Severe, debilitating fatigue is common in cancer patients. For many,it is the symptom that interferes most with normal routines. Virtuallyevery modality used to treat cancer may cause fatigue, as can complicationsof the disease such as sleep disturbances, infections, malnutrition,hypothyroidism, and anemia. There is a significant overlap betweendepression and fatigue in many patients. Given the high prevalenceof cancer-related fatigue, frequent assessment of patients is essential.The evaluation should include an attempt to identify reversiblecauses of fatigue, and screening for depression. However, many cancerpatients suffer from fatigue even in the absence of any identifiable,reversible cause. For these patients, consideration can be given to suitableexercise programs, educational support and counseling, and energyconservation strategies. A trial of a stimulant medication is alsoreasonable. Given the heterogeneity of patients, individualized approachesare needed. For anemic patients undergoing chemotherapy,erythropoietic agents can increase hemoglobin levels. The impact ofthese drugs on fatigue and quality of life is uncertain. Recent reports ofincreased mortality and thrombotic events in cancer patients treatedwith epoetin require further investigation.
ABSTRACT: Severe, debilitating fatigue is common in cancer patients. For many,it is the symptom that interferes most with normal routines. Virtuallyevery modality used to treat cancer may cause fatigue, as can complicationsof the disease such as sleep disturbances, infections, malnutrition,hypothyroidism, and anemia. There is a significant overlap betweendepression and fatigue in many patients. Given the high prevalenceof cancer-related fatigue, frequent assessment of patients is essential.The evaluation should include an attempt to identify reversiblecauses of fatigue, and screening for depression. However, many cancerpatients suffer from fatigue even in the absence of any identifiable,reversible cause. For these patients, consideration can be given to suitableexercise programs, educational support and counseling, and energyconservation strategies. A trial of a stimulant medication is alsoreasonable. Given the heterogeneity of patients, individualized approachesare needed. For anemic patients undergoing chemotherapy,erythropoietic agents can increase hemoglobin levels. The impact ofthese drugs on fatigue and quality of life is uncertain. Recent reports ofincreased mortality and thrombotic events in cancer patients treatedwith epoetin require further investigation.Fatigue is a complex, subjectiveexperience that defies facile definition.Roget's Thesaurus offers30 synonyms for fatigue used asa verb, and 18 as a noun. Despiteambiguities in terminology, a largeproportion of cancer patients, whenasked, report unambiguously that theyare fatigued. Furthermore, cancerrelatedfatigue differs from the commonvariety in that it is unrelieved byrest and interferes with routine activity.In some contexts, fatigue appearsto be the most prevalent cancer symptom,as well as the most troublesometo patients.The material presented below representsa summary and selective updateof a recent evidence report oncancer-related fatigue prepared for theAgency for Healthcare Research andQuality (AHRQ) at the request of theNational Institutes of Health (NIH).The purpose of the evidence reportwas to provide a comprehensive overviewof published studies on the occurrence,assessment, and treatmentof cancer-related fatigue for a Stateof-the-Science Conference on cancersymptoms convened by the NIH in2002.Etiology ofCancer-Related FatigueThe pathophysiology of the debilitatingfatigue experienced by cancerpatients is poorly understood. In someinstances, fatigue is temporally relatedto treatments such as chemotherapy,hormonal therapy, or radiotherapy,resolving spontaneously after theircompletion. Other causative or contributingetiologic factors can sometimesbe identified (eg, infections,malnutrition, depression, endocrinedisorders, anemia). The extent towhich cancer-related fatigue can beattributed to cancer treatment or toidentifiable complications is unknown.It seems certain, however, thatmany cancer patients suffer frompathologic levels of fatigue for whichno obvious cause is evident. This isalso undoubtedly the case in somesubsets of cancer survivors.It has been hypothesized that otherwiseunexplained cancer-related fatigue is mediated by inflammatorycytokines, gonadal dysfunction, or disruptionin sleep patterns. There islimited evidence to support the hypothesisthat any of these factors is apredominant cause of fatigue. The etiologyof cancer-related fatigue is probablymultifactorial, and the termfatigue actually encompasses a widearray of related syndromes. Researchon the etiology of cancer-related fatigueis hampered by a paucity of animalmodels and human studiesassessing putative biologic correlatesof fatigue.Cancer-related fatigue is frequentlyassociated with other cancer symptoms,particularly pain and psychologicaldistress. It is unclear whetherthese clusters of symptoms have acommon, underlying etiology, orwhether they exacerbate one another.Occurrence of Cancer-RelatedFatigueEstimates of the percentage of cancerpatients affected by fatigue arehighly variable, ranging from 4% to91% depending on the populationstudied and the methods of assessmentemployed.[4-30] The majorityof studies in which the occurrencerate of cancer-related fatigue was adefined end point have focused onrelatively small cohorts of patients atreferral centers. These studies mayunderestimate the true burden of cancer-related fatigue, since the patientsmost affected by it may have beenunable to participate.Case-control studies[15,16,19,23,25] suggest that levels of fatigue incancer patients almost always exceedthat of people without cancer. No longitudinalstudies have tracked thecourse of cancer-related fatigue oversuccessive phases of illness, treatment,and remission. Despite these limitations,a clearer picture is emerging of the prevalence and impact of cancerrelatedfatigue in various diseases andtreatment settings. The occurrence offatigue has been evaluated duringtreatments, near the end of life, and incancer survivors. To date, no studieshave examined fatigue as a presentingsymptom of cancer. Data on theoccurrence of fatigue in children andthe elderly with cancer are quite limited.[28,31]Chemotherapy, radiation therapy,combined-modality treatment, and biologicand hormonal therapies haveall been found to exacerbate fatigue.[4,5,7-10,12,14,15,17,18,24,30]The lowest rate of fatigue was reportedin women with early-stage breastcancer prior to chemotherapy (4%).After four cycles of treatment, 28%were fatigued. Similarly, fatiguerates rose from 8% at baseline to 25%after the completion of radiotherapyin men with localized prostate cancer.A decline in fatigue with treatmentwas reported in only one context. In acohort of 127 patients with small-celllung cancer, the proportion with moderateto severe fatigue declined slightlyduring chemotherapy, from 43% to30%-37%. All other disease symptomswere relieved, however, presumablydue to the responsiveness ofsmall-cell carcinoma to chemotherapy.As a result, fatigue was the mostprevalent symptom over the course oftreatment. This study was one of avery few that attributed fatigue to diseaseor treatment factors-43% of theburden of fatigue was ascribed to diseasesymptoms, and 37% to the effectsof treatment.In patients on palliative care services,fatigue is highly prevalent, with48% to 75% suffering from severe orclinically important fatigue, even inthe absence of chemotherapy or radiotherapy.[6,19,29] Fatigue is alsoreported by 17% to 56% of cancersurvivors, months or years after thecompletion of treatment.[11,13,16,20-23,27] Only one study found a rate offatigue in survivors that was no higherthan that in a noncancer controlgroup. The largest study, involving1,957 breast cancer survivors,found that 35% of subjects had fatiguein the disability or limitation range, using an instrument for whichnorms in noncancer subjects are wellestablished. Even at a mean of 12years after treatment, 26% of 459Hodgkin's disease survivors werefound to be fatigued. Little isknown about the cause of this persistentphenomenon.Assessment of Cancer-RelatedFatigueHeterogeneous methods have beenused to assess cancer-related fatigue,including visual-analog scales, Likertscales, nonvalidated questionnaires,and, especially in the more contemporarystudies, sophisticated instrumentsthat captured multiple aspectsof fatigue. While most of the instrumentscurrently employed for researchpurposes are psychometricallyvalid and reliable, the clinical significanceof what they measure remainssomewhat obscure. The definitions offatigue and the grading of its severityare quite variable, and therefore comparisonof the reported rates of cancer-related fatigue in different studiesis problematic. Diagnostic criteria forcancer-related fatigue have been proposedbut have not yet been widelyadopted.The approach to clinical assessmentof cancer-related fatigue is empiric.The National ComprehensiveCancer Network (NCCN) guidelinesfor assessment and management ofcancer-related fatigue recommendthe use of simple verbal (mild, moderate,severe) or numeric (0-10)scales. If moderate or severe fatigue(corresponding to a score > 3/10) isreported, then the time course, associatedsymptoms, and impact on functioningshould be elicited.The evaluation should focus on theidentification of reversible factorsknown to be associated with cancerrelatedfatigue, eg, pain, emotionaldistress, hypothyroidism, sleep disturbance,and anemia. If none of theseis present, or if fatigue persists despitereversal of potential causes, anin-depth evaluation is indicated, includinga review of systems, reviewof medications, nutritional and metabolicevaluation, and assessment ofactivity level. As with pain and other symptoms, frequent reassessment isessential to evaluate the impact of therapeuticinterventions. These recommendationsrepresent the consensusof a panel of experts but have notbeen evaluated prospectively.Treatment of Cancer-RelatedFatigueNonpharmacologic Approaches
Several randomized controlled trials,recently reviewed by Mock,indicate that exercise is beneficial inthe treatment or prevention of fatiguein cancer patients and cancer survivors.Although the numbers of subjectsin these studies weresmall,[52-135] the impact of exercisewas pronounced, with reduction infatigue typically in the 40% to 50%range. Improvements in overall qualityof life were noted in three out offour studies. Numerous nonrandomizedstudies also suggest that exercisehas beneficial effects on cancer-relatedfatigue.Certain caveats regarding thesedata should be noted. The participantsin these studies were probably highlyselected and motivated, resulting ingood adherence to the exercise programs.The majority of exercise trialsfocused on patients with early-stagecancer, particularly breast cancer, althoughbenefits were also observed inpatients with prostate cancer and othermalignancies. Exercise programsmust be individualized; some typesmay present risks for patients withsevere cytopenias, bone metastases,compromised pulmonary function, orcardiovascular disease. No sham-controlledstudies have been performed(in fact, it is difficult to imagine howthey could be designed). One cannotexclude the possibility that some ofthe reported benefits of exercise representa placebo effect. However, itcan be argued that the distinction betweena placebo effect and a "real"improvement in a subjective symptomsuch as fatigue is meaninglesswhen the intervention has negligiblerisks and cost.Sleep disturbances may be a primecause of fatigue in some patients.Mood disorders, pain, cough, and othersymptoms may disrupt sleep. Evenwhen the duration of sleep is adequateor increased, sleep patterns maybe aberrant, leading to disturbancesin circadian rhythms. Some evidencesuggests that energy conservationstrategies may improve sleep patternsand daytime functioning in patientswith cancer-related fatigue. Theimpact of sedatives in cancer patientssuffering from disordered sleep hasnot been studied.Debilitating fatigue may contributeto the high incidence of depressionin cancer patients. Conversely,in some patients the vegetative symptomsof depression may exacerbatefatigue. The vicious cycle of depressivesymptoms and fatigue has notbeen explored in detail, but, not surprisingly,strong correlations betweenmood states and fatigue have been reportedin numerous studies.[20,22,36-42] In some cases, psychologicaldistress appears to be the single mostpowerful predictor of fatigue.There is evidence that behavioralor psychological interventions mayameliorate fatigue. Supportgroups, individual counseling and education,and psychotherapy have beenreported to reduce cancer-related fatigue. However, studies of theseinterventions have generally beensmall and of limited applicability. Giventhe multiple etiologies of cancerrelatedfatigue, and the cultural andpsychological diversity of those whosuffer from it, no single approach islikely to be helpful in all patients.Pharmacologic Approaches
The Data onErythropoietic Agents
In a meta-analysis of 12 randomizedcontrolled trials involving 1,390patients undergoing cancer treatment,the combined odds ratio for transfusionwith rHuEPO, compared with placeboor no treatment, was 0.38 (95%confidence interval [CI] = 0.28-0.51).The number of patients who would needto be treated with rHuEPO to preventone patient from being transfused was4.4 (95% CI = 3.6-6.1). The higherqualitystudies indicated a less robust,although still statistically significanteffect, with one patient avoiding transfusionfor every five to six patientstreated with rHuEPO. The transfusionsparingeffect of rHuEPO seems to besimilar in patients with hemoglobin levelsless than or greater than 10 g/dL.Despite the findings that some patientstreated with recombinant erythropoietincan avoid transfusion, itremains unclear whether this treatmentis associated with improvementsin symptoms or quality of life. TheAmerican Society of Clinical Oncology(ASCO) and the American Societyof Hematology (ASH) have issuedevidence-based guidelines for the useof rHuEPO in patients with cancer. The guidelines are based ona comprehensive, systematic evidencereport on this topic published byAHRQ. Both the ASH/ASCOguidelines, and the AHRQ evidencereport on which they are based, failedto find convincing evidence for symptomaticimprovements in patientstreated with rHuEPO.Several large, community-basedclinical trials of epoetin, involvingover 7,000 subjects in total, have reportedquality-of-life benefits correlatingwith increases in hemoglobinlevels in patients undergoing chemotherapy.[52-54] However, these studieswere nonrandomized, open-label,single-arm studies, and thus subjectto a placebo effect. There was substantialdropout of patients due todeath, intercurrent illness, progressivedisease, discontinuation of treatmentand other causes. Tumor response wasa confounding factor in these studies,affecting both quality of life and, potentially,hemoglobin levels. Althoughin some cases investigators took intoaccount the impact of tumor response,the interpretation of these studies ishampered by the assumptions thatwere made in their analyses to accountfor nonrandom, missingdata.
Randomized Controlled Trials
The effects of any treatment onsymptoms or quality of life are optimallyassessed in randomized, controlledstudies. At least nine suchstudies of recombinant erythropoietinhave been published; several othersremain unpublished. All but oneof the published randomized controlledtrials were small and reportedvery limited data on quality of life,fatigue, or other symptoms. Their applicabilityis generally quite low.Only one adequately powered,double-blind, randomized, placebocontrolledtrial of the effects ofrHuEPO on fatigue and quality of lifein patients undergoing chemotherapyhas been published. Patients wererandomly assigned to receive placebo(n = 124) or rHuEPO (n = 251) subcutaneouslythree times per week. Patientswere required to have a hemoglobinlevel ≤ 10.5 g/dL, or 10.6 to 12g/dL with a decline of ≥ 1.5 g/dL percycle of chemotherapy. The primaryend point in the trial was the proportionof patients transfused after 4weeks. Quality of life was assessedusing the Functional Assessment ofCancer-Anemia (FACT-An) instrument(which contains a fatigue subscale),the Medical Outcomes ShortForm-36 (SF-36), and a Linear AnalogScale Assessment.Hematologic response to rHuEPO was consistent with the results of priorstudies: The proportion of patientsrequiring transfusion after day 28 wasreduced by 14.8% (
= .0057). Themean increase in hemoglobin frombaseline to final measurement was 2.2g/dL in the rHuEPO arm, and 0.5g/dL in the placebo arm, despite greateruse of transfusion in those receivingplacebo. It should be noted,however, that the change in hemoglobinwas not reported on an intentionto-treat basis.The investigators found a statisticallysignificant difference in the meanchange on the fatigue subscale of theFACT-An, favoring rHuEPO over placebo.Significant advantages forrHuEPO were also observed in scoreson the FACT-G, Linear Analog Scoresfor Energy, Ability to do Daily Activities,and Overall QOL scales. Nonsignificanttrends in quality-of-lifeimprovement favoring rHuEPO wereobserved on the SF-36. This study isfrequently cited as providing the mostrobust evidence for an impact of recombinanterythropoietin on fatigueand quality of life. However, its conclusionsare open to question for anumber of reasons.A higher proportion of patients inthe placebo arm had received transfusionswithin 3 months prior to startingthe study (36% vs 28%),suggesting that they may have hadimpaired hematopoiesis, despite similarmean baseline hemoglobin levelsin the two groups. Baseline data onimportant prognostic factors for qualityof life, such as performance statusand weight loss, were not reported.Hence, one cannot assume that thetwo arms were well balanced for thesefactors. Indeed, no baseline data wasreported on any of the quality-of-lifemeasures used in the study; the resultswere reported only as changesfrom baseline.Transfusions were permitted at thediscretion of the physician but wereto be avoided unless the hemoglobinwas < 8 g/dL. Thus, patients wereallowed to become significantly anemic.More reasonable transfusion supportmay have resulted in improvedquality of life and less fatigue in theplacebo group, and consequently attenuatedthe observed differences between placebo and treatment.In addition, the analysis of symptomsand quality of life was not basedon an intention to treat. Twenty-sixpatients were excluded from this analysisbecause of missing data. FACTAnand SF-36 data were missing foran additional 54 patients because validatedversions of these instrumentswere not available in the languagesthey spoke. The minimum differencesin quality-of-life measures consideredclinically significant were notdefined prospectively. Finally, therewas a trend toward prolonged survivalin the rHuEPO arm (17 vs 11months,
= .13), which the investigatorsspeculated might be attributableto higher hemoglobin levels.However, it is also possible that theprolongation in survival was due toimbalances favoring the rHuEPO armin important, but unreported, prognosticfactors for both survival andquality of life, such as burden of disease,number of prior treatments, responseto chemotherapy, performancestatus, and weight loss.
Cancer-related fatigue is highlyprevalent in every context in which ithas been studied. Virtually all modalitiesof cancer treatment may causefatigue, as do many of the medicationsused to manage cancer symptoms. Cancer patients are also proneto complications that may add to theburden of fatigue, such as infections,malnutrition, sleep disturbance, anemia,and depression. Few studies havefocused on the relative contributionof such factors to cancer-related fatigue.Even in the absence of any identifiablecause, many cancer patientssuffer from fatigue. The pathophysiologyof this syndrome, which mightbe referred to as "primary cancerrelatedfatigue," remains obscure. Primarycancer-related fatigue affects not only those with advanced cancer[6,19,29]; cancer survivors alsohave unexplained, high rates of fatigue,relative to the general population.[11,13,16,20-23,27]The extent to which cancer-relatedfatigue can be ameliorated by identifyingand treating reversible causes,such as depression and anemia, remainsunknown. In the absence ofsuch reversible causes, the evidenceto support any specific intervention islimited, as very few randomized controlledtrials have been performed. Thebest available evidence supports exerciseprograms to treat or preventfatigue, but larger studies involvinga wider array of patients are neededto confirm and expand the role ofexercise for cancer-related fatigue.The NCCN guidelines for cancerrelatedfatigue recommend educationand counseling to help patients developstrategies to cope with refractoryfatigue. Evidence from randomizedcontrolled trials suggests that psychotherapy,behavioral approachessuch as energy conservation, and participationin support groups may behelpful for patients experiencing cancer-related fatigue. However, thestudies that support these interventionsare mostly small, often involveheterogeneous patients populations,and provide incomplete data on patientand disease characteristics. Theoptimal approach for different patientpopulations is therefore unknown.One of the features that distinguishcancer-related fatigue from normalfatigue is its refractoriness to sleepand rest. This may be due to the aberrantsleep patterns that have been observedin cancer patients. Adeeper understanding of sleep pathophysiologyin cancer might lead torational treatment trials to amelioratecancer-related fatigue.
Stimulant medications such as methylphenidateand dextroamphetaminemay be helpful for cancer-related fatiguein some patients, but randomizedcontrolled trials are lacking andadverse effects are a concern. Modafinil,which promotes wakefulness withoutthe typical side effects ofconventional CNS stimulants, is currently under investigation for treatmentof cancer-related fatigue.Cancer-related fatigue and depressionfrequently coexist.[2,36-42] Theirclinical manifestations overlap, andthey may exacerbate one another, suggestinga possible common etiology.However, in patients receiving chemotherapy,treatment with an SSRIantidepressant failed to improve cancer-related fatigue, even when depressionwas ameliorated. Nonetheless,patients with cancer-relatedfatigue should routinely be screenedfor depression, and treated for it ifnecessary.The erythropoiesis-stimulating factors-epoetin alfa and beta, and darbepoetin-increase hemoglobin levelsin anemic cancer patients and havebeen shown in randomized studies tospare some patients (one among everyfive to six treated) the need fortransfusion. As noted in the ASHand ASCO guidelines on this subject,the impact of these drugs on symptomsand quality of life is less compelling. The claims that rHuEPOrelieves fatigue are based on severalnonrandomized, open-label studies,[52-54] and on a single adequatelypowered placebo-controlled,randomized controlled trial. Confirmatorystudies are needed.Emerging data from large randomizedcontrolled trials suggest thatrHuEPO may actually increase mortalityunder some circumstances,[46,47] possibly due to the capacityof erythropoietin to stimulate tumorprogression, angiogenesis, and chemotherapyresistance, as recently reportedin animal models and in vitrostudies.[56,57] Recent clinical studiesalso report increased rates of thromboticevents associated with rHuEPO,[47-49] especially when hemoglobin levelsare targeted to normal or near-normalranges. The FDA recently reviewedthese data, and additional clinical trialsare under way or planned to addressthe issues they raise.
The authors have nosignificant financial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.
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