Evidence-Based Treatment for Cancer-Related Fatigue

Transcription

1 Evidence-Based Treatment for Cancer-Related Victoria Mock Despite the high prevalence of cancer-related fatigue and its documented negative effects on patients quality of life, limited evidence is available to support interventions to prevent or treat cancer-related fatigue. Both pharmacologic and nonpharmacologic interventions have been tested, with aerobic exercise programs and anemia correction by erythropoietin demonstrating greatest effectiveness. This article reviews the available evidence and describes gaps in knowledge. Recommendations for future research on interventions for cancer-related fatigue are presented. [J Natl Cancer Inst Monogr 2004;32:112 8] EVIDENCE-BASED TREATMENT FOR CANCER-RELATED FATIGUE Despite the acknowledgment of fatigue as the most prevalent symptom reported by individuals with cancer, interventions to manage cancer-related fatigue are limited in number and in evidence to support their efficacy. The most effective approach to management of any symptom is identifying the cause of the disturbing symptom, if it can be identified, and correcting it, if it can be corrected. In the published National Comprehensive Cancer Network Practice Guidelines, seven factors are identified as frequently contributing to cancer-related fatigue: pain, emotional distress, sleep disturbance, anemia, nutritional deficiencies, deconditioning, and comorbidities (1). The National Comprehensive Cancer Network (NCCN) panel recommended that these factors be assessed and treated as a first step in managing the symptom (2). Although the factors may not be the sole or even primary cause of the individual s fatigue, because these factors are known to increase the level as well as the distress of fatigue, treating these seven factors if present as an initial approach may decrease perceived fatigue to a tolerable level. There has been considerable research to support the close relationships between pain and fatigue (3 5), distress and fatigue (6,7), and deconditioning and fatigue (8,9). Good evidence also supports the correlation between anemia and fatigue (10) and sleep disturbance and fatigue (11,12). If none of these seven factors can be identified as being present, a comprehensive assessment is indicated, including a careful review of systems, evaluation of disease status, and review of current medications (1,2). Data from a comprehensive assessment may indicate appropriate strategies for overall management (13). However, in many cancer patients, the cause of fatigue cannot be readily identified, and the approach to management is a more generalized one. Although cancer-related fatigue has been recognized as a significant problem over the last decade, the underlying mechanisms of cancer-related fatigue are uncertain (14), and few evidence-based interventions are available to mitigate this distressing symptom. Interventions can be classified as pharmacologic and nonpharmacologic. PHARMACOLOGIC THERAPY Pharmacologic interventions include erythropoietin for chemotherapy-induced anemia, other cause-specific treatments such as antidepressants when depression is a cause of fatigue, and psychostimulants to help patients feel energized and less fatigued. Preliminary evidence from clinical trials of erythropoietin in anemic patients with nonmyeloid malignancies receiving chemotherapy indicates that increases in hemoglobin levels are reflected in improved energy and physical functioning, decreased fatigue, and increased quality of life (10,15,16). However, although many anemic patients report moderate to high levels of fatigue (15), most fatigued cancer patients are not anemic (7). Aside from the treatment with erythropoietin, there are few controlled studies investigating pharmacologic therapy for cancer-related fatigue or therapy-related fatigue. In one study, megestrol acetate pharmaceutical was described as reducing fatigue to some degree in advanced cancer patients (17). Psychostimulants have been effective in reducing fatigue related to HIV infection (18) and in multiple sclerosis (19), but there are limited data concerning their efficacy in cancer-related fatigue. Although methylphenidate has been found to be effective in relieving opiate-induced somnolence and in treating acute depression as well as improving cognitive function in the palliative setting (20), only two reports described use of methylphenidate as treatment for fatigue. One was a clinical report on its use in 11 patients with advanced cancer, in which nine responded with a reduction in fatigue (21). The second was a pilot project investigating effects on fatigue levels of an exercise program plus methylphenidate in 12 patients with melanoma who were receiving interferon (22). Although one-third of the sample stopped taking the methylphenidate because of side effects, all subjects reported less fatigue than historic controls receiving interferon. Pemoline is a central nervous system stimulant with similar indications for use as those for methylphenidate (23), and it has been tested to treat fatigue in multiple sclerosis (46% response) but not in cancer. Serious liver problems have been reported in some patients. Modafinil has been approved by the Food and Drug Administration for use in narcolepsy and has been reported to be helpful in cancer-related fatigue (24), but no studies have been published. NONPHARMACOLOGIC INTERVENTIONS Nonpharmacologic interventions for cancer-related fatigue can be categorized as alterations in rest and activity, including Correspondence to: Victoria Mock, DNSc, FAAN, Kimmel Cancer Center, Johns Hopkins University, P.O. Box 50250, Baltimore, MD ( vmock@son.jhmi.edu). See Note following References. DOI: /jncimonographs/lgh025 Journal of the National Cancer Institute Monographs, No. 32, Oxford University Press 2004, all rights reserved. 112 Journal of the National Cancer Institute Monographs No. 32, 2004

2 exercise and sleep therapy, and psychosocial support programs and coping strategies to reduce stress and conserve energy. Exercise Strong evidence from clinical trials supports the use of exercise to manage fatigue in cancer patients (8,25 30). The rationale for testing exercise as a treatment for fatigue is based on the proposition that the toxic effects of cancer and treatment as well as deconditioning caused by a decreased level of physical activity during treatment may lead to a reduction in the capacity for physical performance (31). When deconditioned, patients must use greater effort and expend more energy to perform usual activities, resulting in increased fatigue levels. Exercise training can reduce the loss of energy or even increase functional capacity, leading to reduced effort and decreased fatigue (31). An additional hypothesis is that the increased circulation accompanying exercise may facilitate reduction of circulating cytokines or other substances mediating the fatigue response. To date, there have been numerous reports from studies conducted by a variety of research teams testing the effects of exercise on fatigue during active cancer treatment, and several additional reports of exercise programs after completion of cancer treatment (Table 1). Although the sample sizes for many of the studies were small, all demonstrated lower levels of fatigue in subjects who exercised when compared with control or comparison s. All of the forms of exercise were designed to be aerobic and included some home-based walking programs (8,9,22,26,28,30,32 34) as well as some supervised laboratory treadmill or exercise bicycle formats (25,35 37). Resistive strength training was found to decrease fatigue in a recent report of men with prostate cancer receiving androgen deprivation therapy (27). Aerobic exercise interventions have consistently exhibited a powerful effect on cancer-related fatigue: Significant differences were seen between experimental and control s even with small sample sizes. levels were approximately 40% 50% lower in exercising subjects. The exercise programs varied in length of time, consistent with the cancer treatment, from 6 weeks for patients undergoing radiation therapy to 6 months for chemotherapy and extensive peripheral blood stem cell transplantation. In posttreatment exercise studies, the exercise programs have ranged from 10 to 20 weeks. Adherence to the exercise programs, defined in diverse ways, ranged from 60% to 80% in the home-based programs to 100% in laboratory studies a significant contrast to the 50% dropout rate for healthy individuals who begin an exercise program (38). Most of the samples were composed of women with breast cancer receiving adjuvant chemotherapy or radiation therapy or following cancer treatment. However, single studies of individuals with melanoma (22), Hodgkin s disease (39), and multiple myeloma (40) have demonstrated beneficial outcomes for exercising. Several studies of laboratory-based exercise training in individuals receiving or following peripheral blood stem cell transplants have revealed decreased fatigue and emotional distress as well as improved hematologic parameters in exercisers (29,36). was measured by a variety of self-report instruments that included visual analog scales, the Piper, the Profile of Mood States Subscale, and the Schwartz Cancer all of which are considered reliable and valid and were previously tested in cancer populations. Changes in exercise tolerance and functional capacity were measured by symptom-limited treadmill tests or a 12-minute and were correlated with fatigue levels. The studies included randomized clinical trials, single- pretest/posttest, and quasiexperimental designs. The level of evidence supporting exercise as an intervention for fatigue in cancer populations is considered to be strong as a result of the large number of studies conducted, the overall good quality of the designs, the large effect size of exercise on fatigue, and the consistency of beneficial outcomes across all studies reviewed. Several comprehensive reviews of exercise studies in cancer patients have also concluded that exercise reduces fatigue and improves quality of life (13,41,42). Although little research has been conducted on fatigue interventions in the palliative care setting, a pilot study of increased activity in nine advanced cancer patients demonstrated reductions in fatigue (43). An important limitation of the studies on exercise to manage cancer-related fatigue is that they were offered to s of patients at a set point in their therapy before or after cancer treatment regardless of their current level of fatigue. There is limited information on the effectiveness and acceptability of an exercise program with patients who already suffer from high levels of fatigue. Only two small pilot studies of the investigations of effects of exercise on fatigue involved exercise training for individuals identified as having high levels of fatigue (37,39). However, prevention of fatigue by initiation of exercise programs early in cancer treatment may be more effective, cost saving, and humane than treatment after fatigue levels reach moderate to severe levels. Rest and Sleep Health care professionals commonly recommend additional rest and sleep to patients who report cancer-related fatigue (44,45), and these may be the most frequent self-care activities of fatigued patients. The relationship between sleep disturbance and fatigue in cancer patients has received limited investigation (11). Cancer patients report significant disruptions in sleep patterns, and the essential issue may be quality of sleep rather than quantity (46 48). Several studies using actigraphy to measure sleep demonstrated that cancer patients spend increased time resting and sleeping, but that their pattern of sleep is often severely disrupted (49,50). Patients who use rest and sleep to manage cancer-related fatigue report that this method is not particularly effective (51). Research testing rest or sleep interventions to manage fatigue is in preliminary stages, and only one pilot project has been published (52). Psychosocial Interventions Studies testing interventions to reduce stress and increase psychosocial support in cancer populations have demonstrated reductions in level of perceived fatigue, usually as a component of mood state (53 56). Most of these studies did not have fatigue as a primary endpoint, and fatigue measures were limited to a an instrument to measure emotional distress. It has been proposed that cancer-related fatigue is essentially a response to the stress of cancer diagnosis and treatment (57) or that emotional state influences perception and reporting of cancer-related fatigue. Although a strong correlation exists between emotional distress and cancer-related fatigue (9,28,32), the precise relationship is not clearly understood. Anxiety and Journal of the National Cancer Institute Monographs No. 32,

3 Table 1. Effects of exercise interventions on cancer-related fatigue* Authors (Ref.) Design Sample Type of exercise Measures Results Comments/limitations MacVicar Quasiexperimental and Winningham, (35) 1994 (32) 1997 (28) Dimeo et al., 1999 (29) Schwartz, 1999 (34), 2000 (33) 2001 (9) Schwartz et al., 2001 (8) 2002 (30) Schwartz et al., 2002 (22) Courneya 2003 (25) Segal et al., 2003 (27) Courneya et al., 2003 (26) Oldervoll et al., 2003 (39) Preexperimental 1- Preexperimental 1- RCCT Effects of exercise alone cannot be determined one item VAS. Exercise was self-report Exercise was selfreport Quasiexperimental RCCT RCCT RCCT Preexperimental 1- patients; CT/no staging data (N 10; nonpatients 6) patients; CT/stages I and II (N 14) patients; RT/stages I and II (N 46) Mixed hematologic malignancies and solid tumors; PBSCT (N 59) patients; CT/stages I III (N 27) patients; CT/RT/ stages I III (N 50) patients; CT/stage II (N 61) patients; CT/RT/ stages 0 III (N 111) Melanoma patients; Interferon- (N 12 plus 16 historical controls survivors; mean 14 mo post-therapy (N 52) Prostate cancer androgen deprivation therapy (N 135) diagnoses; mean 16 mo since diagnosis; 44% actively on CT or RT (N 96) Hodgkin s disease survivors (N 9) Laboratory based cycle ergometer, 3 times a week for 10 wk 60% 85% maximum heart rate 30 min plus support. 30 min Bed cycle ergometer, 50% maximum heart rate walking or patient choice, 3 times a week 30 min walking or patient choice, 8 wk, 3 4 times a week for min 30 min, patient-selected, 4 times a week for 15 min plus methyphenidate, 20 mg QD Laboratory based cycle ergometer, 3 times a week for min Laboratory based, resistance exercise, 3 times a week, walking, min Home-Based Aerobic Choice min F F VAS F VAS and PFS F, SCL-90 F Schwartz Cancer ; VAS F PFS F VAS F PFS F Schwartz Cancer F FACT F FACT EX Muscle strength test F FACT F questionnaire 1 Functional capacity. 2Mood disturbance and fatigue in exercising patients (n 6) as well as exercising nonpatients (n 6). 1Mood disturbance in patient controls (n 4). 1Walking ability in exercisers. 2Psychosocial distress compared with controls. Less fatigue in exercisers. 1Walking ability in exercisers. 2 and other symptoms compared with controls. 2 and psychological distress in exercisers 1Pre- to posttest walking ability. 1 Quality of life and less fatigue in active exercisers vs. noncompliers. 1Walking ability in exercisers. 2 and other symptoms compared with controls. 1Pre- to posttest walking ability 2 in active exercisers 1Walking ability in exercisers 2 and other symptoms compared with controls 1Functional ability 2 and cognitive dysfunction in exercisers 2 in exercisers 1Quality of life in exercisers 2 in exercisers 1Quality of life in exercisers 2 in GP exercisers 1Quality of life in GP exercisers 2 pre- to posttest 1Physical functioning and aerobic capacity Nonrandom assignment No exercise outcomes reported 60% of subjects adhered to program Single design Exercise was self-report 70% adherence in EX 61% of subjects adhered to program Single- design Exercise was self-report 72% adherence in EX 100% of subjects adhered to exercise 67% adhered to methylphenidate Changes in peak oxygen consumption correlated with fatigue and overall quality of life No change in body composition Adherence 79% GP alone vs. GP Exercise Single- design (Table continues) 114 Journal of the National Cancer Institute Monographs No. 32, 2004

4 Table 1 (continued). Authors (Ref.) Design Sample Type of exercise Measures Results Comments/limitations Coleman et al., 2003 (40) Multiple myeloma CT (N 14) individualized walking resistance exercise F 2 and improved sleep in exercisers Pilot 42% dropout rate Source. Adapted with permission from Mock V, Atkinson A, Barsevick A, Blackwell D, Cella D, Cianfrocca M, et al. Cancer-related fatigue clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 2003;1: Copyright by the National Comprehensive Cancer Network, Inc. (NCCN). CT chemotherapy; EX exercise; F fatigue; FACT Functional Assessment of Cancer Therapy; GP psychotherapy; PBSCT peripheral blood stem-cell transplant; PFS Piper ; Profile of Mood States; RCCT Randomized Controlled Clinical Trial; RT radiation therapy; SLET Symptom Limited Exercise Test (O 2 uptake); VAS Visual Analogue. depression may be characterized by fatigue, but it is also evident that high levels of fatigue may cause emotional distress when fatigue affects functional status and the ability to engage in valued activities (30,58). The psychosocial interventions tested have included support s, individual counseling, a comprehensive coping strategy, stress management training, and energy conservation (Table 2). In the studies testing effects of support s, the experimental s have shown less overall mood disturbance, less depression, less fatigue, and greater vigor than control s, as measured by the Profile of Mood States (54,56). A comprehensive coping strategy program, which included education and relaxation with guided imagery, was found to significantly reduce fatigue combined with nausea 7 days post-bmt, but there were no significant differences in the two s in fatigue alone (59). A professionally administered stress management training program was compared with a patient self-administered form of stress management training and with usual psychosocial care in a three- experimental design with 411 patients beginning chemotherapy (60). Patients receiving the self-administered intervention reported significantly better mental health, greater vitality, and better physical functioning than either the usual care or the receiving the professionally administered stress management training. Both types of training programs included techniques of abdominal breathing, progressive muscle relaxation, and self statements about coping. The study investigators interpreted low levels on the vitality outcome as representing cancer-related fatigue. Recently, a behavioral supportive care nursing intervention to manage pain and fatigue was tested in a randomized clinical trial, with 113 cancer patients with mixed cancer diagnoses and stages receiving chemotherapy treatments (61). The intervention was tailored to address individual patients problems and included teaching, counseling and support, coordination, and communication as appropriate for each situation, but standardized by computer-based guidelines. Both pain and fatigue were reduced in the experimental, whereas physical and social role function were significantly increased over the control levels. Energy conservation is a frequent treatment recommendation for cancer-related fatigue from care providers. However, at present, there is limited evidence available testing this intervention in cancer patients (62), although one multicenter study of 296 patients has reported effectiveness in decreasing fatigue during treatment (63). Using limited energy to perform highly valued activities may increase personal satisfaction as well as manage fatigue levels when patients are debilitated. Cognitive or attentional fatigue in cancer patients had been described by Cimprich (64 66). This impairment in the capacity for directed attention may occur during stressful situations, such as during the increased demands of life-threatening illness and treatment, resulting in a loss of ability to concentrate and to problem solve. Using a controlled experimental design, Cimprich developed and tested an attention-restoring intervention involving the natural environment in postsurgical breast cancer patients (65). Subjects in the experimental demonstrated enhanced attentional capacity on a variety of neurocognitive tests and returned to work earlier than the control. In a second clinical trial (67), Cimprich tested the intervention in 157 women with newly diagnosed breast cancer who were awaiting surgery. The intervention showed greater pre- to postoperative recovery of capacity to direct attention, compared with the control. The research in this field is preliminary and needs further development. For example, the relationship between cognitive or attentional fatigue and the overall bodily fatigue commonly reported by cancer patients is not clear, and the outcomes in the Cimprich studies did not include fatigue as measured by standard fatigue instruments. CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE RESEARCH Cancer-related fatigue is the most prevalent symptom reported by cancer patients and may have profound effects on functional status of patients. However, evaluation and management of this distressing side effect of cancer and cancer treatment has been limited in clinical practice (68). This limitation is related to several factors, including a scarcity of evidence-based interventions to manage cancer-related fatigue. Only two interventions, anemia correction and exercise, have sufficient research evidence at this time to support their effectiveness. Correction of anemia has consistently demonstrated improvement in energy levels and quality of life (2,15,69). Interventions to manage cancer-related fatigue in non-anemic patients have been predominantly behavioral, with exercise being the most widely tested intervention (70). Studies investigating psychosocial support and other biobehavioral interventions such as energy conservation and sleep therapy are beginning to appear in the literature and to show preliminary potential to manage fatigue. Journal of the National Cancer Institute Monographs No. 32,

5 Table 2. Effects of psychosocial interventions on cancer-related fatigue Authors (Ref.) Sample Design Intervention Results Comments Spiegel et al., 1981 (56) Forester et al., 1985 (55) Fawzy et al., 1990 (54) Fawzy, 1995 (53) Gaston- Johansson et al., 2000 (59) Given et al., 2002 (61) Jacobsen et al., 2002 (60) Barsevick et al., 2004 (63) patients, stage IV (N 86) patients in radiation therapy (N 100) Melanoma patients postsurgery, stages I and II (N 66) Melanoma patients, stages I and II (N 61) ABMT patients (N 110) Patients with mixed solid tumors and lymphoma in CT, stages I IV (N 113) patients; chemotherapy (N 411) patients; RT or CT (N 295) RCCT, 3- Important gaps exist in our current knowledge of cancerrelated fatigue management. Studies of fatigue interventions have been conducted primarily with breast cancer populations, and generalizability to patients with other cancer diagnoses is uncertain. There has been little attention to the investigation of underlying physiologic mechanisms of cancer-related fatigue. Some study designs have been limited by lack of control s, small sample sizes, and a lack of uniformity of instruments to measure fatigue. Little research has been conducted with children, the elderly, ethnically diverse populations, those of low socioeconomic status, or patients in a palliative care setting. Future research on cancer-related fatigue should target more diverse populations in regard to cancer diagnosis, stage of cancer, and cancer treatment, as well as age and ethnicity of subjects. Additional investigation might include pharmacologic therapies for fatigue in randomized clinical trials and compare Support, weekly for 1y Individual, psychotherapy, weekly for 10 wk Support (including education and stress management), weekly for 6wk Individual education and support by RN, 3 h Comprehensive coping strategy program Tailored behavioral intervention in 10 contacts/18 wk Professionally administered stress management training or patient selfadministered stress management training Energy conservation and activity management 2Anxiety, fatigue, confusion, and mood disturbance in experimental 2Emotional and physical symptoms in experimental 1Coping and vigor in experimental at 6 wk 2, depression, and mood disturbance at 6 mo follow-up 2, anxiety, and mood disturbance in experimental 2 and nausea in experimental 2 and pain 1Physical and social functioning in experimental at 20 wk Better physical functioning 1Vitality and better mental health in self-administered intervention compared with usual care of professional intervention 2 in experimental single item on the Schedule of Affective Disorders and Schizophrenia 25% dropped out of control Covariates controlled measured by Visual Analogue the Symptom Experience (measures present or absent only) measured as vitality on SF- 36 Adapted with permission from Mock V. Atkinson A, Barsevick A, Blackwell D, Cella D, Cianfrocca M et al. Cancer-related fatigue clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 2003;1: Copyright by the National Comprehensive Cancer Network, Inc. (NCCN), ABMT autologous bone marrow/peripheral blood stem cell transplantation; Profile of Mood State ; RCCT Randomized Controlled Clinical Trial; SF36 Medical Outcome Study Short Form-36. Preparatory Information, Cognitive Restructuring, Relaxation with Imagery. pharmacologic with nonpharmacologic treatments. Interventiontesting research is needed to further evaluate sleep quality therapies and conservation of energy approaches. The rigor of research designs could be improved with larger sample sizes, standardization of instruments to measure fatigue, and use of randomized control s. Much could be learned about the causes and effects of cancer-related fatigue if investigations included data on potential mediating mechanisms, as the study by Courneya and colleagues (25) documented changes in peak oxygen consumption (functional capacity) as mediator of effects of exercise on fatigue. Finally, the practice guidelines now available for management of cancer-related fatigue need to be tested in clinical settings using appropriate outcomes research designs. Although there is much work yet to be done, the evidence to support interventions for management of cancerrelated fatigue is developing rapidly. 116 Journal of the National Cancer Institute Monographs No. 32, 2004

6 REFERENCES (1) National Comprehensive Cancer Network Practice Guidelines. Cancer- Related Panel 2004 Guidelines, version , March. Rockledge (PA): National Comprehensive Cancer Network. (Available at (2) Mock V, Atkinson A, Barsevick A, Blackwell S, Cella D, Cianfrocca ME, et al. NCCN (v ) Cancer-related fatigue clinical practice guidelines in oncology. J Natl Comp Cancer Network 2003;1: (3) Blesch K, Paice J, Wickham R, Harte N, Schnoor T, Purl S, et al. Correlates of fatigue in people with breast or lung cancer. Oncol Nurs Forum 1991; 18: (4) Bower JE, Ganz PA, Desmond KA, Rowland JH, Meyerowitz BE, Belin TR. in breast cancer survivors: occurrence, correlates, and impact on quality of life. J Clin Oncol 2000;18: (5) Gaston-Johansson F, Fall-Dickson JM, Bakos AB, Kennedy MJ., pain, and depression in pre-autotransplant breast cancer patients. Cancer Pract 1999;7: (6) Jacobsen P, Hann D, Azzarello L, Horton J, Balducci L, Lyman G. in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates. J Pain Symptom Manage 1999;18: (7) Irvine D, Vincent L, Graydon JE, Bubela N, Thompson L. The prevalence and correlates of fatigue in patients receiving treatment with chemotherapy and radiotherapy: a comparison with the fatigue experience by healthy individuals. Cancer Nurs 1994;17: (8) Schwartz AL, Mori M, Gao R, Nail LM, King ME. Exercise reduces daily fatigue in women with breast cancer receiving chemotherapy. Med Sci Sports Exerc 2001;33: (9) Mock V, Pickett M, Ropka M, Lin E, Stewart K, Rhodes V, et al. & quality of life outcomes of exercise during cancer treatment. Cancer Pract 2001;9: (10) Turner R, Anglin P, Burkes R, Couture F, Evans W, Goss G, et al. Epoetin alfa in cancer patients: evidence-based guidelines. J Pain Symptom Manage 2001;22: (11) Lee KA. Sleep and fatigue. Women s health, illness, and issues. Annu Rev Nurs Res 2001;19: (12) Berger AM, Farr L. The influence of daytime inactivity and nighttime restlessness on cancer-related fatigue. Oncol Nurs Forum 1999;26: (13) Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment and management of cancer-related fatigue in adults. Lancet 2003;362: (14) Gutstein HB. The biologic basis of fatigue. Cancer 2001;92(Suppl 1): (15) Littlewood TJ, Bajetta E, Nortier JW, et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19: (16) Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002;20:1 25. (17) Bruera E, Macmillan K, Hanson J et al. A controlled trial of megestrol actetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advanced cancer. Cancer 1990;66: (18) Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J. A randomized, doubleblind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med 2001;161: (19) Weinshenker BG, Penman M, Bass B, Ebers GC, Rice GP. A double-blind, randomized crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology 1992;42: (20) Rozans M, Dreisbach A, Lertora JL, Kahn MJ. Palliative uses of methylphenidate in patients with cancer: a review. J Clin Oncol 2002;20: (21) Sarhill N, Walsh D, Nelson KA, Homsi J, LeGrand S, Davis MP. Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Am J Hospice Palliat Care 2001;18: (22) Schwartz AL, Thompson JA, Masood N. Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate. Oncol Nurs Forum August Online Exclusive 2002;29:1 17. (23) Homsi J, Walsh D, Nelson KA. Psychostimulants in supportive care. Support Care Cancer 2000;8: (24) Cox JM, Pappagallo M. Modafinil: a gift to portmanteau. Am J Hospice Palliat Care 2001;18: (25) Courneya KS, Mackey JR, Bell GJ, Jones LW, Field CJ, Fairey AS. Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes. J Clin Oncol 2003;21: (26) Courneya KS, Friedenreich CM, Sela RA, Quinney HA, Rhodes RE, Handman M. The psychotherapy and home-based physical exercise (-hope) trial in cancer survivors: physical fitness and quality of life outcomes. Psycho-Oncology 2003;12: (27) Segal RJ, Reid RD, Courneya KS, Malone SC, Parliament MB, Scott CG, et al. Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 2003;21: (28) Mock V, Dow KH, Meares C, Grimm P, Dienemann J., Haisfield ME, et al. Effects of exercise on fatigue, physical functioning, and emotional distress during radiation therapy for breast cancer. Oncol Nurs Forum 1997;24: (29) Dimeo FC, Stieglitz R-D, Novelli-Fischer U, Fetscher S, Keul J. Effects of physical activity on the fatigue and psychologic status of cancer patients during chemotherapy. Cancer 1999;85: (30) Mock V, McCorkle R, Ropka ME, Pickett M, Poniatowski B. and physical functioning during breast cancer treatment [abstract]. Oncol Nurs Forum 2002;29:338. (31) American College of Sports Medicine. ACSM s Exercise management for person with chronic diseases and disabilities. Champaign (IL): Human Kinetics; (32) Mock V, Burke MB, Sheehan PK, Creaton E, Winningham M, McKinney- Tedder S, et al. A nursing rehabilitation program for women with breast cancer receiving adjuvant chemotherapy. Oncol Nurs Forum 1994;21: (33) Schwartz AL. Daily fatigue patterns and effect of exercise in women with breast cancer. Cancer Pract 2000;8: (34) Schwartz AL. mediates the effect of exercise on quality of life. Qual Life Res 1999;8: (35) MacVicar MG, Winningham ML. Promoting the functional capacity of cancer patients. Cancer Bull 1986;38: (36) Dimeo FC, Tilmann MH, Bertz H, Kanz L, Mertelsmann R, Keul J. Aerobic exercise in the rehabilitation of cancer patients after high dose chemotherapy and autologous peripheral stem cell transplantation. Cancer 1997;79: (37) Dimeo F, Rumberger BG, Keul J. Aerobic exercise as therapy for cancer fatigue. Med Sci Sports Exerc 1998;30: (38) Dishman RK. Overview. In: Dishman RK, editor. Exercise adherence. Champaign (IL): Human Kinetics; p (39) Oldervoll LM, Kaasa S, Knobel H, Loge JH. Exercise reduces fatigue in chronic fatigued Hodgkins disease survivors results from a pilot study. Eur J Cancer 2003;39: (40) Coleman EA, Coon S, Hall-Barrow J, Richards K, Gaylor D, Stewart CB. Feasibility of exercise during treatment for multiple myeloma. Cancer Nurs 2003;26: (41) Courneya KS and Friedenreich CM. Physical exercise and quality of life following cancer diagnosis: A literature review. Ann Behav Med 1999;21: (42) Pinto BM, Maruyam NC. Exercise in the rehabilitation of breast cancer survivors. Psychooncology 1999;8: (43) Porock D, Kristjanson LJ,Tinnelly K, Duke T, Blight J. An exercise intervention for advanced cancer patients experiencing fatigue: a pilot study. J Palliat Care 2000;16: (44) Vogelzang N, Breitbart W, Cella D, et al. Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. Semin Hematol 1997;34(Suppl 2):4 12. (45) Curt G, Breitbart W, Cella D, Groopman J, Homing S, Itri L, et al. Impact of cancer-related fatigue on the lives of patients: New finding from the fatigue coalition. Oncologist 2000;5: Journal of the National Cancer Institute Monographs No. 32,

7 (46) Berger AM, Farr L. The influence of daytime inactivity and nighttime restlessness on cancer-related fatigue. Oncol Nurs Forum 1999;26: (47) Owen DC, Parker KP, and McGuire DB. Comparison of subjective sleep quality in patients with cancer and healthy subjects. Oncol Nurs Forum 1999;26: (48) Savard J, Morin CM. Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol 2001;19: (49) Berger AM. Patterns of fatigue and activity and rest during adjuvant breast cancer chemotherapy. Oncol Nurs Forum 1998;25: (50) Young-McCaughan S, Mays MZ, Arzola SM, Yoder LH, Dramiga SA, Leclerc KM, et al. Change in exercise tolerance, activity and sleep patterns, and quality of life in patients with cancer participating in a structured exercise program. Oncol Nurs Forum 2003;30: (51) Graydon JE, Bubela N, Irvine D, Vincent L. -reducing strategies used by patients receiving treatment for cancer. Cancer Nurs 1995;18: (52) Berger AM, VonEssen S, Kuhn BR, Piper BF, Farr L, Agrawal S, et al. Feasibility of a sleep intervention during adjuvant breast cancer chemotherapy. Oncol Nurs Forum 2002;29: (53) Fawzy NW. A psychoeducational nursing intervention to enhance coping and affective state in newly diagnosed malignant melanoma patients. Cancer Nurs 1995;18: (54) Fawzy FI, Cousins N, Fawzy NW, Kemeny M, Elashoff R, Morton D. A structured psychiatric intervention for cancer patients: I. Changes over time in methods of coping and affective disturbance. Arch Gen Psychiatry 1990;47: (55) Forester B, Kornfeld DS, Fleiss JL. Psychotherapy during radiotherapy: effects on emotional and physical distress. Am J Psychiatry 1985;142: (56) Spiegel D, Bloom J, Yalom I. Group support for patients with metastatic cancer. A randomized outcome study. Arch Gen Psychiatry 1981;38: (57) Aistars J. in the cancer patient: a conceptual approach to a clinical problem. Oncol Nurs Forum 1987;14: (58) Given B, Given C, Azzouz F, Strommel M. Physical functioning of elderly cancer patients prior to diagnosis and following initial treatment. Nurs Res 2001;50: (59) Gaston-Johansson F, Fall-Dickson JM, Nanda J, Ohly KV, Stillman S, Krumm S, et al. The effectiveness of the comprehensive coping strategy program on clinical outcomes in breast cancer autologous bone marrow transplantation. Cancer Nurs 2000;23: (60) Jacobsen PB, Meade CD, Stein KD, Chirikos TN, Small BJ, Ruckdeschel JC. Efficacy and costs of stress management training for cancer patients undergoing chemotherapy. J Clin Oncol 2002;20: (61) Given B, Given CW, McCorkle R, Kozachik S, Cimprich B, Rahbar MH, et al. Pain and fatigue management: results of a nursing randomized clinical trial. Oncol Nurs Forum 2002;29: (62) Barsevick AM, Whitmer K, Sweeney C, Nail LM. A pilot study examining energy conservation for cancer treatment-related fatigue. Cancer Nurs 2002;25: (63) Barsevick A, Dudley W, Beck S, Sweeney C, Whitmer K, Nail LM. A randomized clinical trial of energy conservation for cancer-related fatigue. Cancer 2004;100: (64) Cimprich B. Attentional fatigue following breast cancer surgery. Res Nurs Health 1992;15: (65) Cimprich B. Developing an intervention to restore attention in cancer patients. Cancer Nurs 1993;16: (66) Cimprich B. Attention and symptom distress in women with and without breast cancer. Nurs Res 2001;50: (67) Cimprich B, Ronis DL. An environmental intervention to restore attention in women with newly diagnosed breast cancer. Cancer Nurs 2003;26: (68) Nail L. in patients with cancer. Oncol Nurs Forum 2002;29: (69) Gabrilove JL, Cleeland CS, Livingston RB, Sarokham B, Winer E, Einhorn L. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times weekly dosing. J Clin Oncol 2001;19: (70) Mock V. Clinical excellence through evidence-based practice: fatigue management as a model. Oncol Nurs Forum 2003;30: NOTE The National Comprehensive Cancer Network Guidelines (NCCN) is a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN guideline is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care or treatment. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These Guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. These Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the Guidelines, visit These Guidelines are a work in progress and will be refined as often as new significant data become available. 118 Journal of the National Cancer Institute Monographs No. 32, 2004