7 examined fatigue, pain, and depression among 127 patients with breast cancer after the completion of adjuvant chemotherapy and before transplantation. Fatigue was the most commonly reported symptom (91%) followed by depression (54%) and pain (47%). Fatigue, depression, and pain were all significantly correlated, supporting the existence of a symptom cluster.7
Measures of CRF
More than 25 self-assessment tools have been developed to measure fatigue, with reviews suggesting that many are valid and reliable.8–13 Some measures assess CRF using a unidimensional approach, whereas others use a multidimensional perspective. The committee reviewed the literature and considered psychometric properties when selecting measures. Several measures were closely examined (Table 1) to determine which were the most valid, reliable, and feasible to use in the clinical setting or as a screening tool for study eligibility. The measures most frequently include fatigue severity, but several include items that address the cognitive, affective, or functional impact of fatigue. The committee agreed that CRF can be measured effectively in clinical trials as the sensation of fatigue or tiredness, through its impact on usual functioning, or using both criteria.1 The committee concurred that recall bias increases as the reference period increases.1 CRF assessment may be as simple as a single question about fatigue severity rated on a 0 to 10 numeric scale or 100-mm visual analog scale, which minimizes response burden, to as complex as multiple-item measures about severity and its impact on usual functioning, which increase assessment time.1 One study showed that 3- and 7-day recall correlate highly with daily diaries.14 The selection of a CRF measure should be tailored to the setting and goals of the research, based on whether the intervention is designed to reduce the symptom of CRF, diminish its impact on usual functioning, or prevent the onset or worsening of CRF.1
Fatigue Scales, Dharacteristics, and Properties
Fatigue in the Older Population
Understanding fatigue may be particularly relevant to the aging population. An estimated 60% of all cancers occur in adults aged 65 years or older,15 with cancer incidence and mortality highest in this age group.15 Elderly patients may also have concurrent health issues that complicate the identification of problems as being the result of a newly diagnosed cancer and its treatment or of the patient's normal aging process and comorbidities.15 The mean number of comorbidities increases with age, with 2.9 in patients aged 55 to 64 years, 3.6 in those aged 65 to 74 years, and 4.2 in those aged 75 years and older.15
One of the 5 characteristics of a “phenotype of frailty” is self-reported exhaustion. Additional criteria for frailty include objective measures of physical decline, such as unintentional weight loss, weakness (decreased handgrip), slow walking speed, and low physical activity.16 Together, these criteria predict the risk for falls, hospitalizations, increased need for assistance with daily activities, and death. Although frailty is not synonymous with fatigue, these seem to be related. Based on this example, the committee agreed that future assessments of CRF should also require an assessment of the impact of fatigue on the patient's physical activity.
Interventions for Fatigue
Several nonpharmacologic and pharmacologic interventions have been studied in the treatment of CRF; however, this section focuses on those interventions recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Related Fatigue (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).2
Nonpharmacologic Interventions
Activity Enhancement: All patients with cancer should be encouraged to engage in moderate levels of physical activity during and after treatment. Several studies have evaluated the feasibility of interventions to increase physical activity during these periods. Kangas et al.17 reviewed 17 randomized controlled trials that reported on the effectiveness of physical activity interventions with a fatigue-related outcome measure. None of the studies had inclusion criteria limiting participation to those who reported a specified level of fatigue at baseline. Among the interventions, 6 (35%) had positive results (reduced fatigue), 7 (41%) had negative results, and 4 (24%) had equivalent results. Patients undergoing therapy derived greater benefit than those with completed therapy, and interventions had a stronger effect among patients with breast cancer than in those with other malignancies.
A Cochrane review of 28 randomized clinical trials examined the effect of physical activity interventions using a fatigue outcome measure.18 The meta-analysis found that exercise intervention was significantly more effective than the control intervention for patients on active therapy and those who had completed therapy. Additional research is needed to define the optimal exercise intervention.
Psychosocial Interventions: Psychosocial interventions have been shown to reduce fatigue severity. In a review of 27 randomized trials that evaluated their effectiveness among patients undergoing therapy, 7 studies reported that the intervention had a significant effect on fatigue and 20 found that it was ineffective.19 Interventions not specific for fatigue were significantly less effective (3/22 [14%]) than those that were (4/5 [80%]; P < .01). A meta-analysis by Jacobsen et al.20 of 24 randomized clinical trials testing psychosocial interventions for reducing CRF indicated that the effect for group-based interventions was significant, but not for individualized. However, none of the studies had inclusion criteria limiting participation to patients who reported a specified level of fatigue at baseline. The interventions' effect sizes were in a positive direction among patients with various cancer diagnoses, but not for those only with breast cancer.
Nutrition Consultation: Because cancer and its treatment may interfere with dietary intake, patients may experience anorexia, diarrhea, nausea, vomiting, or cachexia. Nutrition consultation may be helpful in managing the nutritional deficiencies that occur from these symptoms. A registered dietitian or nutrition counselor can provide information on maintaining a healthy diet and guidance on eating when experiencing lack of taste and during episodes of nausea and vomiting.21
The impact of dietary intervention was assessed in 111 patients with colorectal cancer undergoing radiation therapy.22 Patients were randomized to 3 groups: counseling and consuming regular food; eating additional protein supplements; and a control group eating ad libitum. All patients reported significantly increased fatigue from baseline to end of radiation therapy. At 3 months follow-up, patients who were counseled and consumed regular food reported fatigue scores similar to baseline; however, patients in the other 2 groups reported scores similar to those at the end of radiation therapy and were significantly worse than baseline. This study illustrates that dietary counseling, based on regular foods, is effective at improving nutritional intake, nutritional status, and symptoms, such as fatigue, pain, nausea, and vomiting.
Sleep Therapy: Cancer patients frequently report difficulty sleeping as a contributing factor to fatigue.5,23 Difficulty sleeping encompasses both poor sleep quality and quantity, and includes nocturnal waking, day-time napping, distress, and treatment side effects.24 In addition to education and good sleep hygiene, cognitive behavioral therapy (CBT) is one of the primary psychological treatments for insomnia. A randomized controlled trial conducted in breast cancer survivors with insomnia reported that a multicomponent intervention group that included stimulus control, sleep restriction, and sleep education and hygiene was more effective in improving sleep than sleep education and hygiene.25 Similarly, among cancer survivors with persistent insomnia, CBT produced a median reduction in wakefulness of nearly 1 hour per night compared with no change in the control group.26 These results were sustained for 6 months postintervention. Additionally, patients in the CBT group experienced reduced symptoms of depression, anxiety, and fatigue compared with the control group.
Pharmacologic Interventions
Many of the contributing causes of fatigue in this population are reversed through the use of medications or supportive care therapies, such as thyroid replacement, erythropoietin stimulating agents or red cell transfusion for anemia, effective pain management, and treatment of depression. However, fatigue uniquely associated with cancer and its treatment has not been readily impacted by pharmacologic interventions. The most extensively studied agents include methylphenidate, modafinil, corticosteroids, and hematopoietic growth factors.
Methylphenidate: Methylphenidate works by blocking dopamine reuptake transports and is a promising pharmacologic intervention for CRF. Among 11 patients with advanced cancer enrolled in a prospective, open-label, pilot study investigating the use of methylphenidate to treat CRF, Sarhill et al.27 found that 9 (82%) patients experienced response to methylphenidate, 8 within 3 days at 10 mg/d. Of these 9 patients, fatigue improved from severe to mild in 2 and from moderate to mild in 7.
Randomized clinical trials of methylphenidate for CRF have been conducted in the palliative care setting and in patients undergoing chemotherapy.28,29 A meta-analysis of these 2 trials confirmed a significant reduction in fatigue after an average of 5 weeks of methylphenidate at a dose of 10 to 20 mg/d.30 In a recent phase III, double-blind, placebo-controlled trial that randomized 148 patients to receive methylphenidate or placebo for 4 weeks, Moraska et al.31 did not note a difference in the improvement of CRF or quality of life variables. However, subgroup analyses indicated that patients with advanced disease (stage III or IV) and more severe CRF reported improvement in fatigue.31
Modafinil: Modafinil is FDA-approved to improve wakefulness in patients with narcolepsy, sleep apnea, and excessive sleepiness associated with shift work sleep disorders.32 It is a psychostimulant that may work by blocking dopamine reuptake, although the exact mechanism is unknown. Modafinil has recently been studied as a treatment option for CRF. In an open-label trial among 51 women previously treated for breast cancer who reported persistent fatigue, Morrow et al.33 reported that mean fatigue severity levels before and after the course of modafinil were 6.9 and 3.7, respectively (P < .01). Among these patients, 44 (86%) patients reported an improvement of 1 point or more.
Morrow et al.34 reported the results of a phase III randomized, placebo-controlled, double-blind trial in 642 patients who reported greater than 1 on a 10-point fatigue scale. Treatment was initiated on day 5 of cycle 2 and continued through day 7 of cycle 4. Patients on modafinil with severe fatigue (> 6) at cycle 2 had significantly more improvement than those on placebo (P = 0.017), whereas those with mild or moderate fatigue did not. Spathis et al.35 conducted a pilot study of modafinil in 20 patients with non–small cell lung cancer who reported a score of 4 or greater on the Chalder Fatigue Questionnaire. Among the 11 (73%) patients who responded, the median within-patient change on the Functional Assessment of Cancer Therapy–Fatigue (FACT-F) was significant between days 0 and 7 (8.0) and days 0 and 14 (10.0), but not between days 7 and 14 (3.5). In a 4-week pilot study of modafinil in 27 cancer patients, Blackhall et al.36 found that 15 patients (75%) who completed assessments before and after 4 weeks of modafinil had a significantly improved Brief Fatigue Inventory (BFI) score (P = .025).
Corticosteroids: Corticosteroids have stimulant-like effects that help relieve fatigue. Two randomized, placebo-controlled, double-blind studies have been conducted, although one measured subjective strength37 rather than fatigue. One of these studies37 enrolled 116 patients with gastrointestinal cancer. After 2 weeks of treatment, 26% of patients receiving dexamethasone reported improved strength compared with 15% of patients receiving placebo; after 4 weeks, 34% receiving dexamethasone reported improved strength compared with 13% receiving placebo. The second trial38 enrolled 403 patients with cancer. Compared with patients receiving placebo, those treated with methylprednisolone reported a significantly greater improvement in pain, appetite, vomiting, and well-being after 8 weeks of treatment, although they reported no significant difference in fatigue. These studies found short-term corticosteroid use to be beneficial in reducing fatigue; however, longer duration has unknown benefit and can potentially increase fatigue because of the side effect of muscle wasting.
Hematopoietic Growth Factors: Although not recommended in the NCCN Guidelines for Cancer-Related Fatigue (to view the most recent version of these guidelines, visit www.NCCN.org), erythropoietin stimulating agents have been used. Most of the randomized clinical trials used an open-label design. Most, but not all, trials enrolled patients who were actively on chemotherapy with hemoglobin levels less than 12 g/dL. A review by Minton et al.30 suggested that both erythropoietin and darbepoetin improved fatigue. Since that analysis, additional safety data with the use of ESAs have indicated that these agents are associated with an increased risk of thrombovascular complications and worse disease outcomes when used to maintain hemoglobin levels at 12 g/dL or higher.39
Conclusions
Fatigue in the oncology population is frequently complicated by the coexistence of physical symptoms, anxiety/depression, and difficulty sleeping.5 The committee concurred that the relationship between fatigue, difficulty sleeping, pain, distress, and physical activity should be systematically studied. A better understanding of the incidence and interrelationship of these problems will provide insight into the mechanism of CRF.
Although the committee reviewed the scientific literature for tools that measure the prevalence and interrelationship of fatigue, difficulty sleeping, pain, distress, and physical activity, most of the existing literature examined a solitary symptom and its effect on patients' quality of life and functional status.6 Despite this, the committee concurred that patients rarely experience a symptom in isolation but rather in clusters. Therefore, the committee decided to develop a new measure to collect the most common symptoms of cancer and its treatment, such as fatigue, pain, distress, and symptom interference. The committee developed a brief self-assessment measure that includes a 7-day recall of these symptoms and items assessing the impact of these symptoms on general activity and enjoyment of life (Figure 2). The NCCN Fatigue and Contributing Factors Inventory combines items derived from established measures. These measures were previously validated and are widely used in the oncology setting. The fatigue items were derived from the BFI40; the difficulty sleeping items were derived from the Pittsburgh Sleep Quality Index41; the pain items were derived from the NCCN Clinical Practice Guidelines in Oncology for Adult Cancer Pain42; the distress items were derived from the NCCN Clinical Practice Guidelines in Oncology for Distress Management43 (to view the most recent version of all NCCN Guidelines, visit the NCCN Web site at www.NCCN.org); and the physical activity items were derived from the California Teachers Study.44 Concurrent medication information, including drug name, reason for use, and date/time of the last dose, will be collected for the preceding week.
The NCCN Fatigue and Contributing Factors Inventory self-assessment tool developed by the committee will be validated in a homogenous oncology setting. The committee identified the NCCN Breast Cancer Outcomes Database as an ideal population in which to assess fatigue. The patient population will consist of patients with breast cancer who are post–definitive surgery at 4 distinct periods: baseline (before any drug or radiation therapy), 6 months, 12 months, and 24 months. The proposed assessment periods will allow for the same population to be studied throughout the continuum of care (i.e., before systemic therapy, during systemic therapy, and during survivorship). The serial assessment of fatigue, difficulty sleeping, pain, symptom distress, and function in this homogenous population of individuals with cancer is likely to enhance understanding of the complexity of CRF.
NCCN Fatigue and Contributing Factors Inventory. Data from refs. 40–44.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0101
NCCN Fatigue and Contributing Factors Inventory. Data from refs. 40–44.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0101
NCCN Fatigue and Contributing Factors Inventory. Data from refs. 40–44.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0101
NCCN Fatigue and Contributing Factors Inventory. Data from refs. 40–44.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0101
NCCN Fatigue and Contributing Factors Inventory. Data from refs. 40–44.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 12; 10.6004/jnccn.2010.0101
Discussion
Fatigue is commonly associated with the diagnosis of cancer and its treatment. Most studies report prevalence rates exceeding 60%.45 Although it has been stated that CRF is unrecognized or overlooked by health care professionals in lieu of more acute symptoms such as pain, nausea, and vomiting,46 the committee believes that clinicians are aware that fatigue is a significant, debilitating problem for patients diagnosed with and treated for cancer.
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