Introduction

This supplement summarizes a conference on new research directions in cancer-related fatigue (CRF) held at The University of Texas M. D. Anderson Cancer Center in February of 2000. This conference, now to become an annual event, was stimulated by an increasing awareness of the burden that fatigue places on most cancer patients. The conference was also stimulated by the recognition that there is beginning to be a critical mass of information that might lead to ways to lessen this burden. We now know from research studies what patients have been trying to tell us for a long time: that CRF is qualitatively and quantitatively different from the tiredness that everyone experiences now and then. The fatigue caused by cancer and its treatment can be totally devastating to those who experience it and their loved ones. In stark contrast to everyday fatigue, CRF is rarely relieved by rest or additional sleep. It has pervasive effects on motivation and action. Thinking is more difficult. For most cancer patients, fatigue is very different from anything they have previously experienced. Therefore, patients may attribute what they are feeling to depression, to losing their minds, or to a loss of will power or a capacity to care. The profound effects of this fatigue are hard for patients to communicate to those who take care of them and to family and friends. Communication about this experience may be complicated by the lack of appreciation of those around the patient who have not experienced severe fatigue. Communication with health care professionals is also made difficult because, at least until recently, there has been little that they could offer besides sympathy. As can be seen in the articles that make up this supplement, there has been progress in conceptualizing the nature of CRF and identifying some of its sources. In general, the evolution of cancer biology and a greater understanding of the biology of disease has produced new ways of looking at cancer and its treatment that provide strong leads to understanding why patients get so tired. The “anemia story” is one area where substantial progress has been made, and now there is a greater understanding of the relationship of fatigue to disease and treatment-related anemia. The “cytokine story” is just emerging. The development of interferons as treatment for cancer compelled the observation that such agents often caused devastating fatigue that was dose limiting. Interferon-α and other agents used in treating cancer also excite or inhibit the production of other cytokines that are known to be related to fatigue. For example, interleukin (IL)-6 is a proinflammatory cytokine that has been shown to mediate endocrine and neural activity. Given experimentally to normal subjects, IL-6 induces severe fatigue and inactivity as well as poor concentration.1 There is now clear evidence that cytokines are critical to other aspects of cancer that are related to fatigue, such as cachexia. Links to cancer-related pain, depression, and cognitive impairment are strongly suggested. This work offers the basis for experimental therapies that might significantly reduce fatigue as well as other symptoms. There have also been advances in neuroscience that should be of help. Methods of cortical imaging that have helped advance the understanding of pain2 may help us understand fatigue as well. These studies may help us uncover relationships between fatigue and other symptoms, such as pain, nausea, and depression (see Gutstein, this supplement). Developments in neuropharmacology may help us identify novel psychostimulants that have better side effect profiles than those available today. We are also becoming aware of the large number of cancer patients who experience CRF. Studies that focus on the prevalence, severity, and impact of CRF are relatively recent. These studies suggest that hundreds of thousands of cancer patients will experience profound fatigue each year. Such studies have depended on the development of fatigue scales that can reliably capture what is different between CRF and fatigue experienced by people who do not have cancer. The development of methods for measuring CRF now give us the tools necessary to conduct the descriptive and epidemiologic studies that define who will have the most severe fatigue and what correlates with the development of fatigue. These tools will also be critical in evaluating new treatments for fatigue. The measurement of fatigue has taken much from the measurement of pain and depression. Fatigue shares many elements with pain that need to be taken into account when constructing assessment tools. Pain and fatigue are multifactorial in nature and in etiology. Patients use many different words to describe the experience of both pain and fatigue. Both symptoms are present to some extent in populations that are not ill. Pain and fatigue need to be measured by patients' subjective reports of their experiences; health professionals' observational ratings of symptom severity are liable to be only modestly correlated with what patients report. Despite the various definitions of fatigue, the best definition from a measurement standpoint is the same as that for pain: it is what the person experiencing it says it is. In an article entitled “Dead Tired,” Dr. Jane Poulson, an internist from Toronto, eloquently describes the fatigue associated with treatment for breast cancer.3 No stranger to either chronic disease or long, hard work, Dr. Poulson found herself unprepared for the severity of the fatigue she experienced with combined therapy. Her fatigue, unlike that she had experienced as an intern awake for 36 hours, was not responsive to rest. This unusual kind of fatigue permeated her mood and her ability to think and work. She sees CRF as a discrete phenomenon that significantly impairs quality of life. She sees her colleagues as treating this symptom too lightly and as trying to fit CRF into their own perceptions of what it is like to be really tired. She points out the futility of many physician recommendations, such as trying to ignore it or work through it, or taking a nap or getting an extra hour of sleep. Poulson sees fatigue as the symptom that has the greatest potential for inhibiting the hope of cancer patients that they may be well again. Progress in understanding fatigue, determining its correlates, and developing treatment strategies depends on the methods that we develop to measure fatigue. We need to be able to capture the experience that Poulson is talking about. Historically, fatigue has been assessed as one item on a scale measuring functional status or evaluating mood, or as one item in a toxicity report in which it is often rated by staff who estimate the patient's experience. Recently, several instruments have been employed for the assessment of fatigue in Western countries. These include the Pearson-Byars Fatigue Feeling Checklist,4 the Profile of Mood States (POMS) Fatigue and Vigor subscales,5 the Functional Assessment of Cancer Therapy–Fatigue (FACT-F),6 the Piper Fatigue Self-Report Scale,7 the Fatigue Assessment Instrument (FAI),8 the Multidimensional Fatigue Inventory (MFI),9 the Multidimensional Fatigue Symptom Inventory (MFSI),10 and the Fatigue Symptom Inventory (FSI).11 We have developed the Brief Fatigue Inventory (BFI), a simple, nine-item scale that addresses both fatigue severity and the interference that fatigue creates in daily life.12 The BFI was modeled after the Brief Pain Inventory (BPI),13 a measure now widely used in clinical research and practice. Both instruments use familiar 11-point (0–10) scales to assess severity and symptom interference.14 At least some of these measures demonstrate very high intercorrelation and similar unitary factor structure, suggesting that the severity and impact of CRF can be measured and that cancer patients can report the severity of CRF using these simple instruments. How can we capture the unique severity of fatigue that Poulson is describing? In the past, our group has examined the meanings of different levels of symptom severity by defining these levels in terms of how much a symptom interferes with mood and general function. We have found that for pain, “mild” can be thought of as “worst pain”, rated from 1 to 4 on a 0-to-10 scale; “moderate” as pain rated from 5 to 6; and “severe” as pain rated as 7 or greater. This research has been used as the basis for defining critical treatment pathways, for quality assurance, and for symptom epidemiology.15 We have been able to demonstrate that moderate-to-severe pain, when other factors like disease status are controlled, has a substantial impact on health-related function, but that patients with mild pain function much like those patients without pain. Pain's interference with function increases in a staircase manner, with greater function impairment as pain increases. When patients rate their pain at a level of 7–10, their pain interferes with most things that they want to do and permeates their mood and relations with others. This finding applies to cancer patients from different cultures who speak different languages. We used the same methodology to examine the severity of CRF and found that patients who rated their “worst fatigue” as 7 or greater could be defined as having severe fatigue. We generated broad categories of fatigue severity by conducting an analysis of variance to define cut points based on functional interference as fatigue got worse. This method generated categories similar to the ones for pain: 1–3 for “mild, ” 4–6 for “moderate, ” and 7–10 for “severe” fatigue. For fatigue, the boundary between mild and moderate was not as clear as the one for pain, but the cut point for “severe” fatigue was consistently between 6 and 7. Clearly, those patients who rate their fatigue severity as 7 or greater are very tired and need clinical intervention to improve their function. With the cooperation of service clubs based in Houston, Texas, such as the Kiwanis and Rotary Clubs, we were able to gather data on the fatigue levels of community-dwelling adults of the same age as our sample of cancer patients. These volunteers completed several simple fatigue measures, including the BFI. This was an important step in trying to understand CRF, because cancer patients undergoing treatment should be much more tired than community-dwelling adults. In our sample, 42% of cancer patients had severe fatigue (“fatigue worst” score of 7 or greater), as compared with only 17% of the community-dwelling adults. Half of the community-dwelling adults had scores of 3 or less for “fatigue worst, ” while only 28% of the cancer patients reported this mild level of fatigue. Clearly, the distributions of fatigue scores for the two samples were quite different, with the cancer patients (as expected) being much more tired. The finding of a second approach to defining fatigue severity was published in 2000.16 These investigators defined severe fatigue as scores at or above the 95th percentile of a Fatigue Severity Scale. Using this method of defining severe fatigue, they found its prevalence to be 15% among patients with recently diagnosed breast cancer, 16% among patients with recently diagnosed prostate cancer, 50% among patients with inoperable nonsmall cell lung cancer, and 78% among patients receiving inpatient palliative care. The two methods of identifying patients with severe fatigue seem to yield similar estimates. The data reported by Stone et al.16 for patients with newly diagnosed disease are similar to those reported for early gastrointestinal cancer (see Wang et al., this supplement). The figure of over 40% with severe fatigue for patients in active treatment12 is in line with the 50% of lung cancer patients reported by Stone et al.16 Either method does help define what the experience of severe fatigue can be for patients, and helps those of us without cancer to understand the extreme burden that it imposes. The use of simple, easily administered, easily scored fatigue scales should open the way for an epidemiology of fatigue, improve communication about fatigue between patients and those who care for them, and facilitate clinical trials that are focused on the development of new treatments for fatigue. Short fatigue scales, such as the BFI, the Fatigue subscale of the Profile of Mood States, and the FACT F, do not capture the multiple dimensions that longer instruments were designed to represent, such as the cognitive, affective, and somatic components of fatigue. These multidimensional scales, however, are often overly long for tired patients to complete. In clinical practice, one might wish to screen for patients with high levels of fatigue based on a measure such as the BFI, then do additional assessment to determine the causes of fatigue in those patients. Such an approach is suggested in recent guidelines for the management of fatigue (see Mock, this supplement). The multidimensional measures are also probably too long to be completed when fatigue is of interest in a clinical trial. The inclusion of long assessment instruments in such trials often results in missing data because patients find them difficult to complete, or because it is difficult to schedule sufficient time for their administration. These longer scales might be used in descriptive studies of fatigue, where they can be given in a one-on-one situation with study personnel and time for their completion can be scheduled. The development of assessment methodology opens the door to studies of the correlates of fatigue that may suggest causal links. For example, several studies demonstrate the strong association between anemia and fatigue, either by indirect measurement using quality-of-life criteria or by direct measurement of fatigue.17 There is now little doubt that hemoglobin levels in the range of 7–9 g/dL will be associated with severe fatigue, and that patients demonstrate improvement in fatigue with improvement in hemoglobin (see Glaspy, this supplement). When does this relationship reach asymptote? Analysis of two large trials suggests that patients may continue to demonstrate increased energy levels until hemoglobin approaches 12–13 g/dL.18 Fatigue may be caused by the disease itself, or it may also be caused by treatment. Treatment-related anemia is well known for its impairment of quality of life and function, and it is often associated with severe fatigue in cancer patients.19 In a survey of cancer patients at The University of Texas M. D. Anderson Cancer Center that used the BFI,12 patients with hematologic malignancies reported greater fatigue than patients with solid tumors (47% of the hematologic group reported “worst fatigue” of 7 or greater versus 28% of the solid-tumor group). In patients with hematologic malignancies, low hemoglobin and albumin levels were predictive of who had severe fatigue.20 Hormonal deficiencies occur in large numbers of patients treated with interferon-α, and the possibility that hypothyroidism or other adrenal or gonadal dysfunction may be associated with fatigue in these patients needs to be investigated.21 Interferon-α and other agents used to treat cancer also excite or inhibit the production of cytokines known to be related to fatigue. For example, IL-6 is a proinflammatory cytokine that has been shown to mediate endocrine and neural activity. In normal subjects, IL-6 induces fatigue and inactivity as well as poor concentration.1 Future research should explore the role of proinflammatory cytokines in the production of fatigue experienced by patients treated with interferon-α.22 The majority of patients undergoing chemotherapy or radiotherapy report significant fatigue during the course of treatment.23 Not surprisingly, intensity of treatment is related to fatigue, and fatigue becomes an important toxicity variable as treatment becomes more intense. This relationship may also be predictive of long-term posttreatment fatigue. In a recent literature review, Jacobsen and Stein found that breast cancer patients who underwent adjuvant chemotherapy or autologous bone marrow transplantation experienced clinically significant levels of fatigue for months or even years following the completion of active treatment.24 In contrast, there is little evidence that patients who receive only regional therapy have significant fatigue as a long-term treatment side effect. One reason that fatigue may not be routinely assessed is that, unlike pain, there have not been many options for treatment. Anemia is, in many cases, correctable, and the presence of anemia can be addressed therapeutically. Reversal of anemia may be associated with a reduction in fatigue severity. However, anemia is not the whole story, and the association between anemia and fatigue severity is far from perfect. With the exception of studies of epoetin alfa, there are very few clinical trials dealing with therapies for fatigue. Potential therapies for fatigue include changes in a patient's drug regimen, correction of metabolic abnormalities, and treatments for depression or insomnia. Many health care professionals suggest mild exercise as a way of dealing with fatigue, and a reduction in muscle mass has been suggested as a mechanism for fatigue. Recent controlled studies found that aerobic exercise prevented increases in fatigue and psychologic distress in patients undergoing high-dose chemotherapy.25 Other nonpharmacologic treatments include modification of activity and rest patterns, cognitive therapies, behavioral therapies to modify sleep (sleep hygiene), and nutritional support. Pharmacologic treatments currently used to treat fatigue include psychostimulant drugs and corticosteroids, although these treatments currently have limited support from research studies.26 Informal surveys that we have conducted at meetings indicate that many oncologists are now using stimulants, primarily methylphenidate, to help their patients combat debilitating fatigue. The use of stimulants is essentially empiric. There are no published reports of controlled trials with reduction of fatigue severity as the primary endpoint. However, methylphenidate does improve sedation associated with opioids used to manage cancer pain, and has been shown to improve cognitive function in patients with central nervous system tumors.27 It has been suggested that the activating SSRI antidepressants may have a role in fatigue management,28 but again there are no reports of trials of the efficacy of these agents for fatigue. It is becoming evident that patients are striking out on their own in attempts to deal with fatigue, reflected in the growing market for alternative medicine. Many patients are now taking multiple supplements of unknown efficacy. A recent study of HIV-infected patients found that the two predictors of supplement purchase in this group were higher education and greater fatigue.29 A similar survey of cancer patients may well find the same results. Based solely on the widespread use of these supplements and the need for informed advice about their benefit, we owe it to patients to examine the potential efficacy of at least some of these agents in randomized, controlled clinical trials. The organizers of this conference are grateful to its sponsors for recognizing the enormity of the problem of fatigue for patients with cancer and the urgency of moving forward toward better control of the problem. In particular, we would like to acknowledge the Susan G. Komen Breast Cancer Foundation for sponsoring this supplement to Cancer so that a larger audience can participate in the discussion.

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