g

October 1, 2004

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.[1]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).[2]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.[3] 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.[15] Similarly, fatiguerates rose from 8% at baseline to 25%after the completion of radiotherapyin men with localized prostate cancer.[18]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%.[5] 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.[13] 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.[20] Even at a mean of 12years after treatment, 26% of 459Hodgkin's disease survivors werefound to be fatigued.[16] 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.[2] 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.[27]The approach to clinical assessmentof cancer-related fatigue is empiric.The National ComprehensiveCancer Network (NCCN) guidelinesfor assessment and management ofcancer-related fatigue[32] 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,[33]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.[34]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.[35] 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.[33] Supportgroups, individual counseling and education,and psychotherapy have beenreported to reduce cancer-related fatigue.[2] 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

  • Traditional Stimulants-Sincethe pathophysiology of cancer-relatedfatigue remains obscure in manycases, pharmacotherapy is either empiric,or geared toward reversing possiblecontributing factors. Stimulantmedications such as methylphenidateand dextroamphetamine are probablythe most widely prescribed medicinesfor cancer-related fatigue when no reversiblecause is evident. Methylphenidatehas been shown toameliorate fatigue in people withAIDS.[43] In cancer patients, smallcrossover studies suggest a benefit,and larger randomized controlled trialsare ongoing.The adverse effects of these medicinesare a concern, however. Anorexiaand irritability are common, andhypertension, tachycardia, and arrhythmiasmay occur. There is some evidencethat these medications lower theseizure threshold. Methylphenidate inhibitsthe metabolism of warfarin andsome anticonvulsants. Pemoline hascentral nervous system (CNS) effectssimilar to the other stimulants but lackssympathomimetic effects. Its interactionswith other medications have notbeen well studied.
  • Modafinil-Modafinil (Provigil)is a wakefulness-promoting agent thathas been approved for use in narcolepsy.Its mechanism of action is unknown,but it is not a sympathomimeticagent and does not appear toact on dopaminergic pathways in thebrain. The drug lacks the cardiovascularand hemodynamic effects of theconventional psychostimulants. It hasbeen studied in fatigue associated withsleep deprivation and in multiple sclerosis.Randomized controlled trials ofmodafinil for cancer-related fatigueare ongoing.
  • Paroxetine-Based in part on theobservation that cancer-related fatigueand depression frequently coexist, acommon etiology involving synaptic5-hydroxytryptamine levels has beenhypothesized. This hypothesis was thebasis for a randomized controlled trialof the selective serotonin-reuptakeinhibitor (SSRI) antidepressant paroxetinein patients with cancer-relatedfatigue.[44] Subjects reportingfatigue after two cycles of chemotherapywere randomly assigned to20 mg of paroxetine daily (n = 277),or placebo (n = 272). Of note, 32% ofpatients in both arms had significantdepressive symptoms at baseline, andhalf reported fatigue scores ≥ 5 on a10-point scale. As in numerous otherstudies, depression and fatigue correlatedstrongly. After four cycles ofchemotherapy, those receiving paroxetinehad significantly lower meanlevels of depression, but paroxetinehad no impact-either positive or negative-on fatigue. Even in the subgroupof patients who were depressed,there was no improvement in fatiguewith paroxetine.This study was one of a very fewadequately powered, rigorously designeddrug trials for cancer-relatedfatigue. The findings strongly supportscreening and treating cancer patientsfor depression, but the impactof this treatment on fatigue was disappointing.It is possible that the acutefatigue induced by chemotherapy isso overwhelming that it is not amenableto such an approach. Antidepressantsmight have a greater effect onfatigue in cancer survivors, in whomfatigue and depression are prevalentand frequently coexist.
  • Miscellaneous Drugs-Otheragents currently being investigated fortreatment of cancer-related fatigue includeL-carnitine and infliximab(Remicade).
  • Erythropoiesis-StimulatingAgents-There is little doubt that recombinanthuman erythropoietin(rHuEPO, epoetin alfa [Epogen, Procrit]and epoetin beta) and the relatedcompound darbepoetin (Aranesp)stimulate erythropoiesis and reducethe likelihood of red blood cell transfusionin cancer patients undergoingchemotherapy.[45] The impact ofthese treatments on quality of life andsymptoms (including cancer-relatedfatigue) is less well established. A trendtoward increased survival with recombinanterythropoietin has been reportedin some studies; however, severalrecent reports have raised concernsabout increased thrombotic events, acceleratedtumor growth, and decrementsin survival in cancer patients treatedwith such agents.[46-49]

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.[45]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.[50] The guidelines are based ona comprehensive, systematic evidencereport on this topic published byAHRQ.[51] 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.[51]

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[51]; 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.[55] 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% (

P

= .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,

P

= .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.

  • Question of Increased Mortality-Concerns about the use of erythropoieticagents in cancer patientshave been heightened by recent reportsof two randomized, doubleblind,placebo-controlled trials inwhich subjects receiving recombinanterythropoietin had statistically significantdecrements in survival.Henke et al[46] randomized 351anemic head and neck cancer patientsundergoing radiation therapy to epoetinor placebo. Those treated withrHuEPO had a much higher hematologicresponse rate (82% vs 15%).However, in an intention-to-treat analysistaking into account other knownprognostic factors, locoregional progression-free survival was poorer withrHuEPO (relative risk [RR] = 1.62;95% CI = 1.22-2.14; P = .0008). Overallsurvival was also worse (RR =1.39; 95% CI = 1.5-1.84; P = .02).There were no obvious study designissues that could have accounted forthese findings.In a second randomized, doubleblindstudy,[47] 939 nonanemic patientswith metastatic breast cancerwere assigned to recombinant erythropoietinor placebo in order to preventanemia. The trial was designedto assess the effects of 12 months ofrHuEPO treatment on survival. It wasterminated early, at the recommendationof an independent data monitoringcommittee, due to a highermortality rate in the rHuEPO arm.The 12-month survival rate was 76%in the placebo arm and 70% in theerythropoietin arm (P = .0117), mainlyas a result of increased mortality inthe first 4 months (41 deaths in therHuEPO group and 16 in the placebogroup). Most of the deaths were dueto disease progression or thromboticevents. The investigators could notexclude the possibility that the survivaldifference was due to imbalancesbetween the treatment groups,rather than to the treatment itself, althougha multivariate analysis incorporatingavailable prognostic factorsreached results similar to the univariateanalysis.The basis for increased mortalityin patients treated with recombinanterythropoietin in these studies is unclear.The studies have been analyzedby their industry sponsors and by theUS Food and Drug Administration(FDA) to determine if factors otherthan rHuEPO treatment could havecontributed to the observed outcomes.At present, no firm conclusions canbe drawn.The outcomes of these clinicalstudies have also refocused attentionon the complex and pleiotropic biologiceffects of erythropoietin. Theerythropoietin receptor is widely expressed-in the central nervous system,the gastrointestinal tract, onvascular endothelium, and elsewhere.[56] Expression of the erythropoietinreceptor has also been foundin many tumor types, including 80%of the head and neck tumors from thestudy by Henke.[46,56]Although the clinical significanceof these findings is unknown, erythropoietinhas been found to acceleratethe proliferation of some cancercells in vitro, to render them resistantto chemotherapy, and to promote angiogenesis.[56] In vivo animal studiesalso support the hypothesis thaterythropoietin is a growth factor forsome types of tumors.[57]
  • Thrombosis Risk-As with thebreast cancer study cited above,[47]an increase in the risk of venousthrombosis with rHuEPO was suggestedby a retrospective, case-controlstudy of women with cervical orvaginal cancer.[48] The rate of symptomaticthrombosis in those receivingrHuEPO was 22.6% (17 events in 75patients), compared with 2.8% (2/72)in those not receiving the drug , eventhough the groups were similar interms of other known risks for thrombosis.In multivariate analysis, theodds ratio for thrombosis with rHuEPOwas 15.3 (95% CI = 3.1-76.7).Recently, a randomized trial of recombinanterythropoietin to reducefatigue in patients with metastaticbreast cancer and mild anemia wasterminated after 4 out of 14 patientstreated with the agent developedthrombotic events.[49] None of the13 patients in the control arm had athrombotic event.Among 15 other randomized controlledtrials of rHuEPO included inthe AHRQ evidence report,[51] only6 reported rates of thrombotic events.The total number of subjects in thesestudies was 580; 4.7% of those treatedwith rHuEPO and 2.5% of controlshad deep-vein thromboses or thromboembolism(P = .41). Thus, the numberof cancer patients in whom therisk of thrombosis has been assessedmay not be large enough to exclude asmall but significant increased riskassociated with rHuEPO, especiallyin cancer patients otherwise predisposedto thrombotic events.Due to the concerns raised by thesestudies, several other ongoing clinicaltrials of epoetin were terminatedearly. A common factor in the studiesin which increased adverse events orexcess mortality were reported wasthe targeting of hemoglobin to higherlevels than recommended in the prescribinginformation for these drugs.Rapid increases in hemoglobin levels may also be associated with excesscardiovascular and thrombotic complications.
  • Data Reconsidered-The possibilitythat recombinant erythropoietinhas an adverse effect on survival undersome circumstances, and the dataon thrombotic risks, were reviewedon May 4, 2004, by an OncologicDrugs Advisory Committee of theFDA's Center for Drug Evaluationand Research. Extensive unpublisheddata and analyses were presented inan FDA briefing document, and byindustry representatives. Interestedreaders are referred to the briefingdocument and transcript of the meeting,available on the Internet(www.fda.gov/ohrms/dockets/ac/04/briefing/4037B2_04_Aranesp-Procrit.doc, and www.fda.gov/ohrms/d o c k e t s / a c / 0 4 / t r a n s c r i p t s /4037T2.htm).Aside from these concerns, rHu-EPO appears to be generally well tolerated,with a low incidence of seriousadverse events. Pure red cellaplasia due to anti-erythropoietin antibodieshas been reported in morethan 200 patients, most of whom weretreated with epoetin alfa.[58] Althoughrare, this syndrome should beconsidered when a patient treated witherythropoietin develops worseninganemia.

Discussion

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.[2] 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,[33] 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.[32] Evidence from randomizedcontrolled trials suggests that psychotherapy,behavioral approachessuch as energy conservation, and participationin support groups may behelpful for patients experiencing cancer-related fatigue.[2] 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.[34] Adeeper understanding of sleep pathophysiologyin cancer might lead torational treatment trials to amelioratecancer-related fatigue.

Drug Therapy


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.[44] 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.[45] As noted in the ASHand ASCO guidelines on this subject,the impact of these drugs on symptomsand quality of life is less compelling.[32] The claims that rHuEPOrelieves fatigue are based on severalnonrandomized, open-label studies,[52-54] and on a single adequatelypowered placebo-controlled,randomized controlled trial.[55] 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.

Disclosures:

The authors have nosignificant financial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

References:

1.

Richardson A: Fatigue in cancer patients:A review of the literature. Eur J Cancer Care4(1):20-32, 1995.

2.

Carr D, Goudas L, Lawrence DP, et al:Management of Cancer Symptoms: Pain, Depression,and Fatigue. Evidence Report/TechnologyAssessment No. 61. AHRQ PublicationNo. 02-E032. Rockville, Md; Agency forHealthcare Research and Quality; July 2002.

3.

Lawrence DP, Kupelnick B, Miller K, etal: Evidence report on the occurrence, assessment,and treatment of fatigue in cancer patients.J Natl Cancer Inst Monogr 32:40-50,2004.

4.

King KB, Nail LM, Kreamer K, et al:Patients' descriptions of the experience of receivingradiation therapy. Oncol Nurs Forum12(4):55-61, 1985.

5.

Hurny C, Bernhard J, Joss R, et al: "Fatigueand malaise" as a quality-of-life indicatorin small-cell lung cancer patients. The SwissGroup for Clinical Cancer Research (SAKK).Support Care Cancer 1:316-320, 1993.

6.

Donnelly S, Walsh D, Rybicki L: Thesymptoms of advanced cancer: Identificationof clinical and research priorities by assessmentof prevalence and severity. J Palliat Care 11:27-32, 1995.

7.

Hickok JT, Morrow GR, McDonald S, etal: Frequency and correlates of fatigue in lungcancer patients receiving radiation therapy:Implications for management. J Pain SymptomManage 11:370-377, 1996.

8.

Longman AJ, Braden CJ, Mishel MH:Side effects burden in women with breast cancer.Cancer Pract 4:274-280, 1996.

9.

Richardson A, Ream EK: Self-carebehaviours initiated by chemotherapy patientsin response to fatigue. Int J Nurs Stud 34:35-43, 1997.

10.

Sarna L, Brecht ML: Dimensions ofsymptom distress in women with advanced lungcancer: A factor analysis. Heart Lung 26:23-30, 1997.

11.

Vogelzang NJ, Breitbart W, Cella D, etal: Patient, caregiver, and oncologist perceptionsof cancer-related fatigue: Results of atripart assessment survey. The Fatigue Coalition.Semin Hematol 34(3 suppl 2):4-12, 1997.

12.

Smets EM, Visser MR, Willems-GrootAF, et al: Fatigue and radiotherapy: (A) Experiencein patients undergoing treatment. Br JCancer 78: 899-906, 1998.

13.

Smets EM, Visser MR, Willems-GrootAF, et al: Fatigue and radiotherapy: (B) Experiencein patients 9 months following treatment.Br J Cancer 78:907-912, 1998.

14.

Gaston-Johansson F, Fall-Dickson JM,Bakos AB, et al: Fatigue, pain, and depressionin pre-autotransplant breast cancer patients.Cancer Pract 7:240-247, 1999.

15.

Jacobsen PB, Hann DM, Azzarello LM,et al: Fatigue in women receiving adjuvant chemotherapyfor breast cancer: Characteristics,course, and correlates. J Pain Symptom Manage18:233-242, 1999.

16.

Loge JH, Abrahamsen AF, Ekeberg O,et al: Hodgkin's disease survivors more fatiguedthan the general population. J Clin Oncol17:253-261, 1999.

17.

Miaskowski C, Lee KA: Pain, fatigue,and sleep disturbances in oncology outpatientsreceiving radiation therapy for bone metastasis:A pilot study. J Pain Symptom Manage17:320-332, 1999.

18.

Monga U, Kerrigan AJ, Thornby J, et al:Prospective study of fatigue in localized prostatecancer patients undergoing radiotherapy.Radiat Oncol Investig 7:178-185, 1999.

19.

Stone P, Hardy J, Broadley K, et al: Fatiguein advanced cancer: A prospective controlledcross-sectional study. Br J Cancer79:1479-1486, 1999.

20.

Bower JE, Ganz PA, Desmond KA, etal: Fatigue in breast cancer survivors: Occurrence,correlates, and impact on quality of life.J Clin Oncol 18:743-753, 2000.

21.

Curt GA, Breitbart W, Cella D, et al:Impact of cancer-related fatigue on the lives ofpatients: New findings from the Fatigue Coalition.Oncologist 5:353-360, 2000.

22.

Okuyama T, Akechi T, Kugaya A, et al:Factors correlated with fatigue in disease-freebreast cancer patients: Application of the CancerFatigue Scale. Support Care Cancer 8:215-222, 2000.

23.

Servaes P, van der Werf S, Prins J, et al:Fatigue in disease-free cancer patients comparedwith fatigue in patients with chronic fatiguesyndrome. Support Care Cancer 9:11-17,2001.

24.

Stone P, Hardy J, Huddart R, et al: Fatiguein patients with prostate cancer receivinghormone therapy. Eur J Cancer 36:1134-1141,2000.

25.

Stone P, Richards M, A’Hern R, et al:A study to investigate the prevalence, severityand correlates of fatigue among patients withcancer in comparison with a control group ofvolunteers without cancer. Ann Oncol 11:561-567, 2000.

26.

Stone P, Richardson A, Ream E, et al:Cancer-related fatigue: Inevitable, unimportantand untreatable? Results of a multi-centre patientsurvey. Ann Oncol 11:971-975, 2000.

27.

Cella D, Davis K, Breitbart W, et al:Cancer-related fatigue: Prevalence of proposeddiagnostic criteria in a United States sample ofcancer survivors. J Clin Oncol 19:3385-3391,2001.

28.

Given CW, Given B, Azzouz F, et al:Predictors of pain and fatigue in the year followingdiagnosis among elderly cancer patients.J Pain Symptom Manage 21:456-4662001.

29.

Okuyama T, Tanaka K, Akechi T, et al:Fatigue in ambulatory patients with advancedlung cancer: Prevalence, correlated factors, andscreening. J Pain Symptom Manage 22:554-564, 2001.

30.

Wang XS, Janjan NA, Guo H, et al: Fatigueduring preoperative chemoradiation forresectable rectal cancer. Cancer 92(6suppl):1725-1732, 2001.

31.

Nail LM: My get up and go got up andwent: Fatigue in people with cancer. J NatlCancer Inst Monogr 32:72-75, 2004.

32.

Mock V, Atkinson A, Barsevick A, et al:NCCN Practice Guidelines for Cancer-RelatedFatigue. Oncology 14(11A):151-161, 2000.

33.

Mock V: Evidence-based treatment forcancer-related fatigue. J Natl Cancer InstMonogr 32:112-118, 2004.

34.

Berger AM, Farr L: The influence ofdaytime inactivity and nighttime restlessnesson cancer-related fatigue. Oncol Nurs Forum26:1663-1671, 1999.

35.

Barsevick AM, Whitmer K, Sweeney C,et al: A randomized clinical trial of energy conservationfor cancer-related fatigue. Cancer100:1302-1310, 2004.

36.

Broeckel JA, Jacobsen PB, Horton J, etal: Characteristics and correlates of fatigue afteradjuvant chemotherapy for breast cancer. JClin Oncol 16:1689-1696, 1998.

37.

Redeker NS, Lev EL, Ruggiero J: Insomnia,fatigue, anxiety, depression, and qualityof life of cancer patients undergoing chemotherapy.Sch Inq Nurs Pract 14:275-290,2000.

38.

Irvine D, Vincent L, Graydon JE, et al:The prevalence and correlates of fatigue in patientsreceiving treatment with chemotherapyand radiotherapy. A comparison with the fatigueexperienced by healthy individuals. CancerNurs 17:367-378, 1994.

39.

Akechi T, Kugaya A, Okamura H, et al:Fatigue and its associated factors in ambulatorycancer patients: a preliminary study. J PainSymptom Manage 17:42-48, 1999.

40.

Hann DM, Garovoy N, Finkelstein B, etal: Fatigue and quality of life in breast cancerpatients undergoing autologous stem cell transplantation:A longitudinal comparative study.J Pain Symptom Manage 17:311-319, 1999.

41.

Loge JH, Abrahamsen AF, Ekeberg O,et al: Fatigue and psychiatric morbidity amongHodgkin’s disease survivors. J Pain SymptomManage 19:91-99, 2000.

42.

Bruera E, Brenneis C, Michaud M, etal: Association between asthenia and nutritionalstatus, lean body mass, anemia, psychologicalstatus, and tumor mass in patients with advancedbreast cancer. J Pain Symptom Manage4:59-63, 1989.

43.

Breitbart W, Rosenfeld B, Kaim M, etal: A randomized, double-blind, placebo-controlledtrial of psychostimulants for the treatmentof fatigue in ambulatory patients withhuman immunodeficiency virus disease. ArchIntern Med 161:411-420, 2001.

44.

Morrow GR, Hickok JT, Roscoe JA, etal: Differential effects of paroxetine on fatigueand depression: A randomized, double-blindtrial from the University of Rochester CancerCenter Community Clinical Oncology Program.J Clin Oncol 21:4635-4641, 2003.

45.

Seidenfeld J, Piper M, Flamm C, et al:Epoetin treatment of anemia associated withcancer therapy: A systematic review and metaanalysisof controlled clinical trials. J NatlCancer Inst 93:1204-1214, 2001.

46.

Henke M, Laszig R, Rube C, et al: Erythropoietinto treat head and neck cancer patientswith anemia undergoing radiotherapy: Randomized,double-blind, placebo-controlledtrial. Lancet 362:1255-1260, 2003.

47.

Leyland-Jones B: Breast cancer trial witherythropoietin terminated unexpectedly. LancetOncol 4:459-460, 2003.

48.

Wun T, Law L, Harvey D, et al: Increasedincidence of symptomatic venous thrombosisin patients with cervical carcinoma treated withconcurrent chemotherapy, radiation, and erythropoietin.Cancer 98:1514-1520, 2003.

49.

Rosenzweig MQ, Bender CM, Lucke JP,et al: The decision to prematurely terminate atrial of R-HuEPO due to thrombotic events. JPain Symptom Manage 27:185-190, 2004.

50.

Rizzo JD, Lichtin AE, Woolf SH, et al:Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of theAmerican Society of Clinical Oncology and theAmerican Society of Hematology. J Clin Oncol20:4083-5107, 2002.

51.

Seidenfeld J, Aronson N, Piper MA, etal: Use of Epoetin for Anemia in Oncology.Evidence Report/Technology Assessment No.30. AHRQ Publication No. 01-E009. Rockville,Md; Agency for Healthcare Research and Quality;June 2001.

52.

Demetri GD, Kris M, Wade J, et al: Quality-of-life benefit in chemotherapy patientstreated with epoetin alfa is independent of diseaseresponse or tumor type: Results from aprospective community oncology study. ProcritStudy Group. J Clin Oncol 16:3412-3425,1998.

53.

Glaspy J, Bukowski R, Steinberg D, etal: Impact of therapy with epoetin alfa on clinicaloutcomes in patients with nonmyeloid malignanciesduring cancer chemotherapy in communityoncology practice. Procrit Study Group.J Clin Oncol 15:1218-1234, 1997.

54.

Gabrilove JL, Cleeland CS, LivingstonRB, et al: Clinical evaluation of once-weeklydosing of epoetin alfa in chemotherapy patients:Improvements in hemoglobin and qualityof life are similar to three-times-weeklydosing. J Clin Oncol 19:2875-2882, 2001.

55.

Littlewood TJ, Bajetta E, Nortier JW, etal: Effects of epoetin alfa on hematologic parametersand quality of life in cancer patientsreceiving nonplatinum chemotherapy: Resultsof a randomized, double-blind, placebo-controlledtrial. J Clin Oncol 19:2865-2874, 2001.

56.

Brower V: Epoetin for cancer patients:A boon or a danger? J Natl Cancer Inst95:1820-1821, 2003.

57.

Yasuda Y, Fujita Y, Matsuo T, et al: Erythropoietinregulates tumor growth of humanmalignancies. Carcinogenesis 24:1021-1029,2003.

58.

Verhelst D, Rossert J, Casadevall N, etal: Treatment of erythropoietin-induced purered cell aplasia: a retrospective study. Lancet363:1768-1771, 2004.