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Anemia in Stage II and III Breast Cancer Patients Treated With Adjuvant Doxorubicin and Cyclophosphamide Chemotherapy

^a Hematology-Oncology Associates of Central New York, East Syracuse, New York, USA; ^b Clinical Operations and Medical Affairs, Abt Associates Clinical Trials, Cambridge, Massachusetts, USA; ^c AMF Consulting, Inc., Los Angeles, California, USA; ^d Medical Affairs, Pharmacoeconomics, Amgen, Inc. Thousand Oaks, California, USA

Correspondence: Jeffrey Kirshner, M.D., Hematology-Oncology Associates of Central New York, P.C., 5008 Brittonfield Parkway, East Syracuse, New York 13057, USA. Telephone: 315-472-7504; Fax: 315-479-9639; e-mail: Jkirshner{at}Hoacny.com

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. Identify the prevalence and incidence of anemia in early-stage breast cancer patients and the proportion of patients untreated for anemia.
   
2. Discuss the relationship between certain patient characteristics (i.e., age and prechemotherapy hemoglobin level) and the risk of developing moderate to severe anemia during chemotherapy.
   
3. Explain how anemia may progress from cycle to cycle of chemotherapy and quantify the drop in hemoglobin levels for different groups of patients.
   

	ABSTRACT

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Purpose. The incidence and severity of prechemotherapy anemia and chemotherapy-induced anemia experienced by women treated with adjuvant doxorubicin and cyclophosphamide (AC) therapy for stage II and III breast cancer are described.

Patients and Methods. Medical charts of 310 breast cancer patients who received chemotherapy at eight oncology practices during 1997 through 2001 were reviewed in this historical case series study. Prechemotherapy anemia was defined as a baseline hemoglobin value <12 g/dl. An anemic event during chemotherapy (used to define chemotherapy-induced anemia) was defined as either a drop in hemoglobin level below the threshold (10 g/dl), the receipt of a blood transfusion(s), or treatment with epoetin alfa.

Results. Overall, 40.0% of patients experienced moderate to severe anemia (i.e., their hemoglobin levels dropped to <10 g/dl) and 31.3% (97/310) were anemic prechemotherapy. Of the patients with mild anemia prechemotherapy, 61.9% developed moderate to severe anemia during chemotherapy. Only 47.4% (46/97) of those patients received epoetin alfa therapy during chemotherapy. Of the patients with normal prechemotherapy hemoglobin levels (12 g/dl), 88.3% developed some degree of anemia (<12 g/dl) during chemotherapy and 27.7% (59/213) developed moderate to severe anemia (<10 g/dl). Anemic events were experienced by 41.8% (89/213) of the patients with normal prechemotherapy hemoglobin levels.

Conclusions. We conclude that a significant proportion (31.3%) of stage II and III breast cancer patients are anemic prechemotherapy and that the incidence of anemia increases substantially from prechemotherapy through the postchemotherapy period. This evidence appears to warrant earlier evaluation of anemia and an intervention in the prechemotherapy stage.

Key Words. Anemia • Breast cancer • Chemotherapy • Erythropoietin

	INTRODUCTION

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Approximately 50% of cancer patients develop anemia, generally defined as a hemoglobin level <12 g/dl [1]. The severity of anemia depends on many factors including the nutritional status of the patient, the type of cancer, the stage and extent of tumor burden (especially bone marrow involvement), the intensity of myelosuppressive treatment, and bleeding. Cancer-related anemia can be associated with debilitating symptoms and can have a profound effect on health-related quality of life (HRQOL) [2–5].

Recently published American Society of Clinical Oncology/American Society of Hematology guidelines on the use of epoetin alfa (recombinant human erythropoietin [rHuEpo]) in patients with chemotherapy-associated anemia [6] recommend treatment at a hemoglobin (Hb) level <10 g/dl. For patients with less severe anemia (Hb <12 g/dl but not <10 g/dl), treatment should be determined by an evaluation of the clinical manifestations of anemia. Other proposed evidence-based guidelines (per the United States Cancer Pain Relief Committee 2001) recommend that rHuEpo therapy be initiated in patients for whom symptoms of anemia may impair functional capacity or HRQOL. Additionally, rHuEpo therapy is recommended both for anemia determined to be severe enough to require a blood transfusion and/or if a blood transfusion is not an acceptable option [7].

The incidence and severity of anemia appear to vary with the type of cancer, the extent of the disease, and the myelosuppressive characteristics of the chemotherapy regimen. For example, the incidence of anemia associated with various treatment regimens for metastatic breast cancer ranges from 6% to as high as 98% for grades 1 and 2 anemia and from <1% to 80% for grades 3 and 4 anemia [8]. Little information is available about anemia rates associated with many commonly used adjuvant chemotherapy regimens in early-stage breast cancer (ESBC). A recent retrospective chart analysis evaluated ESBC patients treated with doxorubicin/cyclophosphamide (AC) chemotherapy in community practice and found that 17% of the patients developed anemia [9].

The purpose of this study was to evaluate the incidence and severity of anemia experienced by women with ESBC treated with adjuvant chemotherapy and describe the anemia treatment delivered in eight oncology practices across the U.S. Further, we explored the clinical characteristics of women who are likely to develop anemia and who may require treatment during the course of chemotherapy, as identified in a previous study [9, 10].

	MATERIALS AND METHODS

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Data Collection
Data on stage II and III breast cancer patients who received adjuvant chemotherapy were collected from patient medical records. This study focused on data from 310 patients who received adjuvant AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 3 weeks) chemotherapy (currently, the most prescribed regimen for ESBC) and who had prechemotherapy measures of Hb or hematocrit.

At all eight participating community-based oncology practices, data collection started from 2001 and proceeded backward in time (to 1997). Patients were eligible for inclusion in the study if they received adjuvant chemotherapy for stage II or III breast cancer and were at least 18 years of age. Patients who were on a clinical research protocol (within the previous 30 days) were excluded to limit the applicability of the results to community practice patients on standard treatment. Likewise, patients who had other primary invasive cancers, had received a previous course of chemotherapy, or were HIV positive were excluded.

Data from the patients’ medical charts were abstracted under the supervision of the principal investigator at each site using a standardized electronic clinical report form. The following information was collected: A) patient characteristics, including age, ethnicity, comorbidities, height, weight for each cycle, body surface area (BSA), tumor stage (defined according to the tumor/node/metastasis staging criteria), and number of positive nodes; B) the planned and delivered chemotherapy regimen, including the drugs, doses, route of administration, and number and length of cycles; C) all CBCs; D) epoetin alfa and growth factor use during the course of therapy; E) prior and concurrent radiotherapy, and F) medical record notation regarding chemotherapy dose modifications, mucositis, febrile neutropenia, and early termination of chemotherapy.

Variable Definitions

Patient Characteristics
Patient age was stratified into three groups: 18–49, 50–64, and 65 years or older. BSA was dichotomized at the median, that is, into two groups of <1.8 and 1.8. The number of positive nodes was grouped into three categories: no positive nodes, one to three positive nodes, and four or more positive nodes. Comorbid conditions were recorded for each study patient.

Anemia Measures
Each Hb measure was assigned one of the five severity grades of the National Cancer Institute’s (NCI) grading scale for anemia: grade 0, within normal limits (WNL), Hb 12.0 g/dl; grade 1, mild, Hb = 10–11.9 g/dl; grade 2, moderate, Hb = 8–9.9 g/dl; grade 3, serious/severe, Hb = 6.5–7.9 g/dl; and grade 4, life-threatening, Hb < 6.5 g/dl [8]. Prechemotherapy Hb values were defined by the Hb measures at the beginning of cycle 1 or prior to the initiation of chemotherapy. A prechemotherapy Hb level <12 g/dl was used as an indication of prechemotherapy anemia. For patients with normal prechemotherapy Hb levels, an ‘anemic event’ during chemotherapy was used as an indication of chemotherapy-induced anemia. An anemic event was defined as the occurrence of any one or more of the following: a drop in Hb below the threshold (10 g/dl), receipt of a blood transfusion(s), or treatment with rHuEpo therapy.

Iron Parameters and Iron Therapy
Administration of i.v. or oral iron supplement data (yes/no) were systematically collected. Over 90% of patients were lacking any values for these laboratory measurements and, therefore, were not used in the analysis.

Statistical Methods
We describe the incidence and severity of prechemotherapy anemia (Hb measured at start of chemotherapy) and chemotherapy-induced anemia (anemic event during chemotherapy) based on the NCI grading scale for anemia. The progression of anemia was examined from prechemotherapy throughout chemotherapy up to the 1- and 3-month follow-up visits. Patients were stratified into three groups depending on their prechemotherapy Hb grade and subsequent anemia as follows: patients with prechemotherapy anemia (Hb < 12 g/dl), patients with a normal Hb (12 g/dl) prechemotherapy who experienced an anemic event during chemotherapy, and patients with normal prechemotherapy Hb levels who did not experience an anemic event. Patient demographics are described for each of these three groups. Anemia treatment (rHuEpo, blood transfusion, iron therapy) during chemotherapy is summarized by prechemotherapy anemia status and by the lowest grade of anemia observed. Progression of anemia is cross-tabulated by anemia grade prechemotherapy versus lowest Hb value measured during chemotherapy. We also describe anemia over time (cycles 1–4 nadirs and follow-up of 1 and 3 months) with mean Hb level profile plots of patients stratified by anemia grade prechemotherapy and by delivery of rHuEpo therapy. The nadir Hb concentration for a chemotherapy cycle was calculated as the mean of all available values over days 6 through 17 of the cycle. This way, the higher cycle baseline Hb values were not mixed with the nadirs, especially in cases where nadir values were not available. In the profile plots, we excluded the 11 patients who received blood transfusions to avoid introducing variability due to increases in Hb levels associated with transfusions into the summary statistics. Detailed information to identify risk factors for prechemotherapy anemia was not available, so we concentrated on risk factors associated with chemotherapy-induced anemia. Therefore, the modeling of anemia risk factors focused on the patients with normal prechemotherapy Hb values (12 g/dl). Clinical features that were associated with an anemic event were identified by a continuity-adjusted chi-square test. Prechemotherapy Hb level, age, BSA, cancer stage, number of positive nodes, and menopausal status were evaluated as potential predictors of anemic events. A multiple logistic regression model was used to identify statistically significant risk factors and to estimate a patient’s risk of experiencing an anemic event. The C-statistic was used to measure the overall accuracy of the model, and the Hosmer-Lemeshow (H-L) lack-of-fit test was used to assess the adequacy of the model over the range of risk levels. Analyses were performed using SAS PC version 8.0 software (SAS Institute Inc.; Cary, NC).

	RESULTS

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Patient Characteristics
The characteristics of the 310 patients included in this analysis are summarized in Table 1. Ten patients were excluded from the analysis due to missing data and one patient was excluded due to rHuEpo administration prior to chemotherapy initiation. The majority of the study patients were Caucasian, peri- or postmenopausal, and had stage II disease with one or more positive lymph nodes. Over 60% of patients had no comorbid conditions. All patients received the planned four cycles of chemotherapy, except for nine patients who received three cycles and two patients who received only two cycles.

Prechemotherapy Anemia and Chemotherapy-Induced Anemia
Overall, 40.0% (124/310) of patients experienced moderate to severe prechemotherapy or chemotherapy-induced anemia, that is, their HB levels dropped to <10 g/dl (Table 2). The mean Hb nadir was 10.2 g/dl (standard error [SE] = 0.08). About 31.3% (97/310) of the women started chemotherapy with grade 1 or higher anemia (mean prechemotherapy Hb = 11.1 g/dl, SE = 0.09). Mild anemia (10–11.9 g/dl) was observed in 27.1% (84/310) of patients, and 4.2% (13/310) had moderate anemia (8–9.9 g/dl) prechemotherapy. Of the mild prechemotherapy anemic patients, 61.9% (52/84) developed moderate to serious/severe anemia during chemotherapy. Of the moderate prechemotherapy anemic patients, 23.1% (3/13) developed serious/severe anemia during chemotherapy. Of the patients with normal prechemotherapy Hb levels (12 g/dl), 88.3% (188/213) developed some degree of anemia during chemotherapy (i.e., Hb <12 g/dl). Mild anemia (10–11.9 g/dl) was observed in 60.6% (129/213) of those patients and moderate or lower grade anemia (<10 g/dl) was observed in 27.7% (59/213) of those patients.

Anemia Treatment Patterns
During the course of chemotherapy, 47.4% (46/97) of prechemotherapy anemic patients were treated with rHuEpo (Table 3). The median Hb concentration at the start of rHuEpo therapy was 10.2 g/dl (range, 8.0–11.6 g/dl). The median time to treatment initiation from the start of chemotherapy was 24.5 days

Blood transfusions were required for 6.2% (6/97) of the prechemotherapy anemic patients, with a median hemoglobin concentration of 7.8 g/dl (range, 6.3–11.0 g/dl) at the time of first transfusion. In comparison, 4.1% (5/213) of prechemotherapy nonanemic patients required blood transfusions, with a median hemoglobin concentration of 8.6 g/dl (range, 6.7–10.3 g/dl) at the time of first transfusion.

Supplemental iron therapy during chemotherapy, suggesting iron deficiency, was given to 12.4% (12/97) of prechemotherapy anemic patients, compared with 4.7% (10/213) of the patients who were not anemic prechemotherapy (p = 0.001). The majority (15/22) of patients who received iron therapy also received rHuEpo. All but one patient received oral iron supplements (data not shown).

Overall, only 54.8% (68/124) of patients whose HB levels dropped to <10 g/dl at their lowest anemia grade during chemotherapy were treated with either rHuEpo therapy or blood transfusions and, similarly, only 20.5% (33/161) of those whose levels dropped to 10–11.9 g/dl received such treatment (data not shown).

Anemia During Four AC Cycles and Follow-up
Figure 1 presents Hb levels prechemotherapy, across the four cycles of AC chemotherapy, and through the 1- and 3-month follow-ups. Patients were grouped by the presence of anemia prechemotherapy (Hb <12 g/dl considered anemic) and by rHuEpo administration status during chemotherapy. The mean Hb levels are plotted along with 95% CIs for the means. The proportions of patients receiving rHuEpo are shown for the rHuEpo treatment groups.

View larger version (21K): [in this window] [in a new window]   Figure 1. Nadir Hb levels during AC chemotherapy (cycles 1–4) and at follow-up (1 month and 3 months). Shown are the means and 95% CIs for the lowest Hb measurement within each period. Patients who received RBC transfusions were excluded from these summaries. Patient ratios indicate the proportions of patients receiving rHuEpo therapy at each time point. Decreases in denominators from baseline to cycle 1 are due to missing nadir Hb values between days 6 and 17 of the cycle.

Multiple Logistic Regression Model
Two hundred and thirteen patients who were not anemic prechemotherapy were included in the regression analysis (Table 4). Multivariate logistic regression analysis showed that, among those patients, those that had an anemic event (i.e., their Hb levels dropped to <10 g/dl or they received a blood transfusion[s] or treatment with rHuEpo therapy) during chemotherapy were more likely to be at least 65 years of age and to present with a prechemotherapy Hb level at the lower end of normal (i.e., close to the 12-g/dl threshold). The model had a C-statistic of 68%. As expected, patients with higher prechemotherapy Hb levels were less likely to experience an anemic event. For example, a 1.0 g/dl higher prechemotherapy Hb level was associated with about half (odds ratio = 0.49) the risk for an anemic event. Elderly patients (65 years of age or older) were about 2.5 times more likely to experience an anemic event than younger patients (<50 years old). The interaction term for this multiple logistic regression model was tested and found insignificant.

	DISCUSSION

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Irrespective of anemia grade prechemotherapy, and considering the lowest anemia grade experienced during chemotherapy, the results show higher proportions of rHuEpo therapy and blood transfusions for patients whose Hb level dropped to <10 g/dl than for those whose Hb levels dropped to 10–11.9 g/dl, as expected. Again, our results show that a large proportion of anemic patients (45% and 79%, respectively) did not receive anemia treatment. Supplemental iron therapy, suggesting iron deficiency, was given to 12% of prechemotherapy anemic patients and 5% of the patients who were not anemic prechemotherapy, mostly to patients receiving rHuEpo.

The incidence of anemia may also increase substantially from prechemotherapy to postchemotherapy. Despite treatment with blood transfusions and/or rHuEpo therapy, anemia was frequent during chemotherapy. Of the 213 patients with normal prechemotherapy Hb levels (12 g/dl), 27.7% had their Hb levels drop to <10 g/dl. Most importantly, 46% of the patients who became anemic were not treated with rHuEpo therapy.

In our retrospective study, two risk factors (age 65 years and prechemotherapy Hb level) predicted subsequent development of anemia with a C-statistic of 68%. While this model validated only one of the three risk factors identified by Caggiano et al. [9], these preliminary results suggest that higher age increases a patient’s risk for chemotherapy-induced anemia. One possible explanation for this was the different definitions of anemic event used in these studies. An anemic event was defined only by the drop in Hb level by Caggiano et al. [9], whereas anemic event in this study was defined as either a drop in Hb level, the use of blood transfusions, or rHuEpo therapy.

Our results indicate that patients with prechemotherapy anemia recovered during the follow-up time to Hb levels even higher than their prechemotherapy levels. This is in contrast to the patients who started with normal Hb levels, for whom the recovery was not complete. It is possible that, for those patients, the recovery is slower. It is also possible that, once patients with prechemotherapy anemia were treated with surgery and chemotherapy, the removal of the tumor helped to expedite the recovery of the Hb to normal levels during the follow-up period.

Anemia is a debilitating condition that has a significant impact on patients and their caregivers. It seems to be prevalent in cancer patients even prior to initiating chemotherapy, and preexisting anemia is exacerbated by chemotherapy treatment [10].

	CONCLUSION

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We conclude that a significant proportion (31.3%) of stage II and III breast cancer patients are anemic prechemotherapy and that the incidence of anemia increases substantially from prechemotherapy through the postchemotherapy period. This evidence appears to warrant earlier evaluation of anemia and an intervention in the prechemotherapy stage. It also warrants increased vigilance and more frequent monitoring in treating elderly and patients with prechemotherapy Hb levels at the lower end of normal (i.e., close to the 12-g/dl threshold).

	ACKNOWLEDGMENT

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The authors wish to thank Greg Rossi, Ph.D., for his insightful suggestions to the development of this manuscript. This study was supported in part by research funding from Amgen Inc., Thousand Oaks, California. Data in this study were published, in part, as an abstract (#5580) at the American Society of Hematology 44th Annual Meeting and Exposition, San Francisco, CA, December 2002.

	REFERENCES

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1. Johnston E, Crawford J. The haematologic support of the cancer patient. In: Berger A, Portenoy RK, Weissman DE, eds. Supportive Oncology. Philadelphia, PA: Lippincott-Raven Publishers, 1998:549–569.
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This Article Abstract Full Text (PDF) CME: Take the course for this article: Anemia in Stage II And III Breast Cancer Patients Treated With Adjuvant Dox... eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirshner, J. Articles by Tannous, R. E. Search for Related Content PubMed PubMed Citation Articles by Kirshner, J. Articles by Tannous, R. E.