The Impact of Anemia and Its Treatment on Patients WithGynecologic Malignancies

Susana Campos

Anemia is a frequent complication of cancer and itstreatment. It often impairs the functional status ofpatients and results in decreased functional capacityand quality of life. Its etiologies are multiple, includingchronic inflammation, hemorrhage, nutritional defi-ciencies, hemolysis, bone marrow suppression by che-motherapy, or infiltration by tumor. It can manifest asfeelings of weariness, tiredness, muscular weakness,dysphoric mood, somnolence, or impaired cognitivefunctioning. In gynecologic patients, the incidence ofanemia has been reported to be as high as 80% depend-ing on chemotherapy regimen. Given the various con-sequences of a low hemoglobin level, the importance ofincreasing or maintaining hemoglobin levels and ame-liorating the symptoms is apparent. Clinical studieshave demonstrated that the administration of recom-binant human erythropoietin (rHuEPO, epoetin alfa) iseffective and safe in increasing hemoglobin levels andimproving the overall quality of life in patients withgynecologic cancers undergoing chemotherapy. There-fore, epoetin alfa treatment should be considered inthis patient population.Semin Oncol 29 (suppl 8):7-12. Copyright 2002, ElsevierScience (USA). All rights reserved.

Cancer-related fatigue is a prevalent, but oftenoverlooked, complication of the disease and

treatment. A survey by Curt et al1 showed that76% of 379 patients ranked fatigue as their mostsignificant symptom while receiving chemother-apy. Recent studies have attempted to reproduc-ibly define and characterize cancer-related fatigue,as well as identify potential etiologies.2 Concom-itant systemic disorders such as infection, dehydra-tion, sleep disorders, pain, immobility, depression,and anxiety may contribute to fatigue, but anemiais often the major factor. The contribution ofanemia to fatigue in patients with cancer has beenwell characterized in a large subset of patients, andrepresents an objective entity for which treatmentprovides a dramatic improvement in symptoms.3-5

Anemia itself is multifactorial and may be re-lated to a number of problems associated withcancer, such as bleeding, hemolysis, or bone mar-row infiltration. The anemia of chronic diseasealso represents an often underappreciated entity.Patients with anemia of chronic disease have lowserum iron and serum erythropoietin levels, butthe bone marrow is replete with iron supporting aniron utilization defect rather than “true” iron de-

ficiency, although a “functional” one may exist.6Anemia is common in patients with gynecologicmalignancies who are receiving chemotherapy,and has been reported in 67% to 81% of patientsreceiving platinum-containing regimens, and in47% to 89% of patients receiving nonplatinum-containing regimens.7-10 In addition to the che-motherapy, contributing factors in this populationinclude chronic blood loss from vaginal bleeding.

Regardless of the underlying etiology, a reviewof patients receiving cancer therapy shows that themajority of them develop anemia.11 The relation-ship between functional impairment in patientsand what previously was considered “mild anemia”has prompted the improved reporting of all gradesof anemia in clinical trials. As shown in Table 1,the incidence of anemia is high in patients withgynecologic malignancies when all grades of ane-mia are considered.

THE USE OF EPOETIN ALFA IN ANEMICCANCER PATIENTS

The current indication for the use of recombi-nant human erythropoietin (rHuEPO, epoetinalfa) in patients with nonmyeloid cancers who areanemic and receiving chemotherapy is derivedfrom two placebo-controlled registration trials inpatients receiving either platinum-containingor nonplatinum-containing chemotherapy regi-mens.12 These studies showed that epoetin alfa useincreased hemoglobin (Hb) levels (P � .004), andreduced transfusion requirements (P � .005) inpatients receiving chemotherapy. While not theprimary endpoints of these studies, a suggestion inimprovement in quality of life (QOL) using thelinear analog scale was seen.12 These resultsprompted the development of the large communi-

From the Department of Medical Oncology, Dana-Farber Can-cer Center, Boston, MA.

Dr Campos has received honoraria from Janssen-Cilag and OrthoBiotech.

Address reprint requests to Susana Campos, MD, Dana-FarberCancer Center, 44 Binney St, Boston, MA 02115.

Copyright 2002, Elsevier Science (USA). All rights reserved.0093-7754/02/2903-0803$35.00/0doi:10.1053/sonc.2002.33526

7Seminars in Oncology, Vol 29, No 3, Suppl 8 (June), 2002: pp 7-12

ty-based studies that followed to confirm thesefindings in a typical clinical practice environment.

Two nonrandomized, open-label, community-based studies have evaluated approximately 4,700patients suffering from various malignancies in-cluding gynecologic cancers with regard to im-provement in Hb levels, reduction in transfusionrequirements, and relationship between anemiaand QOL in patients receiving epoetin alfa.3,4These two studies used 3-times-weekly dosing, ei-ther weight-based or 10,000 IU subcutaneously.The eligibility criteria and dosing escalation planare reviewed in Table 2. The baseline patientcharacteristics of the two studies are published asoutlined in Table 3, and are remarkably similarbetween these large patient groups. Of note, base-line Hb levels at study entry, percent of patientsrequiring transfusion, and baseline erythropoietin

levels are similar. In addition, QOL as assessedusing the Linear Analog Scale Assessment(LASA, also known as Cancer Linear AnalogScale or CLAS) is markedly impaired, with initialscores falling below 50 mm on the self-reported100-mm instrument.2 The outcome variables ofeach of these studies were an increase in Hb, areduction in transfusion requirements, and an im-provement in QOL. In the studies by Glaspy et al3and Demetri et al,4 a statistically significant (P �.001) increase in Hb was seen over baseline withmean increases of 1.8 g/dL and 2.0 g/dL, respec-tively. A decrease in the percent of patients re-quiring transfusion was seen (P � .001), as shownin Table 4.

A third nonrandomized, open-label, commu-nity-based study evaluated improvements in Hblevels, reduction in transfusion requirements, and

Table 1. Cancer-Related Anemia as Reported With Chemotherapy Regimens for Ovarian Cancer

AgentNo. of

Patients (n)

Incidence of Anemia (%)

Grade 1/2* Grade 3/4*

Paclitaxel16-21 643 18-90 6-64Docetaxel10,22,23†‡ 170 58-87 27-42Carboplatin or cisplatin24,25 330 8-68 0-26Topotecan19,26,27† 251 64-68 31-40Paclitaxel/cisplatin or paclitaxel/carboplatin28,29 231 51-58 2-8Cyclophosphamide/carboplatin or cyclophosphamide/cisplatin28,30-33 1,439 32-98 2-42

* National Cancer Institute, World Health Organization Common Toxicity criteria, Eastern Oncology Group criteria, Gynecologic OncologyGroup criteria, Southwestern Oncology Group criteria, or toxicity system not specified.† Grade 1/2 and grade 3/4 were not fully reported in all studies.‡ Grade of anemia was unspecified in one study.

Table 2. Community-Based Studies: Eligibility Criteria and Dosing Scheme

Glaspy et al3 Demetri et al4 Gabrilove et al5

Open label (N � 2,342*) Open label (N � 2,370*) Open label (N � 3,012*)Nonrandomized Nonrandomized NonrandomizedNonmyeloid Nonmyeloid NonmyeloidChemotherapy Chemotherapy Chemotherapy150 IU/kg tiw 10,000 IU tiw 40,000 IU weeklyEscalate to 300 IU/kg at 8 weeksif inadequate

Escalate to 20,000 IU at 4 weeksif inadequate

Escalate to 60,000 IU at 4 weeksif inadequate

Retrospective tumor responseanalysis

Prospective tumor responseanalysis

Prospective tumor responseanalysis

Abbreviation: tiw, 3 times weekly.* Number of enrolled patients.

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relationship between anemia and QOL using amore convenient, once-weekly epoetin alfa dosingregimen.5 Approximately 3,000 patients with non-myeloid malignancies including gynecologic can-cers were evaluated and epoetin alfa was adminis-trated at a dosage of 40,000 IU subcutaneouslyonce weekly. The eligibility criteria and dosingescalation of this study are given in Table 2. Astatistically significant (P � .001) increase in Hblevels over baseline was observed in patients re-ceiving epoetin alfa once weekly. Mean increasefrom baseline to final Hb level was 1.8 g/dL. Ad-ditionally, the percentage of patients who requiredtransfusions decreased significantly (P � .007) bymonth 2 and continued to decrease during thecourse of the study (Table 4).

Effect on Quality of Life

Two patient-reported survey instruments wereused to measure QOL. The LASA was used byGlaspy et al3 and Demetri et al.4 Furthermore,Demetri et al included the Functional Assessmentof Cancer Therapy with anemia subscale. Usingthe domains of mean energy, mean activity, andoverall QOL, LASA scores were significantly im-proved over baseline (P � .001) in both publishedstudies, as shown in Table 5.3,4 Patients with thegreatest increases in Hb reported the greatest im-provements in QOL. Furthermore, in the study byDemetri et al, improvements in QOL were associ-

Table 3. Community-Based Studies: Baseline Characteristics

Glaspy et al3

(n � 2,030*)Demetri et al4

(n � 2,289*)Gabrilove et al5

(n � 2,964*)

SexMale 774 903 1,105Female 1,256 1,386 1,907

Age (yrs) 62.4 62.8 63.1Hemoglobin (g/dL) 9.2 9.3 9.5Percent transfused 21.9 28.5 28.5Median serum erythropoietin level (mU/mL) 149 103 –Activity level (mm) 39.2 38.9 40.5Energy level (mm) 38.1 38.6 39.2Overall QOL (mm) 45.0 45.4 46.6

Abbreviation: QOL, quality of life.* Number of assessable patients.

Table 4. Community-Based Studies: TransfusionRequirements

Glaspy et al3

(% Transfused)Demetri et al4

(% Transfused)Gabrilove et al5

(% Transfused)

Baseline 21.9 29 141 month 21.9 21 162 months 14.8* 13 8*†3 months 10.7 8 6*†4 months 10.3 5 4.5*

* Significantly less (� .001) than baseline value.† Significant difference (� .007) from previous month.

Table 5. Community-Based Studies: Linear AnalogScale Assessment (LASA)*

Results(1 to 100 mm)

Glaspyet al3

Demetriet al4

Gabriloveet al5

Energy levelMean change(mm) 15.0 11.5 11.8†

Activity levelMean change(mm) 13.1 11.1 10.5†

Overall QOLMean change(mm) 11.0† 9.8† 9.0†

Abbreviation: QOL, quality of life.* Also known as Cancer Linear Analog Scale or CLAS.† P � .001 compared with baseline.

IMPACT OF ANEMIA AND ITS TREATMENT 9

ated with increases in Hb independent of tumorresponse or tumor treatment. Benefits were shownfor patients with stable disease as well as for thosewith partial or complete responses.4

The study conducted by Gabrilove at al5 admin-istering epoetin alfa to patients at a more conve-nient once-weekly dosing regimen evaluated QOLusing the LASA survey instrument as well as theanemia subscale of the Functional Assessmentof Cancer Therapy with anemia subscale. LinearAnalog Scale Assessment scores significantly(P � .001) improved over baseline (Table 5) and

a positive and significant (r � 0.173; P � .001)correlation between the increase in overall QOLand the increase in Hb levels from baseline wasseen.

The clinical issue has been to determine the Hblevel at which the maximal incremental benefit inQOL is realized. An incremental analysis was per-formed and is currently published in abstractform.13 These data suggest the greatest incremen-tal rate change in QOL per 1-g/dL Hb gain occurswhen Hb concentrations increase from 11 g/dL to12 g/dL (range: 11 g/dL to 13 g/dL). Exciting dataare also emerging regarding the potential impact ofanemia on cancer treatment outcome, as in theradiotherapy of cervix cancer for example, whichmay provide additional support for this Hbrange.14

EPOETIN ALFA IN PATIENTS WITHGYNECOLOGIC MALIGNANCIES

To determine if the gynecologic subset of pa-tients (n � 297) behaved similarly to the generaloncology population (N � 2,370) in the 16-weekopen trial conducted by Demetri et al, a retrospec-tive subset analysis was performed.15 The baselinemedian age of the gynecologic population was 62years; mean baseline Hb was 9.2 g/dL. Patientswere administered epoetin alfa 10,000 IU subcu-

Fig 1. Change in mean Hb levels. Patients with gynecologicmalignancies (diamonds) are compared with all patients(squares). The change from baseline to final level was signifi-cant (P < .001) for both the total population and the gyneco-logic cohort. Adapted and reprinted with permission.4

Fig 2. Change in transfusion requirements.4 Patients with gynecologic malignancies (white bars) are compared with all patients(grey bars). The changes from baseline requirements were significant (P < .001) in all months of the study, and similar for both thetotal population and the gynecologic cohort. Baseline is defined as within 1 month before the start of the study.

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taneous 3 times weekly, with the dosage increasedto 20,000 IU if Hb response was inadequate after 4weeks of therapy. Study endpoints were thechange in Hb levels from baseline to final assess-ment, change in transfusion requirements, changein QOL from baseline to final, and a comparison ofthe change in Hb with the change in QOL.

Epoetin alfa produced a significant (P � .001)and sustained increase in Hb levels (Fig 1). Themean change in Hb exceeded 2.0 g/dL over the4-month study period, and overall transfusionswere reduced from 36% to 6% (P � .001) (Fig 2).Mean increases from baseline QOL to final scorewere statistically significant (P � .001) for energy(13.3 mm; 33% improvement), ability to do dailyactivities (13.8 mm; 34% improvement), andoverall QOL (12.6 mm; 27% improvement). In-creases in all QOL domains were significantly(P � .01) correlated with increases in Hb (Fig 3).The largest increases in Hb levels were associatedwith the greatest improvements in QOL scores. Insummary, results in these patients with gyneco-logic malignancies were similar to the general pop-ulation in terms of benefit in Hb increase, trans-fusion reduction, and improvement in QOL.Epoetin alfa appeared to maximize the QOL ofanemic patients receiving chemotherapy for gyne-cologic malignancies.

CONCLUSIONS

Improvement in overall QOL can be achievedwith epoetin alfa. Data presented with this reviewsupport the value of returning Hb levels to thenormal range (11 to 13 g/dL). Importantly, a moreconvenient once-weekly epoetin alfa dosing regi-men shows similar improvements in Hb levels andQOL when compared with 3-times-weekly dosing.The attention to QOL in the large, community-based studies has served as a catalyst for investiga-tions to further characterize cancer-related fatigue.Epoetin alfa is effective and safe in increasing Hblevels and improving QOL in gynecologic cancerpatients.

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IMPACT OF ANEMIA AND ITS TREATMENT 11

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