The Management of Fatigue in Cancer Patients

October 1, 2004

Fatigue, the most common symptomreported by people withcancer, is associated with functionalimpairments and decrements inquality of life. As Drs. Lipman andLawrence have pointed out, researchon the etiology of cancer-related fatigueis scant. Morrow et al[1] conducteda detailed review of theevidence to support four hypothesesfor cancer-related fatigue and highlightedindependent findings that implicatecytokines, 5-HT, and thehypothalamic-pituitary axis in the developmentof cancer-related fatigue.Additional research is needed in thisarea to articulate the pathophysiologyof fatigue and the associated clinicalimplications.

Fatigue, the most common symptomreported by people withcancer, is associated with functionalimpairments and decrements inquality of life. As Drs. Lipman andLawrence have pointed out, researchon the etiology of cancer-related fatigueis scant. Morrow et al[1] conducteda detailed review of theevidence to support four hypothesesfor cancer-related fatigue and highlightedindependent findings that implicatecytokines, 5-HT, and thehypothalamic-pituitary axis in the developmentof cancer-related fatigue.Additional research is needed in thisarea to articulate the pathophysiologyof fatigue and the associated clinicalimplications.Assessment ofCancer-Related Fatigue
A comprehensive assessment of patientswith cancer-related fatigue is required given the multifactorial natureof the etiology and manifestationof fatigue. Because of the subjectivenature of fatigue, it is important touse standardized instruments that havebeen validated in oncology samples.For a review of instruments availableto assess cancer-related fatigue, seeWagner and Cella.[2]Drs. Lipman and Lawrence believethat while most instruments being usedto assess fatigue within the context ofresearch are psychometrically validand reliable, their clinical significanceremains obscure. We disagree withthat evaluation and highlight threepublications on the clinical significanceof fatigue scores obtained fromtwo standardized questionnaires: theFunctional Assessment of ChronicIllness Therapy-Fatigue subscale(FACIT-F) and the Brief Fatigue Inventory(BFI).Clinical Significanceof Fatigue Scores
Cella et al[3] examined FACIT-Fdata from three samples: anemic cancerpatients (n = 2,369), nonanemiccancer patients (n = 113), and thegeneral US population (n = 1,010).Each sample demonstrated a distinctdistribution of FACIT-F scores. Basedon a discriminant analysis approach,the investigators were able to distinguishbetween cancer patients withanemia, cancer patients without anemia,and respondents from the generalUS population with high sensitivityand reasonable specificity. These findingsalso indicated that cancer-relatedfatigue appears to be significantlymore disruptive to daily functioningthan everyday fatigue.The following example illustratesthe clinical applicability of these results.A patient who obtains a rawscore of 22 on the 13-item FACIT-Fhas performed just below the meanfor anemic cancer patients and hasmore fatigue than 95% of the general population. Mendoza et al[4] examinedfatigue severity ratings on the BFIin relationship to the extent to whichfatigue interfered with functional domains.Based on these results, the authorsrecommended using a cut-off of≥ 7 to differentiate severe from nonseverecases of fatigue.Clinically significant changes onthe FACIT-F have been establishedin a series of coordinated researchprojects. Cella et al[5] examined datafrom three oncology samples (n = 50,131, and 2,402 patients). Usinganchor- and distribution-basedmethods, minimally clinically importantdifferences were calculatedfor the FACIT-F subscale (3.0 points),the Trial Outcome Index-Fatigue(5.0 points), and the FunctionalAssessment of Cancer Therapy-General (4.0 points). One can comfortablyconclude that when comparedto usual care, an interventionthat increases FACIT-F scores by 3or more points overall can be consideredto have yielded a meaningfultherapeutic effect.Diagnostic Criteria forCancer-Related FatigueM
Drs. Lipman and Lawrence correctlypoint out that diagnostic criteriafor cancer-related fatigue set forthby the Fatigue Coalition have not beenwidely adopted. Given the problemsthe authors cite as impeding researchprogress on cancer-related fatigue,such as variability in the definitionsof fatigue and the grading of fatigueseverity, we advocate the use of thesediagnostic criteria. The use of diagnosticcriteria would standardize thecase definition for cancer-related fatigue,thus standardizing eligibilitycriteria for research and developing acommon language for understandingthe phenomenology of fatigue in cancerpatients.We recently reviewed nonpharmacologicand pharmacologic interventions for cancer-related fatigue,[6]with priority given to the most methodologicallysound clinical trials. Fewrandomized clinical trials for the treatmentof cancer-related fatigue havebeen conducted; however, research todate has identified a few potentiallyefficacious management approaches.Nonpharmacologic Interventions
Among nonpharmacologic interventionsfor cancer-related fatigue, theeffectiveness of exercise in reducingfatigue and functional impairmentshas received the most empirical support.Drs. Lipman and Lawrence pointout the pronounced impact of exerciseon fatigue severity and functionalabilities. Effect sizes from recentstudies range from 0.31 for a resistancetraining program among prostatecancer patients receivingandrogen ablation therapy[7] to 0.72for exercise group training (cycle ergometers)among postmenopausalbreast cancer survivors.[8] Despite themethodologic limitations, the availabilityof empirical support for exercise insamples of patients with breast canceras well as other cancer types suggeststhat tailored exercise programs, includinghome-based exercise programs,hold promise as a first-line treatmentfor the prevention or management ofcancer-related fatigue.Seven randomized clinical trialshave supported the efficacy of psychosocialinterventions for the managementof cancer-related fatigue.[6]The type of intervention evaluated andthe mode of delivery (individual orgroup) has varied. Findings publishedby Jacobsen et al[9] on the efficacy ofa stress management training programare particularly noteworthy given thesample size (N = 411), the randomassignment of participants to treatment,and the potential ease of implementingtheir intervention in a clinicalsetting. Jacobsen et al[9] examined asample of mixed cancer patients undergoingchemotherapy and reportedincreased vitality and mental healthamong patients who participated inthe stress management training program.Participants who completed theself-administered stress managementtraining (via audio- and videocassette) also experienced therapeutic benefit.The home-based nature of this interventionfacilitates its ease of implementationin busy clinical settings withlimited access to mental health serviceproviders.Pharmacologic Interventions
Research on pharmacologic approachesto the management of cancer-related fatigue is limited, as fewstudies have been published and manyhave methodological shortcomings.Classes of potentially useful medicationsinclude erythropoietic agents(when anemia is present), psychostimulants,selective serotonin-reuptakeinhibitors, and low-dose corticosteroids.For cancer-related fatigue notattributable to an underlying causativefactor, psychostimulants have receivedthe most empirical support.[6]Erythropoietic Agents:Impact on Fatigue andQuality of Life
As Drs. Lipman and Lawrencehave stated, the efficacy of erythropoieticagents to stimulate erythropoiesisand increase hemoglobin,reducing the likelihood of red bloodcell transfusion, has been clearly established.The authors assert that theassociation between treatment of anemiawith erythropoietic agents andquality of life, including symptomburden, is unclear. This contentionignores supportive data from manyrecent randomized trials.[10-15]While the Agency for HealthcareResearch and Quality technology reportwritten by Blue Cross/Blue Shieldquestioned the handling of missingdata and unclear clinical significanceof differences, several new studies andclarifying analyses of the Littlewoodtrial[11] have addressed the concernsraised in the report. As a result, theprincipal author of that report has acknowledgedLevel 1 evidence in supportof a quality-of-life benefit toepoetin alfa treatment of chemotherapy-receiving patients who begin withhemoglobin levels below 10 g/dL.Drs. Lipman and Lawrence focusedon findings presented in Littlewoodet al,[14] which included results froma univariate linear regression analysis of quality-of-life data. Further resultsfrom an a priori analysis of qualityof-life and fatigue data from the Littlewoodet al[14] trial addressed themethodologic issues raised by Drs.Lipman and Lawrence and by the authorsof the now-outdated technologyevaluation report.Fallowfield and colleagues[11] presentedbaseline quality-of-life data,carefully articulated missing data issues,and conducted a multiple linearregression analysis to control for theeffects of disease progression andmany other potentially confoundingvariables (eg, age, sex, baseline hemoglobin)on quality of life and symptomburden. Findings provided solidevidence that increasing hemoglobinlevels through epoetin alfa administrationsignificantly improved cancerpatients' quality of life and reducedfatigue.These results appear to be equallyapplicable to darbepoetin alfa treatment,as summarized in a recentpooled analysis of five randomizedclinical trials.[10] Clinically meaningfuladjusted mean differences inFACT-Fatigue scores were observedbetween hemoglobin responders andnonresponders. Across all five trials,hemoglobin response was associatedwith reductions in fatigue, which wasassociated with improved physical,functional, emotional, and overallwell-being.Safety Issues
Given the Oncologic Drugs AdvisoryCommittee meeting in May 2004on the safety of erythropoietic agents,Drs. Lipman and Lawrence provideda timely review of safety issues toconsider-namely, the risk of thromboticevents-when administeringerythropoietic therapy. While methodologicshortcomings limit conclusionsthat can be drawn from theclinical trials that initiated these concerns,these safety concerns warrantfurther investigation. Drs. Lipman andLawrence identified pure red cell aplasiaas a potential adverse event oferythropoietic treatment. A recent reportsuggests that there have been nopublished reports of epoetin-associated pure red cell aplasia in patientswith cancer, perhaps due to chemotherapy-associated immunosuppression.[16]Conclusions
Cancer-related fatigue is a prevalentand clinically significant issueamong oncology patients. We appreciatethe excellent review of treatmentstrategies written by Drs. Lipmanand Lawrence and highlight empiricalsupport that exists for nonpharmacologicinterventions, namely exercise andpsychosocial interventions. Updatedevidence supports a role for erythropoieticagents in relieving fatigue associatedwith anemia. Recently identifiedrisks of erythropoietic therapy warrantfurther investigation.

Disclosures:

Dr. Wagner has receivedresearch support and served on thespeakers' bureau for Ortho Biotech, and actedas a consultant for Amgen, Inc. Dr. Cella hasacted as a consultant for and received grantsupport from Ortho Biotech and Amgen, Inc.

References:

1.

Morrow GR, Andrews PLR, Hickok J, etal: Fatigue associated with cancer and its treatment.Support Care Cancer 10:389-398, 2002.

2.

Wagner LI, Cella D: Cancer-related fatigue:Clinical screening, assessment, and management,in Marty M, Pecorelli S (eds): ESOScientific Updates: Fatigue, Asthenia, Exhaustionand Cancer, 5th ed, pp 201-214. Oxford,England, Elsevier Science, 2001.

3.

Cella D, Lai JS, Chang CH, et al: Fatiguein cancer patients compared with fatigue in thegeneral United States population. Cancer94:528-538, 2002.

4.

Mendoza TR, Wang XS, Cleeland CS, etal: The rapid assessment of fatigue severity incancer patients: Use of the Brief Fatigue Inventory.Cancer 85:1186-1196, 1998.

5.

Cella D, Eton DT, Lai JS, et al: Combininganchor and distribution-based methods toderive minimal clinically important differenceson the Functional Assessment of CancerTherapy (FACT) Anemia and Fatigue scales. JPain Symptom Manage 24:547-561, 2002.

6.

Wagner LI, Cella D: Fatigue and cancer:Causes, prevalence and treatment approaches.Br J Cancer 91:822-828, 2004.

7.

Segal RJ, Reid RD, Courneya KS, et al:Resistance exercise in men receiving androgendeprivation therapy for prostate cancer. J ClinOncol 21:1653-1659, 2003.

8.

Courneya KS, Mackey JR, Bell GJ, et al:Randomized controlled trial of exercise trainingin postmenopausal breast cancer survivors:Cardiopulmonary and quality of life outcomes.J Clin Oncol 21:1660-1668, 2003.

9.

Jacobsen PB, Meade CD, Stein KD, et al:Efficacy and costs of two forms of stress managementtraining for cancer patients undergoingchemotherapy. J Clin Oncol 20:2851-2862,2002.

10.

Cella D, Kallich J, McDermott A, et al:The longitudinal relationship of hemoglobin,fatigue and quality of life in anemic cancerpatients: Results from five randomized clinicaltrials. Ann Oncol 15:979-986, 2004.

11.

Fallowfield L, Gagnon D, Zagari M, etal: Multivariate regression analyses of datafrom a randomized, double-blind, placebo-controlledstudy confirm quality of life benefit ofepoetin alfa in patients receiving non-platinumchemotherapy. Br J Cancer 87:1341-1353,2002.

12.

Fairclough DL, Gagnon DD, Zagari MJ,et al: Evaluation of quality of life in a clinicaltrial with nonrandom dropout: The effect ofepoetin alfa in anemic cancer patients. QualLife Res 12:1013-1027, 2003.

13.

Glaspy JA, Jadeja JS, Justice G, et al: Arandomized, active-control, pilot trial of frontloadeddosing regimens of darbepoetin-alfa forthe treatment of patients with anemia duringchemotherapy for malignant disease. Cancer97:1312-1320, 2003.

14.

Littlewood T, Bajetta E, Nortier JWR,et al: Effects of epoetin alfa on hematologicparameters and quality of life in cancer patientsreceiving nonplatinum chemotherapy: Resultsof a randomized, double-blind placebo-controlledtrial. J Clin Oncol 19:2865-2874, 2001.

15.

Littlewood TJ, Nortier J, Rapoport B, etal: Epoetin alfa corrects anemia and improvesquality of life in patients with hematologicmalignancies receiving non-platinum chemotherapy.Hematol Oncol 21:169-180, 2003.

16.

Bennett CL, Luminari S, Nissenson AR,et al: Pure red-cell aplasia and epoetin therapy.N Engl J Med 351:1403-1408, 2004.