Anemia, common in people with cancer, can be due to the disease itself or to the associated therapy. Fatigue, the most prevalent of all symptoms experienced by cancer patients, is the primary symptom of anemia. Caused by many factors, fatigue, regardless of etiology, has an adverse impact on health-related quality of life.
ABSTRACT: Anemia, common in people with cancer, can be due to the disease itself or to the associated therapy. Fatigue, the most prevalent of all symptoms experienced by cancer patients, is the primary symptom of anemia. Caused by many factors, fatigue, regardless of etiology, has an adverse impact on health-related quality of life. Anemia is among the more treatable of those causes. Prior to the development of recombinant human erythropoietin, red blood cell transfusion was the standard treatment for cancer-related anemia. Erythropoietic agents are an effective alternative to blood transfusion: they improve hematocrit, reduce transfusion dependency, and eliminate transfusion-related risks. Although studies are mixed, most clinical trials have also suggested that erythropoietic agents have a positive impact upon cancer patients’ quality of life. However, the cost of drug supply is quite high in the oncology setting, where much higher doses are required relative to the nephrology setting. Thus, although few challenge the treatment’s effectiveness, cost-effectiveness remains an open question. The data collected over the years to address these questions have helped define and clarify the relationship between anemia and health-related quality of life in people with cancer. That relationship is summarized in this article. [ONCOLOGY 16(Suppl 10):125-132, 2002]
Anemia, typicallycharacterizedby hemoglobin levels below12 g/dL, is a common occurrence in oncology practice, particularly in patientsreceiving myelosuppressive chemotherapy. Mild to moderate anemia, withhemoglobin levels between 8 and 12 g/dL, results in symptoms of fatigue, lethargy, dizziness, headache, anddifficulty breathing and rapid or irregular heartbeat after exercise. Moresevere anemia, when hemoglobin levels are below 8 g/dL, results in markedlyreduced exercise capacity, difficulty breathing at rest, rapid or irregularheartbeat at rest, and an increased risk of angina pectoris, myocardialinfarction, or transient ischemic events.[1-3] Anemia can adversely affect theschedule and tolerability of cancer therapy, which may in turn influence theefficacy of the treatment.
Anemia has been shown to have an adverse impact onhealth-related quality of life (QOL).[2-7] Fatigue is the principal symptom ofanemia, but other associated symptoms (eg, headache, depression, cognitiveimpairment) adversely affect patients’ quality of life as well.[3,6]Health-related quality of life is reduced through compromised functional ability(reduced exercise tolerance, ability to work, social interaction, pursuit ofleisure activities) and decline in subjective sense of well-being. Even mildanemia (10-12 g/dL) can substantially impair quality of life.[2,3,5,7,9-12] Inone study of patients with hemoglobin levels below 12 g/dL, 25% were not able towork at all, compared with 8% of patients with hemoglobin levels above 12
g/dL.[2,3] In addition, cancer-related anemia may compromise patients’tolerance of treatments, resulting in the need to reduce duration orintensity.[13,14] Anemia has also been associated with reduced local tumorcontrol and decreased survival.[1,6,9]
Fatigue is highly prevalent in cancer patients, and isassociated with impairments in physical, functional, and emotional well-beingand quality of life.[2-8,15] A number of studies have demonstrated significantassociations between anemia, fatigue, and quality of life in cancerpatients.[5,7,9,10,16]
Figure 1 presents a model depicting the potential impact ofanemia on quality of life. According to the model, anemia directly causesfatigue, which in turn mediates a cascade of other potential problems. Fatiguecan be defined as decreased capacity for work and reduced energy reserve,leading to less activity, lower productivity, cognitive difficulties, and adecline in the ability to function normally in daily activities. These factorsthen often combine to compromise one’s social relationships and social role,due to a lack of interest and energy. If fatigue becomes chronic, self-esteemmay suffer as people are unable to fully participate in the regular activitiesand relationships that provide a sense of accomplishment andfulfillment.[5,17,18] Ultimately, some patients with chronic, unremittingfatigue may be at risk for withdrawal from daily life and major depression.
Fatigue, like anemia, is complex and has a host ofinteractive etiologic factors, including anemia, mood disturbance, anorexia/cachexia,infection, pain, sleep disturbance, tumor burden, and prolongedstress.[13,18-20] In addition to negatively affecting quality of life, fatiguealso poses physical, psychological, and economic problems for patients[14,21]and their caregivers.
In summary, the symptoms of anemia in cancer patients haverather far-reaching consequences for cancer patients and their families. Ifanemia can be corrected with therapy, it is likely to have significant value tothe patient’s quality of life. Assuming cost-effectiveness can bedemonstrated, it will likely have value to society as well.
Prior to the development of recombinant human erythropoietin,red blood cell transfusion was the standard treatment for cancer-related anemia.This treatment had historically not been utilized until hemoglobin levelsdropped well below 10 g/dLoften below 8 g/dL. Given what has been learnedabout the QOL correlates of mild to moderate anemia, this practice hascompromised health status in large numbers of patients. The introduction oferythropoietic agents has added an earlier treatment option, at considerablecost, thus introducing the question of the cost-effectiveness of managing anemiain cancer patients.
Evaluations of the efficacy of erythropoietic agents haverelied on one or more of three criteria: change in hemoglobin, reducedtransfusion requirements, or subjective benefits that fall under a generalheading of patient-reported outcomes. These criteria are summarized in Table1.Absolute or relative change in hemoglobin or hematocrit is the most directindicator of drug effect, with a two-point increase from baseline hemoglobinmost typically considered to be indicative of significant improvement. Anemiacorrection, or bringing the patient above 12 g/dL, has been another proposedapproach to expressing the benefit of therapy to hemoglobin level.
A second indicator is the number of units of transfusedblood, or the proportion of patients who require a transfusion during the periodof study. Erythropoietin trials have consistently shown that these end pointsare achieved, with response rates in the vicinity of 50% to 60% and relativerisk of transfusion reduced by 30% to 50%.[9,11,12,16,22-31a] Among thepatient-reported outcomes, fatigue and quality of life are the two that areutilized most frequently in erythropoietin studies.
Quality of life is now a widely accepted patient-reportedhealth outcome measure for clinical trials among patients with chronicillnesses, particularly cancer. Most of the early trials of recombinanterythropoietin used a set of three linear analog self-assessment (LASA)scales.[24,32] The LASA scale is a 100-mm line on which the respondent isinstructed to make a mark indicating the degree of endorsement. The content ofthe three scales included perceived energy level, ability to perform dailyactivities, and overall quality of life. Scores range from 0, indicating"as low as could be," to 100, indicating "as high as couldbe."
The Functional Assessment of Cancer Therapy-General(FACT-G) is a cancer-specific QOL instrument that measures physical,emotional, social/family, and functional well-being. The FACT-G can besupplemented with condition-specific subscales, including a
20-item anemia subscale that includes a 13-item fatigue component.[2,3] Thegeneral instrument plus the condition-specific subscale is then referred to asthe Functional Assessment of Chronic Illness Therapy (FACIT)-Anemia or FACIT-Fatigue,respectively.[2,3](See Appendix for all scales.) There is now a new subscale forthe FACT measurement system that assesses the cognitive complaints experiencedby cancer patients undergoing chemotherapy (www.facit.org). Some cognitivecomplaints during chemotherapy may be influenced by anemia. This question is nowbeing studied.
In most trials initiated after 1996, the FunctionalAssessment of Cancer Therapy-Anemia (FACT-An) or the Fatigue Subscale has beenincluded with or replaced the LASA scales. In the FACT-An, fatigue and othersymptoms of anemia (eg, dizziness, joint aches, etc) are measured using ananemia-specific symptom scale that assesses self-report of the cognitive,physical, and emotional manifestations of anemia. In one pivotal study, thegeneric SF-36 instrument (see Appendix) was also used in combination with theLASA and FACT-An. In that trial of erythropoietic therapy vs placebo, theFACT-An and LASA scales (but not the SF-36) scores improved significantly in theerythropoietin-treated patients compared to the placebo-treated patients.
Some studies have used the European Organization for Researchand Treatment of Cancer (EORTC) core QOL questionnaire (see Appendix), includingits three-item fatigue subscale, to assess efficacy of erythropoietin.[34,35a]Studies that have employed the EORTC core questionnaire have not supportedevidence for a benefit of erythropoietic therapy on an intent-to treat basis. Itis not clear whether this is due to the true absence of a difference in thesestudies at doses employed, relative imprecision in the measurement of fatigue,or relatively low sample sizes.
A number of clinical trials have demonstrated thaterythropoietic therapy increases hemoglobin levels and reduces transfusionrequirements in anemic cancer patients.[8-11,16] There is a growing body ofliterature demonstrating that such therapy is not only associated withimprovements in hematologic parameters but patient well-being and quality oflife as well.[35b-35d] However, two systematic literature reviews, using strictcriteria for inclusion and interpretation of evidence, have concluded thatwhereas erythropoietin therapy undoubtedly increases hemoglobin and decreasestransfusion requirements, benefits to quality of life remain to be demonstratedin a convincing manner.[36,37] One of these reviews concluded that at the timeof this writing, there were significant methodologic limitations in the existingstudies of anemia and health-related quality of life.
However, it is noteworthy that several well-controlledtrials, including random assignment and placebo treatment, have been publishedsince these reviews. Early placebo-controlled studies examined the effect ofthrice-weekly dosing of recombinant erythropoietin in anemic cancerpatients.[24,32] A decrease in the number of transfused units of blood andimprovements in hematocrit were observed. Quality-of-life results were mixed.For example, Abels et al showed LASA differences in overall quality of life infavor of such therapy, but no significant difference in energy level oractivities of daily living.
Two more recent, placebo-controlled, double-blind phase IIIstudies of erythropoietic agents more emphatically supported the QOL benefits oftreating anemia.[9,38] These trials are particularly significant for tworeasons: First, the use of rigorous, random-controlled trial methodologyaddresses concerns about reliance on positive findings from poorly controlledstudies; and second, eligibility criteria in both trials specified that subjectsmust meet criteria for anemia, thus addressing methodologic critiques ofprevious studies that included nonanemic subjects who were unlikely, therefore,to benefit from the drug.
The Littlewood Trial
In one of these studies, Littlewood et al evaluated thisquestion in patients who were receiving non-platinum-based chemotherapy forsolid tumors or nonmyeloid hematologic malignancies. Eligibility criteriarequired that subjects have a baseline hemoglobin of 10.5 g/dL or a baselinelevel of between 10.5 and 12 g/dL that represented at least a 1.5 g/dLhemoglobin decrease after starting chemotherapy. Over the 12 to 24 weeks ofthrice-weekly drug administration, the primary end pointproportion ofpatients transfusedwas significantly lower in the treatment arm (24.7% vs39.5%). Hemoglobin levels, anemia-specific QOL concerns, and cancer-relatedquality of life improved significantly in the erythropoietic therapy group, butnot in the placebo group. General health status, as measured by the SF-36,showed a trend in the same direction. Finally, the correlations betweenhemoglobin change and QOL change were significant.
The Osterborg Trial
A second well-controlled trial evaluated the use oferythropoietin in 349 severely anemic, transfusion-dependent patients with ahematologic malignancy. The treatment arm received erythropoietin threetimes per week, and a significant increase in overall quality of life,
as measured by the FACT-An and FACIT-Fatigue scales, was observed in the last 4weeks of the trial (weeks 12 through 16). These improvements were observed insocial/family well-being and emotional well-being after 12 weeks and physicalwell-being and social/family well-being after 16 weeks. Interestingly, thegroups did not differ on the QOL subscales that measured specific anemia- orfatigue-related concerns. When QOL reports between responders and nonrespondersto the erythropoietic therapy were compared, statistically significantdifferences were observed for most QOL subscales, including the fatigue- andanemia-specific subscales.
Initial placebo-controlled registration studies in anemiccancer patients showed that three-times-weekly dosing of recombinanterythropoietin was associated with significant increases in hematocrit,decreases in units transfused, and improvements in energy level and dailyactivities that contributed to improvement in overall quality of life.[12,24]Further evidence stems from two prospective, multicenter, community-based,open-label, nonrandomized studies of three-times-weekly dosing of erythropoietin,each involving more than 2,000 patients.[10,16] Both studies assessed quality oflife with the LASA, and Demetri et al also used the FACT-An questionnaire.Both studies demonstrated a relationship between increased hemoglobin levels andimprovement in quality of life. Increases in FACT-An scores reflectedsignificant increases in QOL scores from baseline and a significant relationshipbetween higher hemoglobin levels and higher scores for physical and functionalwell-being subscales of the FACT-An. In addition, the salutary effect ofhemoglobin increase on quality of life was independent of tumor response tochemotherapy. An analysis of the ratio of change in QOL scores (LASA andFACT) to change in hemoglobin level showed that women experienced asignificantly greater improvement in quality of life on average, with twice theincrease in QOL score for every 1 g change in hemoglobin level compared withmen. This enhanced QOL response among women has been confirmed byothers.[22,39a,39b]
Several more recent studies have confirmed and expanded onthese findings. Gabrilove et al used a once-weekly dosing schedule forerythropoietin in a multicenter, open-label, nonrandomized trial of over 3,000patients receiving chemotherapy. This study used the LASA and the 20-item anemiasubscale of the FACT-An and similarly found a significant increase in hemoglobinlevels, reduced transfusion requirements, and improvements in QOL.
Once-weekly dosing of recombinant erythropoietin wassimilarly shown to be effective in increasing hemoglobin levels and improvingpatient-assessed energy and activity levels and overall quality of life(assessed via LASA) in both lung cancer and breast cancer patientsreceiving concomitant or sequential chemoradiation.
Results from an international, randomized, double-blind,placebo-controlled clinical trial of 375 patients receiving nonplatinumchemotherapy were consistent with previous trials in showing increasedhemoglobin levels, reduced transfusion requirements, and significantimprovements in all cancer- and anemia-specific QOL domains for theerythropoietin-treated group compared to placebo. Additionally, although notpowered for survival as an end point, the results were suggestive of a survivaladvantage for patients treated with erythropoietin compared with placebo. Theseresults must be interpreted with caution, however, as other variablespotentially influencing survival (eg, stage, bone marrow involvement,chemotherapy intensity, disease progression) were not controlled for orstratified. This is currently being investigated in properly powered anddesigned trials.
Quirt et al expanded on previous investigations thatincluded cancer patients likely to experience anemia, but not receivingchemotherapy. He treated this cohort of patients with a higher dose (150 vs 100U/kg) and for a longer duration (12 vs 8 weeks) than a previousplacebo-controlled study. They also collected prospective disease responsedata and measured quality of life with the FACT-An questionnaire inaddition to the LASA. Results from this recent study revealed thatnonchemotherapy patients experienced significant increases in hemoglobin levelsthat were correlated with significantly improved QOL scores and change inEastern Cooperative Oncology Group (ECOG) performance status scores. Thesechanges were comparable with the results reported for patients receivingchemotherapy in the two large open-label studies,[16,25] and suggest that anemiccancer patients may benefit from erythropoietic therapy whether or not they arereceiving chemotherapy.
Demonstration of the benefits of erythropoietic therapy wasextended to patients with multiple myeloma with the results of a multicenter,randomized trial that included a 12-week double-blind, placebo-controlledtreatment phase and a 12-week open-label extension phase. Erythropoietin-treatedpatients experienced significantly reduced transfusion requirements comparedwith placebo, an increase in hemoglobin levels of at least 2 g/dL insignificantly more patients than placebo, and significantly improved ECOGperformance status. Although univariate analyses revealed significantimprovements in various QOL domains, multivariate analyses failed to revealgroup differences. Significantly, however, the hematologic benefits oferythropoietic therapy were observed in patients with progressive multiplemyeloma considered resistant or refractory to chemotherapy. The stability ofquality of life and performance status scores in patients treated witherythropoietin during the open-label phase led the authors to suggest thaterythropoietin might be useful in both improving and maintaining quality of lifein multiple myeloma patients.
As noted above, a number of randomized trials and supportingopen-label studies suggest that erythropoietic agents improve quality of life,probably through an indirect pathway resulting from increases in hemoglobin andassociated oxygen transport. However, these significant results are oftenexpressed as numbers that change over the course of erythropoietic therapy, orthat change after hemoglobin is normalized. By themselves, these numberscommunicate little. Therefore, efforts to provide meaning to these numbers areimportant to the clinical, regulatory, and/or paying communities.
A recently completed study compared FACT-An scores of anationally representative sample of healthy individuals to those of a sample of375 anemic cancer patients from a randomized, double-blind, clinical trialevaluating erythropoietin vs standard care. Cancer patients’ responsesreflected QOL deficits for general quality of life and the 13-item fatiguesubscale of the FACT-An. By the end of the trial, the erythropoietin-treatedgroup had nearly erased deficits from the general quality of life and anemiasubscale and halved the deficit from the fatigue subscale, providing an exampleof the magnitude of impact from erythropoietin treatment for cancer-relatedanemia.
In an effort to aid in the interpretation of the sameclinical trial described above, changes in QOL scores were mapped ontochanges in hemoglobin concentrations. This study had confirmed results frommany previous studies in finding lower transfusion requirements, improvedhemoglobin levels, and improved quality of life in erythropoietin-treatedpatients. Additionally, comparison of patients with improved (³1 g/dL) and stable hemoglobin levels (< 1g/dL) indicated that a ³ 1g/dL hemoglobin increase was associated with improved quality of life, and thatthe QOL improvements in the erythropoietin-treated group are clinicallysignificant. This was done by positioning the change in FACT-G and LASA QOLscores to hemoglobin change score, in such a way that allowed one to estimate aunit change in quality of life that could be compared to a unit change inhemoglobin.
Fatigue is a serious symptom in the cancer population;however, it is also a common problem in the general population. This observationallowed us to establish "normative data" in the general United Statespopulation, so that the fatigue of cancer patients can be compared on the samemeasure. We compared the level of fatigue in anemic cancer patients withnonanemic cancer patients and the general United States population over timeusing a standardized set of 13 questions from the FACIT measurement system.Results showed that fatigue scores were significantly worse in the anemic cancerpatients. Additionally, the study highlighted the impact of hemoglobin levels onthe level of fatigue in cancer patients (see Figure2). While all studyparticipants were able to relate to fatigue, the impact of fatigue in the cancerpopulation, in particular the anemic subgroup, was decidedly worse.
Using these normative data, Kallich et al portrayedclinical trial results against the backdrop of these normative scores, andscores from baseline assessment in the Demetri et al erythropoietincommunity-based trial. This is illustrated in Figure3, allowing one to notethat after erythropoietic therapy patients achieve improvements in fatigue thatlie between the normative levels of fatigue in the general population and thebaseline scores of patients with anemia prior to starting erythropoietictherapy.
Novel Erythropoiesis-Stimulating Protein
Recent studies have evaluated a novel erythropoiesis-stimulatingprotein (NESP), darbepoetin alfa (Aranesp), which has a 2- to 3-fold longerserum half-life than erythropoietin and may therefore require less-frequentadministration.[10,29-31] (Figures 4 and5) Preliminary results suggest that, inaddition to favorable hematologic responses, an increase in hemoglobin levelsfrom baseline may be associated with a positive impact on quality of life, asmeasured by FACT-Fatigue scale scores, in patients with nonmyeloidmalignancies, solid tumors, and lung cancer. Kallich et alreported that darbepoetin alfa improved patients’ fatigue (as measured by theFACT-Fatigue scale) over placebo an average of 35% when hemoglobin levelsincreased by ³2 g/dL. This group also found a differential impact of darbepoetin alfa onFACT-Fatigue scores, with women’s scores increasing more than men’s byincrement of hemoglobin change from baseline.
It has been conclusively demonstrated that cancer-relatedanemia can be treated successfully in most patients. A recent estimate suggeststhat only 15% to 35% of anemic cancer patients receive a trial of anerythropoietic agent.[42,43] There are several factors that contribute to thisundertreatment. One factor is the under-recognition of the problem on the partof both providers and patients.[15,18] A second factor is the inconvenience ofcurrent therapy, which requires injection typically one to three times per week,depending upon local practice and reimbursement regulations. If a patient mustcome to a clinic for injections, this is very inconvenient. A third factor isthe fact that nearly 50% of patients will not respond to the therapy. Giventhere is no reliable way to predict responders, this can lead to lack ofconviction regarding its value, given that most chemotherapy patients willeventually recover on their own.
Finally, hanging over all of these considerations is the veryhigh cost of the therapy. Because the charges for all currently approvederythropoietic agents are based upon considerably lower dose requirements seenin nephrology, the cost of treating a cancer patient is often seen asunacceptable. Drawing on data from one of the community studies,Barosi et al modeled the cost-effectiveness of erythropoietin therapyrelative to standard care as a preventive measure, and reported marginalcost-effectiveness to be $189,652 per quality-adjusted life year. Similarly,Ortega et al reported that patients were unwilling to pay the netincremental treatment cost of $2,943 realized if erythropoietin were added tocare. However, Cremieux and colleagues, drawing assumptions from theliterature and three US-based clinical trials, showed that the effectivenessfrom $1 spent on standard care could be achieved with $0.81 if erythropoietinwere added. The area of cost-effectiveness remains controversial, as none ofthese reports are based on a prospectively designed and implemented randomizedclinical trial. Further study of this important issue may help achieve a fairand rational basis for pricing this helpful therapy.
For patients with cancer, anemia and its primary symptomfatiguerepresentprevalent problems that profoundly impact functional status, sense ofwell-being, and quality of life. Clinical trials have suggested a benefit tofatigue and quality of life of erythropoietin therapy for anemia in a number ofcancer populations, as have recent studies exploring more convenient dosingschedules and new longer-acting drugs. Future trials designed to correct themethodologic limitations of earlier studies are likely to make significantcontributions to the growing body of literature on the QOL effects oferythropoietin as well as novel pharmacotherapies for anemia. These studies willhopefully also help to further delineate the nature of the QOL benefit, itsclinical significance, the best way to identify responding patients early intreatment, and a cost-effective management strategy that allows more people withcancer-related anemia access to this therapy.
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