The Oncologist, Vol. 5, Suppl 2, 19-23,
June 2000
© 2000 AlphaMed Press
The Relationship between Anemia and Quality of Life in Cancer Patients
Paul Sabbatini
Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Correspondence:
Paul Sabbatini, M.D., Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-6423; Fax: 212-639-8865; e-mail: sabbatip{at}mskcc.org
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Abstract
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Anemia is a common occurrence in patients with cancer, and especially in those who undergo chemotherapy. Traditionally, significantly decreased hemoglobin levels have been considered to be 
8 g/dl and have been associated with physiologic manifestations. More recent data have shown that milder anemia (hemoglobin levels 10-12 g/dl) has functional consequences as well. This article reviews several communitybased studies that have analyzed changes in hemoglobin concentrations, transfusion requirements, and QOL parameters in anemic patients with cancer before and after treatment with epoetin alfa. The results of these studies have been consistent and show an increase in hemoglobin and a reduction in transfusion requirements when compared with baseline. Furthermore, a relationship between increasing hemoglobin levels and an improvement in QOL is suggested that is independent of tumor response. Additional studies are evaluating the optimal hemoglobin levels for the greatest incremental improvement in QOL.
Key Words. Functional anemia • Epidemiology • Epoetin alfa • Quality of life • FACT-An
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Introduction
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Currently evidence supports the value of anemia management as a contributor to improving patient quality of life (QOL) by reducing fatigue in cancer patients receiving chemotherapy [1-5]. This article examines recent data regarding the prevalence of chemotherapy-related anemia and reviews data supporting the QOL benefits of epoetin alfa in patients with cancer and anemia who were treated with chemotherapy agents.
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Anemia in Medical Oncology Practice: Defining "Functional" Anemia
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Both anemia and fatigue are multifactorial disorders. Fatigue is a symptom associated with anemia but can also arise from other etiologies in patients with cancer. Moreover, anemia can result from direct disease effects or from cancer-related therapy [5]. Recent studies have outlined the prevalence and severity of cancer-related anemia, but historically many clinical trials have only reported the incidence of more severe anemia (grade III, IV) thought to have physiologic consequences [6]. However, prevalence data regarding milder anemia possibly with functional consequences for patients (Hb < ~12 g/dl) are now beginning to emerge. Cella and associates, who used the Functional Assessment of Cancer Therapy instruments for general (FACT-G) and anemia-related effects (FACT-An) to assess the impact of anemia (Hb < 12 g/dl) in patients with cancer, demonstrated some functional impairment in patients whose Hb levels were less than 12 g/dl [4]. Nonrandomized community-based data also support the idea that modest anemia may interfere with patient function and impacts QOL [1, 2, 4].
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Reducing Anemia with Epoetin Alfa: Evidence from Clinical Studies in Medical Oncology
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The goal of raising hemoglobin levels can be accomplished through blood transfusions or the administration of recombinant human erythropoietin (rHuEPO; epoetin alfa). Blood transfusions have certain inherent risks such as infection, and, in general, the process of transfusion has been shown to have a negative impact on QOL [5]. Several studies have assessed the effects of epoetin alfa in cancer patients who are receiving chemotherapy. Cisplatin therapy was thought to be associated with a deleterious effect on endogenous erythropoietin production [1, 7]. Based on observations made from studies demonstrating the efficacy and safety of epoetin alfa in anemic patients with renal failure, a series of placebo-controlled registration studies were designed to assess the efficacy and safety of epoetin alfa in patients with cancer receiving either non-cisplatin-containing or cisplatin-containing chemotherapeutic regimens, administered three times weekly [6]. The results demonstrated that epoetin alfa therapy significantly (p < 0.004) increased hematocrit concentrations and reduced transfusion requirements (p 0.005) versus placebo (Table 1
) [3].
The impact of epoetin alfa therapy on QOL parameters was assessed with the use of the Linear Analog Scale Assessment (LASA). Patients rated their energy level, ability to perform daily activities, and overall QOL on a scale of 0 (lowest) to 100 (highest). The results suggested that epoetin alfa therapy (p < 0.05) improved overall QOL in anemic patients with cancer who responded to therapy (Fig. 1). Epoetin alfa therapy was well tolerated.
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Figure 1. Change in baseline quality-of-life scores in patients receiving placebo or epoetin alfa for cancer-related anemia Adapted with permission [3].
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Quality of Life in Patients with Cancer and Anemia: Two Community-Based Studies
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The results of the registration studies [3] were confirmed by two open-label, community-based trials [1, 2] that examined the effects of epoetin alfa treatment in more than 4,000 cancer patients with chemotherapy-associated anemia (Hb < 11 g/dl). Results of studies by Glaspy et al. [1] and Demetri et al. [2] demonstrated a relationship between an increase in Hb levels (p < 0.001) and an improvement in QOL. The study design characteristics are summarized in Table 2. Both studies were nonrandomized, consisting of anemic patients with nonmyeloid malignancies receiving chemotherapy. The Glaspy study, with 2,342 patients, used an initial dose of 150 units/kg administered subcutaneously three times per week. The dose was increased to 300 units/kg if there was an inadequate response at eight weeks. The Demetri study, with 2,370 patients, used an initial dose of 10,000 units subcutaneously three times a week. However, the dose was increased to 20,000 units if the hemoglobin response was inadequate at four weeks. An obvious question is whether improvements in QOL were associated only with tumor response. While the Glaspy study used a retrospective tumor response analysis with its inherent difficulties, tumor responses were collected prospectively in the Demetri study. The outcome variables for both studies assessed the effects on hemoglobin, transfusion requirements, and QOL measured by LASA. The Demetri study also separately employed the FACT-An instrument to assess QOL.
The demographic and baseline characteristics for the populations in these studies are listed in Table 3. The patient characteristics in both studies were similar. In the Glaspy study, the mean hemoglobin increase (p < 0.001) over the four months of epoetin alfa therapy was 1.8 g/dl from baseline. [1]. The Demetri study demonstrated similar results, with a mean increase of 2.0 g/dl from baseline (p < 0.001), regardless of tumor type [2]. In both studies, maximum hemoglobin concentrations were reached after three to four months of epoetin alfa therapy. A substantial hemoglobin response was defined as an increase in hemoglobin level of at least 2 g/dl (both studies) or attainment of a hemoglobin concentration of 12 g/dl or greater (the Demetri study only) over the course of treatment without any transfusions. Overall hemoglobin responses meeting those criteria occurred in 53.4% (1,084) of patients in the Glaspy trial and in 61% (1,406) of patients in the Demetri study.
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Table 3. Community-based studies of epoetin alfa therapy for cancer- and chemotherapy-related anemia: baseline patient characteristics [1, 2]
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In both studies, a significant (p < 0.001) decrease in the percentage of patients who required transfusions was noted (Table 4) [1, 2]. Likewise, a significant (p < 0.001) decrease in the number of units of blood transfused per patient was demonstrated in both studies.
Two patient-reported survey instruments were used to measure QOL: LASA was used in both studies, with the addition of the FACT-An instrument in the Demetri study. Upon completion (four months) of epoetin alfa therapy, mean energy, mean activity, and mean overall LASA scores were statistically significantly (p < 0.001) higher compared with baseline in both studies (Table 5). In the Demetri study, increases in QOL measures were observed as early as one month after initiation of therapy. In addition, the data collected by the FACT-An questionnaire correlated with the data collected by LASA (r = 0.72) [2]. A consistent relationship was seen between hemoglobin concentrations and QOL scores, independent of tumor response, except in patients who experienced progression of disease.
To help identify the hemoglobin level at which QOL is optimized, an incremental analysis was conducted and is currently reported in abstract form [8]. Results from this analysis suggested the greatest incremental improvement in QOL per 1 g/dl hemoglobin increase occurred when hemoglobin concentrations rose from 11 g/dl to 12 g/dl (range, 11 g/dl to 13 g/dl).
Similar results showing a relationship (p = 0.001) between an increase in hemoglobin concentration and patient-reported QOL parameters were observed in a recent community-based study (n = 302) assessing a weekly dosing schedule currently reported in abstract form [9]. The starting dose was 40,000 units subcutaneously once weekly, with dose escalation to 60,000 units weekly if hemoglobin response was inadequate. Mean hemoglobin levels increased from 9.4 g/dl at baseline to 11.6 g/dl at the conclusion of the study, a mean increase of 2.2 g/dl (p < 0.001). In addition, there was a significant (p < 0.001) reduction in both the percentage of patients who required transfusion and the number of units transfused. In preliminary analyses, the once-weekly dosing schedule of epoetin alfa showed increases in hemoglobin, reduction in transfusion requirements, and improvements in QOL measures similar to the three times weekly dosing schedules used in previous studies [9].
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Conclusion
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The consistency of these data showing a relationship between hemoglobin concentrations and patient QOL supports a shift in the threshold for anemia intervention. The traditional approach of allowing patients to keep hemoglobin in the 8 g/dl range may have consequences beyond physiological ones. The attention to cancer-related fatigue in these studies has further led to investigations regarding its epidemiology, other etiologies in addition to anemia, and practical interventions.
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References
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Glaspy J, Bukowski R, Steinberg D et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997;15:1218-1234.[Abstract/Free Full Text]
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Demetri GD, Kris M, Wade J et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. J Clin Oncol 1998;16:3412-3425.[Abstract]
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Abels R. Erythropoietin for anaemia in cancer patients. Eur J Cancer 1993;29(suppl 2):S2-S8.
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Cella D. Factors influencing quality of life in cancer patients: anemia and fatigue. Semin Oncol 1998;25:43-46.[Medline]
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Ludwig H, Fritz E. Anemia in cancer patients. Semin Oncol 1998;25:2-6.
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Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91:1616-1634.[Abstract/Free Full Text]
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Bray GL, Reaman GH. Erythropoietin deficiency: a complication of cisplatin therapy and its treatment with recombinant human erythropoietin. Am J Pediatr Hematol Oncol 1991;13:426-430.[Medline]
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Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin level for optimum quality of life: results of an incremental analysis. Proc Am Soc Clin Oncol 1999;18:574a.
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Gabrilove JL, Einhorn LH, Livingston RB et al. Once-weekly dosing of epoetin alfa is similar to three-times-weekly dosing in increasing hemoglobin and quality of life. Proc Am Soc Clin Oncol 1999;18:574a.
Received April 7, 2000;
accepted for publication April 21, 2000.
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Abstract
Introduction
