Fatigue and Cancer

We are among the majority ofpeople who experience fatigue

throughout our battle with cancer.(1) Itis a near universal problem that affectsapproximately three-fourths or moreof us and is the most common sideeffect of our cancer experience. Morethan half of us experience fatigue onmost days, and it affects our daily livesmore than pain or nausea. Fatigueassociated with cancer is not the kindthat will resolve after we take a nap orget a good night’s sleep, but tends tobe more severe and ongoing. Forthose of us who are fortunate, ourfatigue is mild and temporary. Forothers, it can last for months orsometimes years after treatment andmakes going about our daily activitiesnearly impossible. The impact of ourfatigue is profound and affects ourability to work, walk short distances,

be intimate, and meet the needs ofour families. We often have difficultyperforming even the most simple oftasks such as cooking, cleaning, orshowering. Some of us experiencedifficulty concentrating or makingrelatively simple decisions. Fatigueeven causes us to feel distant from ourfriends and social networks.

We refer to our specific type offatigue as CRF (cancer-related fatigue).It is one of the most debilitating yetleast understood or addressed sideeffects of cancer treatment.(1)

Although the majority of us as patientsexperience fatigue, it is also one of themost overlooked and under-treatedside effects of cancer. In fact, CRF isnow the most important untreatedside effect of cancer today.(1,2) It is byfar the most problematic symptomthat affects our overall quality of life.

We feel completely exhausted –physically, emotionally and mentally.

The exact cause of our CRF isunknown. Sometimes the root of ourfatigue is caused by the cancer itself;in other instances, it is caused by thetreatment. What we do know is thatcancer-related fatigue can be causedby a variety of other factors such asdehydration, depression, anemia,electrolyte imbalances, decreasednutrition, and medications.(1) There isoften more than one contributingcause. It is not predictable by tumortype, treatment or stage of illness.Usually, our CRF comes on suddenly,does not result from activity orexertion, and is not relieved by rest orsleep. We often describe it as“paralyzing” and may continue evenafter our treatment is complete.

WHO

WEAR

E

Cancer Facts

Project DirectorNicholas K. Iammarino, PhD, CHES

Research AssistantsMohammed Ansar Ahmed

Prem Ramkumar

Causes/Etiology

� Cancer-related fatigue (CRF) is a multi-factorial, multi-dimensional phenomenon that consists of physical,psychological, social, cognitive, and behavioral aspects.(3)

� Possible causes of fatigue after completion of cancertreatment are still not confirmed.(3)

� The exact cause of cancer-related fatigue is unknown;however, anemia and lack of sleep have both been stronglyassociated with its onset.(4-6)

� Depression has been positively associated with CRF.Psychostimulants used in the treatment of depression havebeen shown to decrease fatigue levels.(5)

� Stress has been shown to increase fatigue in healthyindividuals and could be a contributor to the fatigue levels incancer patients.(5)

� The most well-identified causes of CRF in adults and childreninclude the natural progression of the disease, poor nutrition,depression, and anemia. Specifically, some studies havefound that in addition to other physiological factors, CRFmight be induced by the loss of nutrients as a result ofanorexia, nausea, vomiting, or hyper-metabolism.(6)

� At present, the etiology of CRF is poorly understood and therelative contributions of the neoplastic disease, various formsof cancer therapy, and comorbid conditions remainunclear.(7)

� Patients with lung cancer have self-reported higher levels offatigue than patients with cancers of other organs.(8)

� Mild cases of cancer-related anemia have been shown toincrease patients’ levels of fatigue; however, high levels ofCRF have also been reported by cancer patients withoutanemia.(8,9)

These ICC Cancer Fact Sheets wereupdated through an educational grant

from Ortho Biotech.

� Fatigue is the most prevalent symptom of individuals withcancer who receive radiation therapy, cytotoxicchemotherapy, or biological response modifiers. (6, 10)

� Physiological factors that contribute to the development ofCRF are interrelated. These proposed mechanisms includeabnormal metabolism function related to increased energyrequirements (e.g. due to tumor growth, infection, fever, orsurgery); decreased availability of metabolic substrate (e.g.due to anemia, hypoxemia, or poor nutrition); or theproduction of substances that impair metabolism or normalfunctioning of muscles (e.g. cytokines or antibodies). (6, 10)

� Okuyama et al. reported no relationship between fatigue andstage of disease. However, others have reported that patientswhose cancer has metastasized have described higher levelsof cancer-related fatigue. (11)

� Cancer-related fatigue is believed to be caused by cancer andcompounded by the effects of cancer therapy. Studies haveshown that fatigue is usually noticed before treatmentbegins. (12)

� The occurrence of cancer related fatigue has been linked tophysiological and psychological disorders including anemia,stress, insomnia, and depression. (13)

� Symptoms of cancer-related fatigue have shown a highcorrelation to the blood levels of circulating cytokines. (14)

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� Multiple studies have found the greatest amount of fatigue tobe during periods of less daytime activity (more daytimesleep) and less nighttime rest (more night time activity). (15, 16)

� Barriers to effective management of cancer-related fatigueinclude a lack of awareness that fatigue is the most prevalentsymptom, a lack of physician and patient knowledge of itscauses, and a lack of proven treatment methods. (17)

Screening

� Authors report there is a lack of adequate assessmentinstruments for measuring the different subjectivedimensions of fatigue whose properties have been sufficientlypsychometrically tested. (11, 17)

� Most clinical assessments of CRF rely on self-reports bypatients, although this assessment method is both an assetand a liability.While these symptoms are best measured bypatients themselves, the sickest patients may not be able tocomplete these assessments. (17)

� Assessment should include discussion about commonsymptoms experienced by cancer patients. Repeatedassessments for these symptoms should continue over thecourse of the illness. (17)

� Although multidimensional assessment instruments for CRFexist, they are often not feasible for use in cancer care. Briefsymptom rating scales are preferred in clinical practicesettings. (17)

� Cancer-related fatigue is left unaddressed by physiciansbecause it is a condition that can persist long after treatmentshave ended. (18)

� Fatigue scales used to measure the severity of fatigue do notaccount for the patients’ perception of fatigue. Therefore, aquantitative measure of fatigue is usually not possible. (19)

DEFINING CANCER-RELATED FATIGUE

The National Comprehensive Cancer Network (NCCN)Clinical Practice Guidelines in Oncology (1) defines cancer-related fatigue (CRF) as: “a persistent, subjective sense oftiredness related to cancer or cancer treatment that interfereswith usual functioning.”

The NCCN Consensus Panel further states that: “Comparedwith the fatigue experienced by healthy individuals, cancer-related fatigue is more severe, more distressing, and less likelyto be relieved by rest. In terms of the defining characteristics, itis important to note the subjective sense of tiredness reportedby the patient. As with pain, the clinician must rely on patients’descriptions of their fatigue and accompanying distress. Fatiguethat interferes with usual functioning is another substantialcomponent of the definition for cancer-related fatigue and thesource of much distress for patients.” (1)

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� Generally, fatigue scales rely on patients’ self-report, whichcan be problematic as clinical interpretation of the scorescan vary from patient to patient and among the variousscales.(19 - 21)

Disparities

� CRF symptoms, alone or in combination, may be perceivedand managed differently in children and adolescents, olderadults, those from low-income or low-educationalbackgrounds, and those from ethnically and culturally diversegroups.(17)

� Evidence regarding the treatment of fatigue in children andadolescents, older persons, and other special populations isinsufficient.(17)

� Although the relationships between fatigue and demographiccharacteristics, physiologic factors, and psychosocial factorsare not well-defined, findings from Eversley et al. show thatincreased levels of post-treatment symptoms, includingfatigue, exist among minorities and are also associated withdecreased income.(22)

� Eversley et al. found that Latinas reported significantly higherrates of fatigue than African American/black and non-Hispanic/Latino women with breast cancer.(22)

� Fatigue is a commonly reported symptom among childrenand adolescents with cancer. However, the mechanisms, riskfactors, clinical features, prevalence and duration are poorlyunderstood. At present, no therapeutic interventions areavailable.(23)

Outcomes

� Fatigue is one of the most prevalent side effects duringchemotherapy, usually persisting for more than two weeks;also, it has been shown to have the greatest and most long-lasting impact after chemotherapy.(2)

� Patients who experience daily cancer-related fatigue are alsomore likely to be experiencing pain and other psychosocialsymptoms such as depression, lack of motivation, anddisturbances in mood and cognition.(2)

� Cancer-related fatigue has occupational repercussions,sometimes causing patients to discontinue or changeemployment, go on disability, or use unpaid family andmedical leave because of their extreme fatigue.(2)

� Research has shown that non-pharmacological interventionscan be beneficial by providing patients with preparatoryknowledge about their disease and treatment. Non-pharmacologic treatments for CRF include: patienteducation, exercise, modification of activity and rest patterns,stress management and cognitive therapies, and adequatenutrition and hydration.(6)

� In some women with breast cancer who are receivingchemotherapy, a home-based exercise program of low tomoderate intensity has shown to be a feasible and effectiveway to reduce the effects of fatigue as well as improve qualityof life and functional ability.(6, 15, 26, 28)

� Patients receiving radiotherapy begin with a lower level offatigue that rises gradually as treatment progresses anddecreases once treatment ends.(15)

� The large range found for CRF prevalence (4-91%) suggests alack of uniformity in measurement methodology. Lack ofconsistency in estimates of symptoms across studies could beattributed to an inability to agree on the criteria to definethese symptoms. There is also a lack of consensus on themost valid and reliable measures.(17)

� At present, published studies on CRF have focused onprevalence data because there are no reliable studies on itsincidence.(17)

� Studies have shown that patients adapt to their conditionduring treatment to distance themselves from the disease.They begin to consider their condition normal and mayreport their fatigue as less severe.(24)

� Often, patients do not report episodes of cancer-relatedfatigue to their physicians and/or other health professionalsdue to its lack of perceived severity. These patients tend toadjust to more sedentary activities, change their dailyschedules, and decrease their productivity.(2, 3, 15, 25)

Fatigue and Cancer4

� Some patients do not discuss their fatigue with a health careprofessional because they assume CRF is a normal andexpected outcome of their cancer treatment, that it would notcontinue to persist, that it was caused by the cancer itself, orthat nothing could be done to alleviate their fatigue.(3, 25)

� Studies report that the number of people affected by cancer-related fatigue falls between the range of 60-100%; manyreport an average of 75%.(6, 25)

� Cancer-related anemia, a symptom highly associated withcancer-related fatigue, can be effectively treated without theuse of blood transfusions. Epoetin alfa, the most clinicallyused drug intervention for cancer-related anemia, has beenshown to increase hemoglobin levels in anemic cancerpatients receiving chemotherapy.(9, 15, 17, 26, 27)

� Many patients report experiencing physical manifestations offatigue at least a few days each month, such as a significantlydiminished energy level, a need to slow down from a normalpace, a general sense of sluggishness or tiredness, and anincreased need for sleep or rest.(2, 28, 29)

� Exercise reduces fatigue by improving physical efficiency andperformance through gains in muscle mass and plasmavolume, improved pulmonary ventilation and perfusion,increased cardiac reserve, and higher concentrations ofoxidative muscle enzymes.(29)

� Ancoli-Israel et al. have found that women with breast cancerreport disruptions in sleep and higher levels of fatigue priorto receiving treatment.(30)

� Fatigue causes substantial functional and psychologicalimpairment, and is rarely discussed or treated. Many patientsreport that fatigue affects the quality of their daily lives bypreventing them from leading a normal life and forcing themto alter their daily routine.(2, 31)

� Berger and Higginbotham found that patients most oftenexperienced pain along with their fatigue. The next highestassociation was found to be between sleeping problems anddepression.(11, 31)

� Breast cancer patients experience a “roller coaster” pattern offatigue, in which the experience of fatigue is significantlygreater at the start of each treatment cycle than it is at themidpoint.(32)

� In patients receiving multiple forms of treatment for cancer, a“response shift” during the initial treatment may influenceperceptions of fatigue during the second treatment, aspatients become accustomed to their fatigue. Response shiftis defined as a re-conceptualization of the quality of lifebrought about by a change in health status.(10, 32)

� Studies suggest that fatigue gradually decreases after the lasttreatment. However, fatigue is still a frequent complaint bydisease-free cancer patients months and years after curativetreatment for cancer has ended.(3, 6, 11, 32)

� Lung cancer patients report that fatigue was the mostfrequent symptom that interfered with their daily lives. (33)

� During the first 24 to 48 hours of chemotherapy, a sharp risein fatigue levels has been observed.(34) After the first twoweeks of therapy, fatigue levels continue to rise slightly andbegin to decrease once treatment ends. (10,15, 32)

Fatigue and Cancer 5

American Cancer Societywww.cancer.org

The American Cancer Society is the nationwidecommunity-based voluntary health organizationdedicated toeliminating cancer as a major healthproblem by preventing cancer, saving lives, anddiminishing suffering from cancer, through research,education, advocacy, and service.

American Pain Foundationwww.painfoundation.orgAs a nonprofit information resource for people withpain that provides practical information for patients,the American Pain Foundation raises public awarenessand understanding of pain and promotes better painmanagement.

American Society of Clinical Oncologywww.asco.orgThe American Society of Clinical Oncology (ASCO) isthe world’s leading professional organizationrepresenting physicians who treat people with cancer.ASCO’s efforts are directed toward advocating forpolicies that provide access to high-quality care for allpatients with cancer and at supporting the increasedfunding for clinical and translational research.

CancerCarewww.cancercare.orgCancerCare is a national non-profit organization thatprovides free professional support services to anyoneaffected by cancer: people with cancer, caregivers,children, loved ones, and the bereaved.

Chemo Carewww.chemocare.comA program of the Scott Hamilton CARES Initiative (theCancer Alliance for Research Education andSurvivorship), this is Scott Hamilton’s personal programdesigned to promote cancer awareness while raisingsignificant funds for cancer research.

Department of Pain Medicine & Palliative Care atBeth Israel Medical Centerwww.stoppain.orgThis is a resource that provides patients and themedical community with information about painmanagement and palliative care. Also addresses thephysical, psychosocial, and spiritual concerns ofpatients with lifethreatening illnesses (i.e. facts,treatments, educational programs, resources, clinicaltrials).

WEB RESOURCES

National Cancer Institutewww.cancer.govThe National Cancer Institute (NCI) is a component ofthe National Institutes of Health (NIH), one of eightagencies that compose the Public Health Service (PHS)in the Department of Health and Human Services(DHHS). The NCI, established under the NationalCancer Act of 1937, is the Federal Government’sprincipal agency for cancer research and training.

National Comprehensive Cancer Networkwww.nccn.orgThe National Comprehensive Cancer Network (NCCN),an alliance of 19 of the world’s leading cancer centers, isan authoritative source of information to help patientsand health professionals make informed decisionsabout cancer care.

National Ovarian Cancer Coalition (NOCC)www.ovarian.orgThe NOCC provides patients and the medicalcommunity with information about ovarian cancer,(i.e. facts, treatments, peer-support forum, database ofcancer-related resources).

OncoLinkwww.oncolink.upenn.eduFounded by University of Pennsylvania cancerspecialists, Oncolink provides cancer patients, families,healthcare professionals and the general public withcomprehensive information about cancer, itstreatments and research initiatives.

Oncology Nursing Societywww.ons.orgThe ONS provides oncology nurses, healthcareprofessionals and patients with access to educationalprograms, cancer-care resources and peer-supportnetworks.

People Living With Cancerwww.plwc.orgPeople LivingWith Cancer, the patient informationwebsite of the American Society of Clinical Oncology(ASCO), is designed to help patients and families makeinformed health-care decisions. The site providesinformation on more than 85 types of cancer.

The purpose of this and other ICC Fact Sheets is to draw attention tothe cancer disparities that exist among various medically underservedpopulations.With specific regard to cancer-related fatigue (CRF), atpresent there is a dearth of scientific research on this subject reported inthe medical literature.

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References

1. The National Comprehensive Cancer Network andthe American Cancer Society. Cancer-Related Fatigueand Anemia Treatment Guidelines for Patients(version II). Atlanta, 2003.

2. Curt G, BreitbartW, Cella D, et al. Impact of Cancer-Related Fatigue on the Lives of Patients: New Findingsfrom the Fatigue Coalition. The Oncologist. 2000;5:353-60.

3. Servaes P, Verhagen S, Bleijenberg G. Determinants ofChronic Fatigue in Disease-free Breast CancerPatients: A Cross-Sectional Study. Ann Oncol.2002;13:589-98.

4. Cell D, Lai JS, Chang CH, Peterman A, Slavin M.Fatigue in Cancer Patients Compared with Fatigue inthe General United States Population. Cancer.2002;94(2):528-38.

5. Brix C, Schleußner C, Füller J, Röhrig B, Strauß B.Fatigue and its Determinants in Radio Oncology.Psychother Psychosom Med Psychol. 2008;DOI:10.1055/s-2008-1067341.

6. Ahlberg K, Ekman T, Gaston-Johansson F, Mock V.Assessment and Management of Cancer RelatedFatigue in Adults. Lancet. 2003;362: 640-50.

7. Ryan JL, Carroll JK, Ryan EP, Mustian KM, Fiscella K,Morrow GR. Mechanisms of Cancer-Related Fatigue.The Oncologist. 2007; 12(1):22-34.

8. Holzner B, Kemmler G, Greil R, et al. The Impact ofHemoglobin Levels on Fatigue and Quality of Life inCancer Patients. Ann Oncol. 2002;13(6): 965-73.

9. Cortesi E, Gasco P, Henry D, et al. Standard of Care forCancer-Related Anemia: Improving HemoglobinLevels and Quality of Life. Oncology. 2005;68: 22–32.

10. De Jong N, Courtens A, Abu-Saad H, Schouten H.Fatigue in PatientsWith Breast Cancer ReceivingAdjuvant Chemotherapy: A Review of the Literature.Cancer Nurs. 2002;25(4): 283-97.

11. Okuyama T, Akechi T, Kugaya A, Okamura H, Imoto S,Nakano T. et al. Factors CorrelatedWith Fatigue inDisease-free Breast Cancer Patients: Application ofthe Cancer Fatigue Scale. Support Care Cancer.2000;8(3):215-22.

12. Langeveld NE, Grootenhuis MA, Voute PA, De HaanRJ, van den Bos C. No Excess Fatigue in Young AdultSurvivors of Childhood Cancer. Eur J Cancer.2003;39(2):204-14.

13. Van Belle S, Paridaens R, Evers G, Kerger J, Bron D,Foubert J. Comparison of Proposed DiagnosticCriteriaWith FACT-F and VAS for Cancer-RelatedFatigue: Proposal for Use as a Screening Tool. SupportCare Cancer. 2005;13(4):246-54.

14. Meyers C, Albitar M, Estey E. Cognitive Impairment,Fatigue, and Cytokine Levels in PatientsWith AcuteMyelogenous Leukemia or MyelodysplasticSyndrome. Cancer. 2005;104(4):788-93.

15. Wells J, Fedric T. Helping Patients Manage Cancer-Related Fatigue. Home Healthc Nurse. 2001;19(8):486-94.

16. Ancoli-Israel S, Moore PJ, Jones V. The RelationshipBetween Fatigue and Sleep in Cancer Patients: AReview. Eur J Cancer Care. 2001;10:245-55.

17. Patrick DL, Ferketich SL, Frame PS, et al. NationalInstitutes of Health State-of-the-Science Panel.National Institutes of Health State-of-the-ScienceConference Statement: SymptomManagement inCancer: Pain, Depression, and Fatigue, July 15-17,2002. J Natl Cancer Inst. 2003;95(15): 1110-17.

18. Perry S, Kowalski TL, Chang CH. Quality of LifeAssessment inWomen with Breast Cancer: Benefits,Acceptability and Utilization. Health Qual LifeOutcomes. 2007;5:24.

19. Gielissen MF, Knoop H, Servaes P, et al. DifferencesIn the Experience of Fatigue in Patients and HealthyControls: Patients’ Descriptions. Health Qual LifeOutcomes. 2007;5:12.

20. Hjollund, NH, Andersen JH, Bech P. Assessment OfFatigue in Chronic Disease: A Bibliographic Study ofFatigue Measurement Scales. Health Qual LifeOutcomes. 2007;5:12.

21. Lawrence DP, Kepelnich JH, Miller K, Devine D, Lau J.Evidence Report on the Occurrence, Assessment, andTreatment of Fatigue in Cancer Patients. J NatlCancer Inst Monogr. 2004;(32):40-50.

22. Eversley R, Estrin D, Dibble S,Wardlaw L, Pedrosa M,Favila-Penney,W. Post-Treatment Symptoms AmongEthnic Minority Breast Cancer Survivors. Oncol NursForum. 2005;32(2): 250-56.

23. Gibson F, Garnett M, Richardson A, Edwards J, SepionB. Heavy to Carry: A Survey of Parents’ andHealthcare Professionals’ Perceptions of Cancer-Related Fatigue in Children and Young People. CancerNurs. 2005; 28(1):27-35.

24. Westerman MJ, The AM, Sprangers MAG, Groen HJM,Wal G, Hak T. Small-Cell Lung Cancer Patients areJust ‘A Little Bit’ Tired: Response Shift and Self-Presentation in The Measurement of Fatigue. QualLife Res. 2007;16(5):853-61.

25. Morrow GR, Andrews PL, Hickok JT, Roscoe JA,Matteson S. Fatigue Associated with Cancer and itsTreatment. Support Care Cancer. 2002;10:389-98.

26. Stasi R, Abriani L, Beccaglia P, Terzoli E, Amadori S.Cancer-Related Fatigue: Evolving Concepts inEvaluation and Treatment. Cancer. 2003;98(9):1786-1801.

27. Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B,Winer E, Einhorn LH. Clinical Evaluation of Once-Weekly Dosing of Epoetin Alfa in ChemotherapyPatients: Improvements in Hemoglobin and Qualityof Life are Similar to Three-TimesWeekly Dosing. JClin Oncol. 2001;19:2875-82.

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28. Turner J, Hayes S, Reul-Hirche H. Improving thePhysical Status and Quality of Life ofWomen Treatedfor Breast Cancer: A Pilot Study of a StructuredExercise Intervention. J Surg Oncol. 2004;86:141-46.

29. WinninghamM. Strategies for Managing Cancer-Related Fatigue Syndrome: A RehabilitationApproach. Cancer. 2001;92(4):988-97.

30. Ancoli-Israel S, Liu L, Marler MR, et al. Fatigue, Sleepand Circadian Rhythms Prior to Chemotherapy forBreast Cancer. Support Care Cancer. 2006; 14(3):201-9.

31. Mock V, Pickett M, Ropka M, et al. Fatigue and Qualityof Life Outcomes of Exercise During CancerTreatment. Cancer Pract. 2001;9:119-27.

32. Donovan K, Jacobsen P, Andrykowski M, et al. Courseof Fatigue inWomen Receiving Chemotherapy and/orRadiotherapy for Early Stage Breast Cancer. J PainSymptom Manage. 2004;28(4):373-80.

33. Tanaka K, Akechi T, Okuyama T, Nishiwaki Y, UchitomiY. Impact of Dyspnea, Pain, and Fatigue on Daily LifeActivities in Ambulatory Patients with Advanced LungCancer. J Pain Symptom Manage. 2002;23(5):417-23.

34. Schwartz AL. Daily Fatigue Patterns and Effect ofExercise inWomen with Breast Cancer. Cancer Pract.2000;8(1):16-24.

Information provided by theIntercultural Cancer Council

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