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612 Vol. 2, No. 17 October 2002

ABSTRACT

Approximately one third to one half of patients with cancer are anemic, a condition thatdiminishes the ability to engage in daily activitiesand undermines the overall quality of life. Althoughcancer-related anemia has many causes, one of themost important is inadequate production andimpaired utilization of erythropoietin. At any givenlevel of anemia, patients with cancer produce muchless erythropoietin compared with a healthy per-son and, as a result, are unable to compensatefor the impaired production and shortened life-

span of red blood cells that occur in this situation.Supplemental recombinant erythropoietin canstimulate the production of red blood cells, cor-rect anemia, and improve quality of life. Newdosing regimens offer increased convenience topatients and may hasten drug response.( Advanced Studies in Medicine. 2002;2(17):612-619)

The causes of anemia, a common compli-

cation of cancer, are varied, ranging fromblood loss to inadequate red blood cellproduction. The consequences of anemia,while equally diverse, all contribute to

undermine quality of life and, perhaps, response toantineoplastic therapies. Although the causes of can-cer-related anemia are many, impaired erythropoietinproduction and impaired responsiveness of erythroidprogenitor cells to this hormone are central to itspathophysiology. Therefore, alleviating the anemia of cancer requires an understanding of how erythropoi-etin stimulates red blood cell formation and how theproduction of and response to this glycoprotein arealtered in patients with cancer.

ANEMIAANDCANCER

The prevalence of cancer-related anemia, whilenot rigorously documented, appears to be substan-tial. In an audit of more than 2700 patients with avariety of solid tumors and who were receivingchemotherapy at 28 oncology centers in the UnitedKingdom, 33% of the patients were sufficiently ane-

mic to require blood transfusion.1

The incidence of transfusion varied widely by tumor type; the inci-dence was 19% for breast cancer and 43% for lungcancer. Seven percent of patients with breast cancerand 22% with lung cancer required more than 1transfusion. The overall proportion of patients witha hemoglobin level below 11 g/dL increased from17% at the start of chemotherapy to 38% by thesixth cycle, despite transfusion in 33% of the

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A N EM IA A N D ERYTH RO PO IESIS IN C A N C ER

—

Jerry L. Spivak, M D

Address correspondence to Jerry L. Spivak, M D , JohnsH opkins U niversity School of M ed icine, D ivision ofH em atology, 720 Rutland Avenue, Traylor 924, Baltim ore,M D 2 1 20 5.

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Advanced S tudies in Medicine 613

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patients. Of those patients receiving transfusion,25% required hospitalization.

Other reports suggest that among patients withsolid tumors, anemia is most common in those withlung cancer (52%) or ovarian cancer (51%). These

patients are also the most likely to require bloodtransfusion (28% and 25%, respectively).2 Patientstreated with platinum-based chemotherapy agentsare at especially high risk for developing anemia.Reported transfusion rates in these patients rangefrom 47% to 100%, depending on the cumulativedose of platinum and other risk factors, particularly alow baseline hemoglobin level (<11 g/dL) or a reduc-tion in the hemoglobin level of 1 g/dL to 2 g/dL afterthe first cycle of chemotherapy. In one study, morethan 50% of 81 patients referred for radiation thera-py were anemic.3

THECONSEQUENCESOFANEMIA

Although severe anemia has traditionally been treatedwith blood transfusion, mild-to-moderate anemia oftengoes untreated. This lack of treatment may result from adesire to avoid unnecessary use of a therapy that, despiteimprovements in donor screening, carries definite risks,including immediate and delayed hemolytic reactions,alloimmunization, contamination by infectious agents,iron overload, volume overload, graft-versus-host disease,and immunosuppression.

An equally valid explanation, however, is thatmany physicians consider the clinical consequences of mild-to-moderate anemia to be minimal.4 This per-ception is being challenged by new data on the nega-tive influence of anemia on patients’ performance of everyday activities and quality of life. Anemic patientscan experience dyspnea, tachycardia, dizziness,anorexia, hypersensitivity to cold, and, perhaps mostcommonly, fatigue (Table 1).5,6 Of the symptoms of anemia, fatigue is identified by patients as having themost profound and intrusive effect, limiting their

ability to work and engage in daily activities to agreater degree than even nausea and pain.6 In addi-tion, anemia impairs tissue oxygenation and organfunction, increases postoperative mortality, increasesthe likelihood of transfusion after chemotherapy,eliminates the possibil ity of donating blood for autol-ogous transfusion, increases susceptibility to throm-bocytopenic bleeding, and, in certain instances,increases iron absorption.

There appears to be a link between anemia andmortality.6 In studies of patients with solid tumors,those with anemia had worse outcomes after radia-tion therapy, including reduced overall survival andless effective locoregional tumor control. Because

hypoxia has been shown to limit the radiosensitivityof cells, the poorer outcome may be related toreduced tumor oxygenation in patients with cancer-related anemia.

An analysis of 60 studies reporting survival of patients with cancer according to hemoglobin levelshowed that anemia was associated with a 65%increase in the risk of death.7 The relative risk var-ied by tumor type, from 19% among anemicpatients with lung cancer to 75% among patientswith head and neck cancer. Whether these findingssuggest a causal link or merely reflect the association

between anemia and advanced-stage disease is notyet clear.

ROLEOFERYTHROPOIETIN

Many factors cause anemia in patients with solidtumors (Table 2), including intrinsic or iatrogenicblood loss; nutritional deficiencies, primarily involv-ing iron or folic acid; autoimmune, traumatic, ordrug-induced hemolysis; and bone marrow failuredue to tumor encroachment, myelofibrosis, or mar-row necrosis. Infection, inflammation, and hyper-splenism also cause anemia. In some cases, the

Im paired tissue oxygenation

Im paired organ function

Im paired quality of life

Increased postoperative m ortality

Increased probability of blood transfusion after chem otherapy

Inability to donate blood for autologous transfusion

Increased susceptibility to throm bocytopenic bleeding

Increased iron absorption (som e form s of anem ia)

Table 1.Consequences of Anemia

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614 Vol. 2, No. 17 October 2002

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presence of malignant disease may be the only expla-nation for anemia.2,8,9

One of the common denominators among thedisparate causes for cancer-related anemia is abnor-mal production and utilization of erythropoietin,

the glycoprotein hormone that stimulates produc-tion of red blood cells and maintains their viabili-ty.8,9 Erythropoietin is a 166-amino acid proteinthat is heavily glycosylated. The circulating, biolog-ically active form of the protein comprises 165amino acids glycosylated on 3 N-linked groups and1 O-linked group. The N-linked carbohydratesmaintain erythropoietin in a biologically active con-formation, and their sialic acid residues ensure sur-vival in the circulation.

Erythropoietin is produced primarily in the kid-neys by peritubular interstitial cells and, to a lesser

extent, in the liver by fibroblastoid interstitial cells andhepatocytes.10-12 Normally, plasma erythropoietin levelsare maintained at a constant level by basal productionof the hormone. Plasma levels are characterized by adiurnal variation, with the highest levels observed inthe morning. Although the normal plasma erythropoi-etin level is constant in a given individual, the levelvaries widely from one person to another (normalrange, 4–26 mU/mL).11

Erythropoietin production increases in response totissue hypoxia. Normally, an inverse relationshipexists between the plasma level of erythropoietin andhemoglobin or hematocrit, as well as between eryth-ropoietin and arterial oxygen saturation.11 A hypoxia-triggered increase in erythropoietin productionnormally causes an increase in red blood cell produc-tion; a decrease in the plasma erythropoietin leveloccurs with restoration of tissue oxygenation.

Erythropoietin interacts with erythroid progenitorcells in the bone marrow through specific surfacereceptors to promote cell proliferation and differentia-tion and to maintain cell viability.11-13 The burst-form-ing unit-erythroid is the earliest erythroid progenitor

cell to express erythropoietin receptors. Because burst-forming unit-erythroid cells contain few erythropoi-etin receptors, an increased concentration of erythropoietin is required to trigger these dormantcells into cycle. The colony-forming unit-erythroidcell, the other target of erythropoietin, expresses a largenumber of erythropoietin receptors. Therefore, amuch smaller amount of the hormone is needed tomaintain cell viability.13

HOWCANCER INFLUENCESERYTHROPOIESIS

Erythropoietin production is impaired in severalsituations, including renal parenchymal disease,inflammation, infection, surgery, and blood hypervis-

cosity.11 In cancer, the causes for reduced productionare multifaceted. At any level of anemia, patients withcancer produce much less erythropoietin than normal.As a result, they are unable to compensate for theimpaired production and shortened lifespan of redblood cells (Table 3).8,9

The release of inflammatory cytokines in responseto malignancy may cause impaired erythropoietin pro-duction in patients with cancer.8,9,13 These cytokines—primarily tumor necrosis factor, interferon gamma,and interleukin 1—not only reduce erythropoietinproduction, but also suppress the response of erythroid

progenitor cells to the hormone.Compounding the deleterious effects of inflam-

matory cytokines are the effects of cancer therapy onerythropoiesis. Many chemotherapeutic agents notonly impair erythropoietin production, but alsoreduce progenitor cell proliferation. Platinum-basedchemotherapeutic agents are reported to cause can-

Blood loss

N utritional deficiencies

H em olysis

H em odilution

M yelofibrosis

M arrow necrosis

M arrow involvem ent w ith tum or

C hem otherapy and radiation therapy

Infection

Inflam m ation

H ypersplenism

Renal failure

M alignancy

A bnorm alities in erythropoietin production and utilization

Table 2.Causes of Anemia in Patients With Cancer

D ata from references 2, 8, and 9.

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cer-related anemia through myelosuppression anddamage to the renal tubules where erythropoietin isproduced.2 Irradiation can damage erythroid prog-enitor cells.

Inflammatory cytokines play an additional,

although probably not central, role in cancer-relatedanemia through disordered iron metabolism.9 Iron isbound to transferrin during transport from the reticu-loendothelial system to the bone marrow, where thecomplex is internalized by developing erythroid cells.12

The iron molecule is used in the erythroid cells forhemoglobin synthesis or is stored in the cytoplasm asferritin. Serum ferritin provides a measurement of stor-age iron, with normal values of 20 mcg/L to 100 mcg/Lin women and 30 mcg/L to 300 mcg/L in men.14

Transferrin saturation reflects the iron content of circu-lating transferrin. Values below 20% are associated with

reduced delivery of iron to the bone marrow.Normally, tissue iron deficiency is characterized by

low transferrin saturation and a low serum ferritinlevel. In cancer, as in many chronic inflammatory dis-orders, reduced transferrin saturation is usually associ-ated with a normal or elevated serum ferritin level, acombination characteristic of the so-called anemia of chronic disease.

The anemia of chronic disease is a hypoprolifera-tive anemia that may be normocytic and nor-mochromic or microcytic and hypochromic. Thisdisease is characterized by reduced levels of serum iron,reduced transferrin saturation, increased reticuloen-dothelial iron stores, normal or elevated serum ferritinlevels, increased erythrocyte free-protoporphyrin, andreduced gastrointestinal iron absorption.9,15

These observations have supported the belief thatabnormal iron metabolism plays a major role in the ane-mia of chronic disease. Other evidence, however, refutesthis concept. Although iron absorption is reduced andreticuloendothelial iron stores are increased, there is noactual impairment of iron delivery to the bone marrowand no marked impairment in the utilization of iron by

erythroid cells.16,17

This lack of impairment has beendemonstrated by the ability of recombinant erythropoi-etin therapy to correct the anemia of chronic disease,which would not be possible if iron deficiency were animportant element in this form of anemia.18 It is likely,therefore, that reduced iron absorption, decreased eryth-roblast transferrin receptor expression, and iron seques-tration by the reticuloendothelial system actuallyrepresent the consequences of impaired erythropoietin

production in this situation, which is caused by theinflammatory cytokines.

PATIENTOUTCOMES

Treatment with recombinant human erythropoi-etin is generally recognized as appropriate forpatients with a hemoglobin level below 10 g/dL orfor patients with anemia-related symptoms despite ahigher hemoglobin level.2 Other potential recipientsinclude patients with a low baseline hemoglobin level(10 g/dL to 12 g/dL) who are beginning chemother-apy and patients who are receiving platinum-basedchemotherapy and have had a marked decrease(1 g/dL to 2 g/dL) in hemoglobin from baseline tothe second cycle of treatment. These patients are athigh risk for becoming anemic and requiring blood

transfusion during chemotherapy.The value of supplemental erythropoietin in patients

with cancer-related anemia is now being judged not onlyby its effects on the hemoglobin or hematocrit, but alsoby its influence on quality of life. Data from several largestudies, both randomized placebo-controlled trials andcommunity-based observational studies, indicate thatcorrecting cancer-related anemia with recombinanthuman erythropoietin improves overall quality of life, aswell as participation in physical activity, energy level, andpsychosocial well-being.

Recently, Littlewood et al reported on a randomized,double-blind, placebo-controlled clinical trial of 375


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C haracteristic Effect of A nem ia of C hronic D isease

Intensity of stim ulus Erythropoietin production

suppressed

Functional capacity Erythroid progenitor cell

of bone m arrow proliferation suppressed

A vailable nutrients Iron sequestered and

protein synthesis reduced

Red blood cell survival Red blood cell survival reduced; blood

loss increased due to diagnostic testing

Table 3.Essential Factors in Erythropoiesis andthe Effect of Anemia of Chronic Disease

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patients with cancer-related anemia who were receivingnonplatinum chemotherapy for solid or nonmyeloidhematologic malignancies.19 Study participants had ahemoglobin level of 10.5 g/dL or below, or 12.0 g/dL orbelow in conjunction with a decrease of 1.5 g/dL or

more with each cycle of chemotherapy. Patients wererandomized to treatment with either epoetin alfa, 150IU/kg to 300 IU/kg by subcutaneous injection 3 timesper week for 12 to 24 weeks, or placebo. Comparedwith placebo, epoetin alfa significantly reduced the needfor blood transfusion (P = .0057) and increased hemo-globin levels (P < .001). Equally important, all key mea-sures of quality of life, including energy level, the abilityto perform daily activities, and fatigue, were significant-ly better in patients treated with epoetin alfa (P < .01).

These data support an earlier analysis by Henry andAbels of 3 randomized, double-blind, placebo-controlled

trials of recombinant erythropoietin for the treatment of anemia in a total of 413 patients with cancer.20 Thosepatients receiving chemotherapy were treated with epo-etin alfa (150 U/kg subcutaneously) 3 times per week for12 weeks. In patients who were not undergoingchemotherapy, the epoetin dose was 100 U/kg, and theduration of treatment was 8 weeks. In all cases, epoetinalfa produced a significantly greater increase in hemat-ocrit compared with placebo (P < .004). When theresults from these 2 chemotherapy trials were consideredtogether, epoetin therapy was associated with a signifi-cant reduction in the need for blood transfusion after thefirst month of therapy (P ≤ .009). Quality of lifeimproved significantly among patients who respondedto epoetin therapy with at least a 6–percentage pointincrease in hematocrit (P < .05).

Community-based studies have also demonstratedthe value of treating cancer-related anemia with epoet-in alfa. Gabrilove et al prospectively evaluated datafrom 3012 patients with nonmyeloid malignanciesundergoing chemotherapy at 600 community-basedoncology practices in the United States.21 In this non-randomized open-label study, patients received epoet-

in alfa 40 000 U once weekly, or 60 000 U onceweekly after 4 weeks if the hemoglobin response wasinadequate. After 16 weeks of therapy, epoetin alfa sig-nificantly increased hemoglobin levels, decreasedblood transfusion requirements, and improved func-tional status and fatigue. The latter 2 characteristicswere assessed by the linear analog scale assessment,which measures energy level, ability to perform dailyactivities, and overall quality of life, and by the anemia

subscale of the Functional Assessment of CancerTherapy–Anemia questionnaire. Improvements inquality of life were significantly correlated withincreased hemoglobin levels (P < .001).

In an earlier study, Glaspy et al evaluated 2342

patients with a variety of malignancies who wereundergoing cytotoxic chemotherapy.22 Treatment withepoetin alfa (150 U/kg 3 times per week) was associat-ed with a significant increase in mean hemoglobin lev-els and a significant decrease in the need for bloodtransfusion (P < .001). Patients also reported signifi-cant increases in energy level, activity level, and overallquality of life (Figure). These improvements correlatedwith the magnitude of the hemoglobin increase and wereindependent of tumor response. Demetri et al reportedsimilar results in a study of 2370 patients with non-myeloid malignancies who were being treated with

chemotherapy in 621 community-based oncology prac-tices in the United States.23 Epoetin alfa therapy was asso-ciated with an improvement in quality of life that notonly correlated significantly with hemoglobin levels butalso was independent of tumor response.

More recently, Glaspy et al retrospectively analyzeddata from these latter 2 community-based studies todetermine if the selection of chemotherapeutic agentinfluenced the effectiveness of epoetin alfa.24 Datafrom 4298 of the 4712 patients were included in the

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Figure.Effects of Erythropoietin on Quality of Life

Results of linear analog scale assessm ent scores. Scores are basedon a scale of 1–100 m m .P < .001 for all.

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analysis; of these patients, 1601 received a platinum-based chemotherapeutic agent and 2697 received anonplatinum-based agent. The investigators foundthat in patients receiving erythropoietin, hemoglobinlevels increased from baseline to final evaluation by a

mean of 1.6 g/dL to 2.0 g/dL; the need for bloodtransfusion was reduced after 2 months, and quality of life improved by 20% to 43%. All of these changeswere statistically significant and none was influencedby the type of chemotherapy the patient received.

Despite their importance in defining the value of erythropoietin therapy, quality-of-life analyses havesuffered from methodological weaknesses. Recently,researchers studying outcomes have scrutinized theavailable data and, in some cases, found it wanting.

Bottomley et al, of the Quality-of-Life Unit of theEuropean Organization for Research and Treatment of

Cancer Data Center in Brussels, conducted a criticalreview of 13 trials of erythropoietin therapy in patientswith cancer.25 They concluded that, although evidenceshowed that erythropoietin therapy had positiveeffects on quality of life, methodological limitationsinherent in most of the studies hampered interpreta-tion of the data. They called for new studies of morerobust design to evaluate the quality-of-life benefits of erythropoietin therapy.

Seidenfeld et al, of the Blue Cross and Blue ShieldAssociation Technology Evaluation Center, conducteda meta-analysis of 22 controlled clinical trials of vary-ing quality (all were randomized, but not all wereplacebo controlled).26 The researchers concluded thaterythropoietin therapy reduced the need for bloodtransfusion in patients with cancer-related anemia butthat lower-quality trials overestimated the magnitudeof this benefit compared with higher-quality trials.Only those studies whose participants had mean base-line hemoglobin concentrations of 10 g/dL or belowreported statistically significant effects of epoetin treat-ment on quality of life. The evidence was insufficientto determine if initiating erythropoietin therapy earli-

er spared more patients from blood transfusion orresulted in better quality of life.Yount et al, from the Center on Outcomes,

Research, and Education at Evanston NorthwesternHealthcare and Northwestern University, Evanston,Illinois, reviewed literature published betweenNovember 2000 and October 2001.27 The investiga-tors concluded the evidence supported a positive effectof epoetin therapy on quality of life in patients with

cancer; however, they also called for future studieswith more rigorous methodological design to clarifyand strengthen the association.

DARBEPOETIN ALFA

The standard dosing schedule for recombinant eryth-ropoietin has been 3 times per week. However,Gabrilove et al recently reported that once-weekly epo-etin alfa therapy appeared to be similarly effective inincreasing hemoglobin levels, decreasing blood trans-fusion requirements, and improving quality of life inpatients with cancer-related anemia.21This was a majoradvance with respect to patient convenience, andnewer analogs of recombinant erythropoietin, such asdarbepoetin alfa, may offer even more convenient dos-ing options for patients with cancer-related anemia.

Darbepoetin alfa’s effects are identical to those of native erythropoietin. Darbepoetin, however, differsfrom native or recombinant erythropoietin in having 2additional N-linked carbohydrate side chains withadditional sialic acid residues. Darbepoetin’s structuraldifferences provide additional metabolic stability invivo and markedly extend its half-life.6,28 In patientswith renal failure, darbepoetin alfa has a half-life of approximately 26 hours following intravenous admin-istration—an estimated 3-fold increase compared withepoetin alfa.6,28 Subcutaneous administration has beenshown to further extend the half-life of darbepoetin to49 hours in patients with renal failure. In a study of patients with nonmyeloid cancers undergoing multi-ple cycles of chemotherapy, subcutaneous darbepoetinwas found to have a half-life exceeding 40 hours.6

Data are now available from small studies investi-gating the safety and effectiveness of darbepoetinadministered once per week to treat cancer-relatedanemia in patients with solid tumors who are and whoare not undergoing chemotherapy.6,29,30 These studiesshow that darbepoetin produced a dose-dependentincrease in hemoglobin levels. In one study focusing

on patients with nonmyeloid malignancies who werenot undergoing chemotherapy, the proportion of patients responding to darbepoetin ranged from 61%in the group treated with 1.0 mcg/kg per week to 83%in the group treated with 4.5 mcg/kg per week.29

Darbepoetin’s prolonged half-life and greater invivo biological activity present the opportunity foreven less frequent dosing. Preliminary evidence fromstudies investigating the use of higher doses delivered


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at 2-week or 3-week intervals suggests that an equiva-lent proportion of patients achieve the target hemo-globin response when darbepoetin is administeredevery 2 weeks or 3 weeks compared with weekly dos-ing. Evidence also shows that darbepoetin alfa admin-

istered once every 2 weeks produces a hemoglobinresponse equivalent in both magnitude and speed tothat achieved with once-weekly dosing of epoetin alfa6;response rates of approximately 54% have been report-ed with 2-week dosing regimens and 50% with 3-weekdosing regimens.

Other approaches being evaluated include a fur-ther reduction in dosing frequency to every 4 weeksand a new 2-part regimen that combines loadingand maintenance phases. In the loading phase, dar-bepoetin is administered weekly until the targethemoglobin response is achieved, then every 2

weeks or 3 weeks thereafter. At the 2002 meeting of the American Society of Clinical Oncology, Glaspyet al reported the results of a clinical study of 122patients with solid tumors and a hemoglobin levelof 11 g/dL or below who received darbepoetin alfa4.5 mcg/kg weekly for 4 weeks, followed by 3.0mcg/kg every 2 weeks. The researchers observed arapid and sustained hemoglobin response and relief of fatigue in patients receiving this front-loadedapproach to therapy. (See Poster Presentations inthis issue for details.)

CONCLUSION

Clinical understanding of the consequences of can-cer-related anemia has been broadened to include itsnegative impact on quality of life, most often becauseof fatigue. Fortunately, these negative effects can becorrected with recombinant human erythropoietinand its newer analogs. Future studies should define themost efficient means of exploiting these importantbiologic agents.

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