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a University of California Los Angeles, Los Angeles, California, USA; b Hôpital Saint Louis, University of Paris, Paris, France; c Centre University and Luxembourg Medical Centre, Luxembourg; d Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA; e PROCRIT Study Group
Correspondence: George D. Demetri, M.D., Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA. Telephone: 617-623-3985; Fax: 617-623-3408; e-mail:george_demetri{at}dfci.harvard.edu
LEARNING OBJECTIVES
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Learning Objectives
Abstract
Introduction
Methods
Results
Discussion
References
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ABSTRACT |
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Patients and Methods. Patients received epoetin alfa 150-300 IU/kg (Glaspy: Study 1; n = 2,342) or 10,000-20,000 IU (Demetri: Study 2; n = 2,370) s.c. three times each week for 4 months. Efficacy end points were changes in transfusion requirements, hemoglobin (Hb) levels, and quality of life (QOL). A total of 4,298 out of 4,712 patients (platinum-based, n = 1,601; nonplatinum-based, n = 2,697), who both received chemotherapy and had available data, were eligible for this retrospective analysis.
Results. Baseline characteristics across groups were comparable with few exceptions, which were anticipated in view of the characteristics of the two different chemotherapy types. Decreases in transfusion requirements after 2, 3, and 4 months were significant, regardless of chemotherapy type. Mean increases in Hb level from baseline to final evaluation ranged from 1.6 g/dl to 2.0 g/dl across study groups and were significant, regardless of chemotherapy type. QOL, as measured by the Linear Analog Scale Assessment (LASA), improved significantly by 20%-43%, regardless of chemotherapy type, and improvements were associated with increases in Hb. Epoetin alfa was well tolerated in both studies, regardless of chemotherapy type.
Conclusion. Treatment of anemic cancer patients with epoetin alfa results in significant reduction in transfusion requirements, increase in Hb levels, and improvements in QOL, regardless of whether the chemotherapy is platinum- or nonplatinum-based.
Key Words. Hemoglobin • Anemia • Quality of life • Epoetin alfa
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INTRODUCTION |
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Numerous clinical studies have documented the efficacy of recombinant human erythropoietin (rHuEPO, epoetin alfa), the hematologic growth factor that regulates the proliferation, maturation, and differentiation of red blood cells, in correcting anemia associated with chemotherapy for a variety of malignancies [5–13]. In all of these trials, treatment with epoetin alfa consistently increased hematocrit or hemoglobin (Hb) levels and reduced the need for transfusion; several studies evaluated QOL and demonstrated improvements that were associated with increased Hb [11–13]. A series of clinical studies evaluated the efficacy of epoetin alfa in patients undergoing platinum- and nonplatinum-based chemotherapy, with results demonstrating no differences in efficacy between chemotherapy types [7]. A recent placebo-controlled trial with patients receiving only nonplatinum-based chemotherapy (n = 375) demonstrated that epoetin alfa significantly decreased transfusion requirements, increased Hb, and led to improved QOL, especially as it related to energy levels, ability to perform daily activities, and overall QOL [13].
The clinical efficacy of epoetin alfa in ameliorating anemia in the community setting was demonstrated in two large, community-based trials with a combined patient population of more than 4,000 patients who received a variety of platinum- and nonplatinum-based chemotherapy regimens [11, 12]. The retrospective subanalysis reported here used this large database to further explore the efficacy of epoetin alfa based on chemotherapy type and to address the question of potential differences in clinical and QOL outcomes in patients who received platinum- and nonplatinum-based chemotherapy regimens.
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METHODS |
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Treatment Protocols
The dosing regimen for epoetin alfa (administered as PROCRIT®; manufactured by Amgen Inc. and distributed and marketed by Ortho Biotech Products, LP, in the U.S. Outside of the U.S., epoetin alfa is manufactured by Ortho Biologics, LLC and distributed and marketed as EPREX® or ERYPO® by Ortho Biotech and Janssen-Cilag) in both studies was s.c. administration three times each week (tiw). In Study 1, epoetin alfa was initiated at 150 IU/kg each dose; the dosage was to be increased to 300 IU/kg if patient response, with regard to transfusion requirements and hematocrit level, was estimated by the clinician to be inadequate after 8 weeks of therapy. If the hematocrit rose to greater than 40% or increased more than four percentage points in a 2-week period, epoetin alfa was to be withheld until the hematocrit decreased to 36% or less, then was to be restarted at a 25% reduced dose and titrated to maintain desired hematocrit.
In Study 2, epoetin alfa was initiated at 10,000 IU each dose; dosage was to be increased to 20,000 IU after 4 weeks of therapy if Hb increased by less than 1.0 g/dl, and discontinued after an additional 4 weeks if Hb increase from baseline remained less than 1.0 g/dl. If Hb increased to over 13 g/dl or increased by more than 1 g/dl in any 2-week period, epoetin alfa was to be withheld until Hb decreased to 12 g/dl and then restarted at a 25% reduced dose and titrated to maintain the desired Hb level.
No specific guidelines for transfusion were defined in either study, since the decision to administer transfusion was left to the clinical discretion of the treating physician. Also, no guidelines were provided for administration of supplemental iron. However, as indicated in Study 1, evaluation of patients' iron status before and during epoetin alfa therapy was advisable, since virtually every patient requires iron supplementation to prevent restriction of erythropoiesis.
Efficacy Evaluations
Efficacy end points in both studies were changes from baseline in transfusion requirements, Hb levels, and QOL measures. QOL was measured by the Linear Analog Scale Assessment (LASA, also known as the Cancer Linear Analog Scale, or CLAS) in both studies, and with the Functional Assessment of Cancer Therapy-Anemia (FACT-An) in Study 2. Both the LASA and the FACT-An are validated, cancer-specific, patient-administered questionnaires [11, 12, 14, 15]. The LASA consists of three 100-mm linear analog scales that measure Energy Level, Ability to Do Daily Activities, and Overall QOL. On each scale, the left extreme represents the worst possible score (0 mm) and the right extreme represents the best possible score (100 mm). Patients rate their perception of each measure by placing a mark at the appropriate spot on each line. Patients from both studies completed the LASA at baseline and at the end of the study; patients from Study 2 also completed the LASA at month 2. The FACT-An includes the FACT-General core questionnaire, which measures the four general domains of QOL (physical, social/family, emotional, and functional well-being), plus the Anemia and Fatigue subscales, which assess the impact of fatigue and other anemia-related symptoms on the patient. Patients from Study 2 completed this instrument at baseline, month 2, and the end of the study. In addition, tumor response was analyzed prospectively in Study 2.
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RESULTS |
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) with two exceptions. As anticipated, there was an uneven distribution of malignancy types between patients who received platinum and nonplatinum chemotherapy. Specifically, there were higher percentages of patients with breast, gastrointestinal, and hematologic malignancies in the nonplatinum chemotherapy group, and higher percentages of patients with lung and gynecologic malignancies in the platinum chemotherapy group. In addition, in Study 2, a significantly (p < 0.05) greater percentage of patients who received nonplatinum chemotherapy required transfusions at baseline (29.8%) compared with patients who received platinum-based chemotherapy (17.7%). Mean Hb level was 9.3 g/dl for all groups, and 18%-30% of patients received a transfusion within 1 month of the start of the studies. Baseline QOL scores were relatively poor, with LASA scores for Energy and Ability to Do Daily Activities below 40 mm, and Overall QOL below 50 mm, on the 100-mm linear analog scale. Normal scores are usually in the 80 mm+ range.
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Hemoglobin Changes
Significant (p < 0.001) and comparable increases from baseline in mean Hb levels were noted for all patients, regardless of chemotherapy type (Table 2
). For patients who received nonplatinum-based chemotherapy, mean increases in Hb were 1.6 g/dl and 1.9 g/dl (in Study 1 and 2, respectively). Similar increases were noted in patients who received platinum-based chemotherapy (1.8 g/dl and 2.0 g/dl for Study 1 and 2, respectively). Mean Hb levels at baseline and at the 4 monthly evaluations for platinum- and nonplatinum-treated patients in each study are displayed in Figure 1.
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). In general, the increases were comparable among patients who received nonplatinum- and platinum-based chemotherapy: Energy Level improved between 29% and 43%, Ability to Do Daily Activities improved between 28% and 34%, and Overall QOL improved between 20% and 27%.
As shown in Figure 2, increases in Hb levels were associated with significant improvements in Energy Level, Ability to Do Daily Activities, and Overall QOL, as measured by the LASA for patients who received nonplatinum-based (p < 0.001) and platinum-based (p < 0.05) chemotherapy. As Hb level increased, improvements in QOL increased. Change in QOL was assessed by disease response in Study 2 (Figs. 3 and 4). Results of these analyses showed that increases in Hb levels were associated with improvements in QOL for patients who received nonplatinum- or platinum-based chemotherapy and achieved complete response or partial response, or had stable disease, as a result of the chemotherapy. Overall, patients in both chemotherapy categories who had progressive disease experienced slight improvements in QOL as Hb levels increased.
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, mean improvements in all parameters were significant (p 
0.001) for patients whose Hb level increased by 
2 g/dl, and were comparable among patients who received nonplatinum- and platinum-based chemotherapy. Mean improvement was also significant (p 0.05) for Energy Level for patients in both chemotherapy groups who had increases in Hb <2 g/dl.
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Prognostic Factors for Responsiveness to Epoetin Alfa
In Study 2, several baseline variables for the patients in the two chemotherapy groups combined were analyzed to determine any prognostic value of these variables with respect to response to treatment. Erythropoietin level, tumor type, previous chemotherapy, chemotherapy regimen (cisplatin versus noncisplatin, single-agent versus combination), and baseline Hb level were not predictive of sensitivity or resistance to epoetin alfa; however, patients who had not required prestudy transfusions were significantly (p 0.001) more likely to respond to this agent. Also, 81% of patients who had an increase in Hb level of 1 g/dl by week 4 had a meaningful (2 g/dl) increase in Hb level by study end, suggesting that early response was predictive of successful treatment. However, 44% of patients who initially appeared resistant to epoetin alfa, but had a dose increase, also achieved a meaningful increase in Hb level by study end, indicating that further treatment may eventually lead to clinical improvement. The results of Study 1 similarly showed that more patients who achieved an Hb increase of 1 g/dl by week 4 had a 2 g/dl Hb increase by the end of the study than patients whose Hb increase by week 4 was <1 g/dl (75.1% versus 29.5%, respectively). Also, the likelihood of a meaningful increase in Hb level was greater for patients who did not undergo transfusion during the first 4 weeks of the study, compared with patients who were transfused during this interval (57.4% versus 39.1%).
Safety
Epoetin alfa was well tolerated. The only adverse event reported in either of the two studies as possibly drug-related was hypertension, which occurred in approximately 1% of patients.
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DISCUSSION |
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The continuing development of new nonplatinum chemotherapy agents has focused recent investigation on the efficacy of epoetin alfa specifically in patients who are receiving nonplatinum chemotherapy. Early placebo-controlled studies evaluated the efficacy of epoetin alfa by chemotherapy type (cisplatin, n = 132; noncisplatin, n = 157; or no chemotherapy, n = 124) [7]. Analyses showed that epoetin alfa resulted in significantly greater increases in hematocrit (p < 0.004) than did placebo, both in patients who received cisplatin and in those who received noncisplatin chemotherapy, and that these increases were comparable between cisplatin and noncisplatin regimens (6.9% and 6.0%, respectively) [7]. Further, for the two chemotherapy groups combined, epoetin alfa treatment, compared with placebo treatment, resulted in a significantly smaller mean proportion of patients transfused (28% versus 46%, p 0.005) and significantly fewer units of blood transfused per patient (1.04 versus 1.81, p = 0.009) over months 2 and 3 combined. QOL, as assessed with the LASA, was also significantly (p < 0.05) improved among patients who responded to epoetin alfa (increases ranging from approximately 11 mm to 13 mm) compared with patients treated with placebo (whose changes ranged from approximately +4 mm to –2 mm); results were not analyzed by chemotherapy group.
A more recent placebo-controlled study (n = 375) specifically investigated epoetin alfa in patients who received nonplatinum chemotherapy, most frequently cyclophosphamide, doxorubicin, vincristine, and fluorouracil [13]. The most common malignancies were breast cancer, non-Hodgkin's lymphoma, and myeloma. Compared with placebo, epoetin alfa significantly decreased transfusion requirements (24.7% versus 39.5%; p = 0.0057), increased Hb (2.2 g/dl versus 0.5 g/dl; p < 0.001), and improved all primary cancer- and anemia-specific QOL domains (p < 0.01). These results were consistent with published clinical studies in which all chemotherapy regimens were included [5, 8, 9, 11, 12, 16].
Results of the subanalysis presented here, based on data from over 4,700 patients from two large, community-based studies, demonstrated that regardless of chemotherapy type, epoetin alfa significantly increased Hb levels (p < 0.001), reduced transfusion requirements (p < 0.001), and improved QOL (p < 0.001). In addition, as in the two overall studies, for both chemotherapy types, larger increases in Hb were associated with greater improvements in QOL. For patients from Study 2, this relationship was demonstrated for those whose responses to chemotherapy were categorized as complete, partial, or stable disease.
One rather surprising finding in both studies was that about half of all treating physicians in the community practices did not increase the epoetin alfa dosage in patients who failed to achieve an adequate hematologic response or who remained transfusion-dependent during treatment. This finding indicates a need for the development of and adherence to specific guidelines for the use of epoetin alfa, in order to optimize usage of this agent.
Several studies have demonstrated the importance of anemia and fatigue in chemotherapy-treated cancer patients: fatigue has been shown to have a relatively greater negative impact on QOL than other cancer-related symptoms [1, 3, 4, 17–19], and patients with Hb levels 12 g/dl have reported significantly less fatigue and better physical and functional well-being on the FACT-An questionnaire than patients with Hb levels <12 g/dl [15]. Thus, the relationship demonstrated in Study 2 between an epoetin alfa-induced increase in Hb level and improvement in fatigue-related QOL parameters, as measured by the FACT-An questionnaire, is of particular importance. Specifically, this study showed significant (p 0.001) improvement in four FACT-An items reflecting direct functional consequences of fatigue (i.e., lack of energy, need for bed rest, ability to carry out usual activities, ability to work) in patients who achieved an Hb increase of 2 g/dl with epoetin alfa. Moreover, the improvements achieved were comparable among patients in the platinum and nonplatinum treatment groups. Collectively, the data obtained in Studies 1 and 2 support the efficacy and safety of epoetin alfa for anemia management in cancer patients receiving chemotherapy, irrespective of the type of therapy (nonplatinum- or platinum-based) administered. Further, by demonstrating significant improvement in QOL in patients with mild or moderate anemia (mean Hb ~9.3 g/dl), these data suggest that treatment of anemia should be initiated early, i.e., before Hb levels reach the traditional transfusion trigger level of 7-8 g/dl. These findings are consistent with those of several other studies reported in the literature. In one study [20], the greatest incremental improvement in QOL was observed when the Hb level increased from 11 g/dl to 12 g/dl (range, 11-13 g/dl), which is considered the lower level of normal. Further, incremental analysis of data from a large, multinational, placebo-controlled study [13] found consistent, large improvements in QOL for each 1-g/dl change in Hb up to 13 g/dl. QOL continued to improve beyond levels of 12-13 g/dl, but at a slower rate. These analyses suggest that optimal management of Hb, i.e., to a final Hb of 12-13 g/dl, results in the greatest incremental gains in QOL [21].
In summary, the efficacy of epoetin alfa in ameliorating anemia associated with cancer has been demonstrated repeatedly over the past decade of use. Results from this subanalysis underscore the comparable efficacy and safety of epoetin alfa in patients with a variety of tumor types receiving both platinum- and nonplatinum-based chemotherapy regimens.
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ACKNOWLEDGMENT |
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G.D.D. is a consultant for Ortho Biotech, Amgen, and Pharmacia. M.D. receives Congress support from Ortho Biotech. J.G. receives research support from Amgen and Ortho Biotech.
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REFERENCES |
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This article has been cited by other articles:
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  J. L. Ryan, J. K. Carroll, E. P. Ryan, K. M. Mustian, K. Fiscella, and G. R. Morrow Mechanisms of Cancer-Related Fatigue Oncologist, May 1, 2007; 12(suppl_1): 22 - 34. [Abstract] [Full Text] [PDF]
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 T. Watson and V. Mock Exercise as an Intervention for Cancer-Related Fatigue Physical Therapy, August 1, 2004; 84(8): 736 - 743. [Full Text] [PDF]
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E. Cortesi, A. Mancuso, A. De Pasquale Ceratti, N. Pizzardi, G. D'Auria, C. Accettura, P. Beccaglia, D. Bertelletti, and F. De Marinis Effectiveness and Safety of an Induction Therapy with Epoetin Alfa in Anemic Cancer Patients Receiving Concomitant Chemotherapy Oncologist, July 1, 2004; 9(4): 459 - 468. [Abstract] [Full Text] [PDF]
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M. Dicato Anemia in Cancer: Some Pathophysiological Aspects Oncologist, February 1, 2003; 8(90001): 19 - 21. [Abstract] [Full Text] [PDF]
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