The. JOHN GLASPY, a,e LAURENT DEGOS, b,e MARIO DICATO, c,e GEORGE D. DEMETRI d,e LEARNING OBJECTIVES ABSTRACT

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1 The Oncologist Comparable Efficacy of Epoetin Alfa for Anemic Cancer Patients Receiving Platinum- and Nonplatinum-Based Chemotherapy: A Retrospective Subanalysis of Two Large, Community-Based Trials JOHN GLASPY, a,e LAURENT DEGOS, b,e MARIO DICATO, c,e GEORGE D. DEMETRI d,e 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 LEARNING OBJECTIVES After completing this course, the reader will be able to: ABSTRACT Background. Data from two large, community-based clinical trials that evaluated the efficacy of epoetin alfa in anemic cancer patients receiving chemotherapy were retrospectively analyzed to determine if clinical outcomes were different depending on whether chemotherapy was platinum- or nonplatinum-based. Patients and Methods. Patients received epoetin alfa 15-3 IU/kg (Glaspy: Study 1; n = 2,342) or,- 2, IU (Demetri: Study 2; n = 2,37) 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 = 1,61; nonplatinum-based, n = Key Words. Hemoglobin Anemia Quality of life Epoetin alfa 1. Understand the etiology, symptoms, and impact (as reported by patients) of cancer- and chemotherapy-associated anemia. 2. Recognize the clinical evidence supporting the efficacy of epoetin alfa in reducing transfusion requirements, increasing hemoglobin levels, and improving quality-of-life in anemic cancer patients receiving platinum- versus nonplatinum-based chemotherapy. 3. Identify potential prognostic factors for responsiveness to epoetin alfa. CME Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com 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. 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 2%-43%, regardless of chemotherapy type, and improvements were Downloaded from by guest on January 13, 219 Correspondence: George D. Demetri, M.D., Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 2115, USA. Telephone: ; Fax: ; george_demetri@dfci.harvard.edu Received November 11, 21; accepted for publication February 13, 22. AlphaMed Press /22/$5./ The Oncologist 22;7:

2 127 Epoetin Alfa and Chemotherapy Type 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. The Oncologist 22;7: INTRODUCTION The etiology of cancer-related anemia is multifactorial and includes intrinsic factors such as anemia of chronic disease, bone marrow involvement, blood loss, and nutritional deficiencies; and extrinsic factors such as the use of radiotherapy and chemotherapy. Chemotherapy-associated anemia has been observed with single-agent and combination regimens, both platinum- and nonplatinum-based [1]. Multiple mechanisms may be involved in chemotherapyassociated anemia, a serious complication that causes fatigue, exhaustion, weakness, headache, cardiac decompensation, and impaired quality of life (QOL) [2-4]. 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, 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. METHODS Data were analyzed from two 4-month, open-label, multicenter, community-based trials in anemic cancer patients. All patients selected had to have solid or nonmyeloid hematologic malignancies for which they were receiving platinum- or nonplatinum-based chemotherapy, and a life expectancy of 6 months or greater. Exclusion criteria included anemia known to be caused by factors other than cancer or chemotherapy, e.g., iron or folate deficiency, and hemolysis; however, screening for these laboratory abnormalities was not required by the protocol. The full study design and results for both studies, referred to in this subanalysis as Study 1 (Glaspy: n = 2,342) and Study 2 (Demetri: n = 2,37), have been published previously [11, 12]. In this subanalysis, all patients from both studies were divided into two groups by type of chemotherapy (platinum or nonplatinum). 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 15 IU/kg each dose; the dosage was to be increased to 3 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 4% 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, IU each dose; dosage was to be increased to 2, IU after 4 weeks of therapy if Hb increased by less than 1. g/dl, and discontinued after an additional 4 weeks if Hb increase from baseline remained less than 1. 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 Downloaded from by guest on January 13, 219

3 Glaspy, Degos, Dicato et al. 128 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 -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 ( mm) and the right extreme represents the best possible score ( 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 wellbeing), 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. RESULTS A total of 4,298 out of 4,712 patients (Study 1: 2,9; Study 2: 2,289), who not only received chemotherapy but also had available data, were eligible for this retrospective analysis. Patients from both studies were combined and divided into two groups based on whether chemotherapy was platinum-based or nonplatinum-based. The nonplatinum-based group consisted of 2,697 patients (1,216 from Study 1 and 1,481 from Study 2). The platinum-based group consisted of 1,61 patients (793 from Study 1, and 88 from Study 2). Demographics and baseline characteristics among groups were comparable (Table 1) 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 <.5) 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%-3% 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 4 mm, and Overall QOL below 5 mm, on the -mm linear analog scale. Normal scores are usually in the 8 mm+ range. Changes in Transfusion Requirements In both studies, significant (p <.1) decreases in transfusion requirements from baseline rates were noted at months 2, 3, and 4 with epoetin alfa treatment for patients who received nonplatinum- and platinum-based chemotherapy. In Study 2, the percentage of nonplatinum-treated patients requiring transfusions was decreased by as much as 25 percentage points, i.e., from 29.8% to 4.7% (Table 2). No differences in transfusion requirements were noted between chemotherapy types in Study 1. In Study 2, there were significant (p <.5) differences between chemotherapy types in the percentages of patients who received transfusions at baseline, as well as at months 1 and 2; however, these differences were not observed after month 2. Hemoglobin Changes Significant (p <.1) 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. 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. QOL Changes Significant (p <.1) improvements from baseline, for patients who had both baseline and final evaluations, were reported for all three QOL domains as measured by LASA (Table 2). 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 2% 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 <.1) and platinum-based (p <.5) chemotherapy. As Hb level increased, improvements in QOL increased. Change in Downloaded from by guest on January 13, 219

4 129 Epoetin Alfa and Chemotherapy Type Table 1. Baseline characteristics (n = 4,298) Nonplatinum PatientsPlatinum Patients Study 1 Study 2 Study 1 Study 2 (Glaspy) (Demetri) (Glaspy) (Demetri) (n = 1,216) (n = 1,481) (n = 793) (n = 88) A) Demographic and hematologic Sex, n (%) Male 443 (36) 583 (39) 319 (4) 32 (4) Female 773 (64) 898 (61) 474 (6) 488 (6) Mean age, years Primary malignancy, n a (%) Solid Breast 332 (27) 359 (24) 33 (4) 23 (3) Gastrointestinal 117 () 175 (12) 5 (<1) 29 (3) Lung 92 (8) 164 (11) 355 (45) 381 (46) Gynecologic 81 (7) 9 (6) 23 (26) 27 (25) Other 275 (22) 217 (15) 56 (7) 159 (18) Hematologic 327 (27) 476 (32) 14 (18) 39 (5) Mean Hb (g/dl) Transfused 1 month prior to study start (%) b b B) QOL Measurements LASA, mm (range: 1- mm) Energy level Ability to do daily activities Overall QOL a Total number of tumors was higher than total number of patients in Study 2. b p <.5, between nonplatinum and platinum patients, Study 2 only. Abbreviations: QOL = quality of life; Hb = hemoglobin; LASA = Linear Analog Scale Assessment (also known as Cancer Linear Analog Scale, or CLAS); FACT-An = Functional Assessment of Cancer Therapy-Anemia. 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. QOL was also assessed in Study 2 using the FACT-An. When increases in FACT-An scores were analyzed by tumor response and change in Hb, there was a trend toward greater improvements in QOL with larger increases in Hb seen among all patients with complete response, partial response, or stable disease, whether they received nonplatinum- or platinum-based chemotherapy. For both chemotherapy types, patients whose Hb levels increased and those with progressive disease experienced neither a significant increase nor significant decrease in QOL (Fig. 5). Four statements from the FACT-An questionnaire were selected as representative of the direct functional consequences of fatigue and were analyzed by change in Hb for patients in Study 2. These statements were: A) I have a lack of energy; B) I am forced to spend time in bed; C) I am able to do my usual activities, and D) I am able to work (includes work at home). As shown in Figure 6, mean improvements in all parameters were significant (p.1) 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.5) for Energy Level for patients in both chemotherapy groups who had increases in Hb <2 g/dl. Dosages Employed Both study protocols recommended doubling the starting dose of epoetin alfa in the event of an inadequate response; this was to be done after 8 weeks of treatment in Downloaded from by guest on January 13, 219

5 Glaspy, Degos, Dicato et al. 13 Mean hemoglobin level (g/dl) Table 2. Summary of results Study 1 (based on no decreased transfusion requirements or no increased hematocrit) and after 4 weeks in Study 2 (based on Hb increase <1 g/dl). However, in Study 1, the physicians did not always increase the starting dose in patients who failed to exhibit an increase in hematocrit level or who continued to require transfusion(s) while receiving epoetin alfa. Of 1,47 patients who completed 4 months of epoetin alfa therapy, 233 received one or more Nonplatinum PatientsPlatinum Patients Study 1 Study 2 Study 1 Study 2 (Glaspy) (Demetri) (Glaspy) (Demetri) Transfused (%) Month 1 (baseline) a a Month a, b a, c Month b 11.1 a, b 15.1 b 9.7 a, b Month b 8. b 9.7 b 6.6 b Month b 4.7 b 8.6 b 6. b Mean Hb (g/dl) Baseline Final Change from baseline 1.6 b 1.9 b 1.8 b 2. b Change in QOL from baseline LASA, mm (% improvement) Energy level 13.9 (35) b 11.6 (29) b 16.4 (43) b 11.4 (29) b Ability to do daily activities 12.6 (31) b 11.2 (28) b 13.7 (34) b 11. (28) b Overall QOL.1 (22) b 9.5 (2) b 12.3 (27) b.2 (22) b a p <.5, between nonplatinum and platinum patients, Study 2 only. b p <.1, from baseline. c p <.5, from baseline. Abbreviations: Hb = hemoglobin; QOL = quality of life; LASA = Linear Analog Scale Assessment (also known as Cancer Linear Analog Scale, or CLAS). Nonplatinum chemotherapy study 1 Nonplatinum chemotherapy study 2 Platinum chemotherapy study 1 Platinum chemotherapy study 2 Baseline Month 1 Month 2 Month 3 Month 4 transfusions during treatment. One hundred fourteen (49%) of these patients had an increase in their starting dose, but the remaining 119 patients (51%) had no dose adjustment or actually had their dosage reduced. This dosing pattern is reflected in the similarity of total weekly epoetin alfa doses (mean ± standard deviation; IU/kg/wk) for the completers across the 4-month study period, i.e., ± 58. at month 1, 438. ± 9.9 at month 2, ± at month 3, and ± at month 4 (overall mean dose not specified). Mean values for the 2,3 patients eligible for efficacy analysis were comparable at the respective time intervals. In Study 2, 847 of all 2,289 patients eligible for efficacy analysis had Hb increases of <1. g/dl after 4 weeks. Of these, 525 (62%) had the recommended increase of epoetin alfa to 2, IU tiw. The mean weekly dose of epoetin alfa for all eligible patients ranged from 32, IU to 4, IU, with the doses fairly stable after month 2 (mean dosage per month not specified). Doses of epoetin alfa for patients who did not achieve increases in Hb level ranged from 33, IU to 49, IU per week. Dosage changes were not analyzed by subgroup for either study. Downloaded from by guest on January 13, 219 p <.7 from baseline for all groups (adjusted for multiple comparisons). p <.7 from previous month for all groups (adjusted for multiple comparisons). Figure 1. Mean hemoglobin levels by month for platinum/nonplatinum patients in Studies 1 and 2. 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,

6 131 Epoetin Alfa and Chemotherapy Type Change in LASA (%) Change in LASA (%) A Nonplatinum chemotherapy group (Study 1, n = 883) Energy Activity Overall QOL p <.1 < (n = 154) >-2 (n = 34) 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.1) 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%). (n = 268) (n = 121) C Platinum chemotherapy group (Study 1, n = 597) Energy Activity Overall QOL < (n = 7) p.1 p.5 >-2 (n = 192) (n = 19) (n = 8) Change in LASA (%) Change in LASA (%) B Nonplatinum chemotherapy group (Study 2, n = 1,81) Energy Activity Overall QOL p <.1 < (n = 136) >-2 (n = 369) (n = 45) (n = 171) D Platinum chemotherapy group (Study 2, n = 676) Energy Activity Overall QOL < (n = 83) p.1 p.5 >-2 (n = 239) (n = 24) (n = 114) Figure 2. Mean percentage change in Linear Analog Scale Assessment (LASA) by hemoglobin (Hb) change for patients with baseline and final quality of life (QOL) and Hb values. 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. DISCUSSION Many factors contribute to anemia in patients with cancer. Regardless of the primary cause, the majority of patients with anemia experience fatigue, exhaustion, and decreased QOL. With the introduction of epoetin alfa in the early 199s, a treatment became available to effectively attenuate or correct anemia in cancer patients. Many placebo-controlled and open-label clinical trials have consistently demonstrated that epoetin alfa effectively increases Hb levels, decreases transfusion requirements, and improves cancer- and anemia-specific measures of QOL [5-7, 9, 11-13, 16], independent of tumor response to chemotherapy [12]. These results were reported in patients with a variety of nonmyeloid tumor types receiving many different chemotherapy regimens, both platinum- and nonplatinum-based. The continuing development of new nonplatinum chemotherapy agents has focused recent investigation on the Downloaded from by guest on January 13, 219

7 Glaspy, Degos, Dicato et al. 132 A Complete response (n = 185) 4 Energy Activity Overall QOL B Partial response (n = 245) 4 Energy Activity Overall QOL < (n = 12) >-2 (n = 56) (n = 71) (n = 46) -2 < (n = 25) >-2 (n = 74) (n = 7) (n = 39) p.1 p.1 p.5 C Stable disease (n = 296) 4 Energy Activity Overall QOL < (n = 38) p.1 p.5 >-2 (n = 98) (n = 12) (n = 4) 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 <.4) 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.%, 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.5) and significantly fewer units of blood transfused per patient (1.4 versus 1.81, p =.9) over months 2 and 3 combined. QOL, as assessed with the LASA, was also significantly (p <.5) 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. D Progressive disease (n = 289) 4 Energy Activity Overall QOL < (n = 5) >-2 (n = 116) (n = 86) (n = 37) Figure 3. Mean change in Linear Analog Scale Assessment (LASA) by hemoglobin (Hb) change (baseline to final) and tumor response in patients who received nonplatinum chemotherapy in Study 2. 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 =.57), increased Hb (2.2 g/dl versus.5 g/dl; p <.1), and improved all primary cancer- and anemia-specific QOL domains (p <.1). 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 4,7 patients from two large, community-based studies, demonstrated that regardless of chemotherapy type, epoetin alfa significantly increased Hb levels (p <.1), reduced transfusion requirements (p <.1), and improved QOL (p <.1). 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 Downloaded from by guest on January 13, 219

8 133 Epoetin Alfa and Chemotherapy Type A Complete response (n = 138) 4 Energy Activity Overall QOL B Partial response (n = 175) 4 Energy Activity Overall QOL p <.1 < (n = 9) >-2 (n = 37) (n = 52) (n = 4) < (n = 18) p.1 p.5 >-2 (n = 59) (n = 67) (n = 31) Mean change in FACT-An C Stable disease (n = 161) 4 Energy Activity Overall QOL A Nonplatinum chemotherapy group 3 Progressive disease Partial response < (n = 25) p.1 p.5 >-2 (n = 56) Stable disease (n = 6) Complete response (n = 2) < >-2 B Platinum chemotherapy group 3 Progressive disease Partial response Stable disease Complete response 25 Mean change in FACT-An D Progressive disease (n = 155) Energy Activity Overall QOL < (n = 25) >-2 (n = 67) (n = 45) < >-2 (n = 18) Figure 4. Mean change in Linear Analog Scale Assessment (LASA) by hemoglobin (Hb) change (baseline to final) and tumor response in patients who received platinum chemotherapy in Study 2. Downloaded from by guest on January 13, 219 Figure 5. Mean change in Functional Assessment of Cancer Therapy-Anemia (FACT-An) by hemoglobin (Hb) change (baseline to final) and tumor response in Study 2. Statistics not analyzed. 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,

9 Glaspy, Degos, Dicato et al. 134 Mean change in QOL A Nonplatinum chemotherapy group B Platinum chemotherapy group Hb change 2 g/dl Hb change <2 g/dl 2 Mean change in QOL 15 5 Hb change 2 g/dl Hb change <2 g/dl -5 Energy level p.1 p.5 Less time in bed Ability to do usual activities Ability to work -5 Energy level p.1 p.5 Less time in bed Ability to do usual activities Ability to work Figure 6. Mean change in four fatigue-related Functional Assessment of Cancer Therapy-Anemia (FACT-An) questions by hemoglobin (Hb) change (baseline to final) and tumor response in Study ], and patients with Hb levels 12 g/dl have reported significantly less fatigue and better physical and functional wellbeing 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.1) 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 [2], the greatest incremental improvement in QOL was observed when the Hb level increased from 11 g/dl to 12 g/dl (range, 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 g/dl, but at a slower rate. These analyses suggest that optimal management of Hb, i.e., to a final Hb of 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. ACKNOWLEDGMENTS This analysis was supported by a research grant from Ortho Biotech Products, L.P., Raritan, NJ. This publication was supported by Ortho Biotech, a division of Janssen-Cilag in Europe. 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. Downloaded from by guest on January 13, 219 REFERENCES 1 Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91: Ludwig H, Leitgeb C, Fritz E et al. Erythropoietin treatment of chronic anaemia of cancer. Eur J Cancer 1993;29A(suppl 2):S8-S12. 3 Cella D. Factors influencing quality of life in cancer patients: anemia and fatigue. Semin Oncol 1998;25(3 suppl 7): Portenoy RK, Itri LM. Cancer-related fatigue: guidelines for evaluation and management. The Oncologist 1999;4:1-.

10 135 Epoetin Alfa and Chemotherapy Type 5 Ludwig H, Fritz E, Kotzmann H et al. Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 199;322: Abels RI. Recombinant human erythropoietin in the treatment of the anaemia of cancer. Acta Haematol 1992;87(suppl 1): Abels R. Erythropoietin for anaemia in cancer patients. Eur J Cancer 1993;29A(suppl 2):S2-S8. 8 Henry DH, Abels RI. Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: results of double-blind and open-label follow-up studies. Semin Oncol 1994;21(2 suppl 3): Leitgeb C, Pecherstorfer M, Fritz E et al. Quality of life in chronic anemia of cancer during treatment with recombinant human erythropoietin. Cancer 1994;73: de Campos E, Radford J, Steward W et al. Clinical and in vitro effects of recombinant human erythropoietin in patients receiving intensive chemotherapy for small-cell lung cancer. J Clin Oncol 1995;13: 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. Procrit Study Group. J Clin Oncol 1997;15: 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. Procrit Study Group. J Clin Oncol 1998;16: Littlewood TJ, Bajetta E, Nortier JW et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 21;19: Maxwell C. Sensitivity and accuracy of the visual analogue scale: a psycho-physical classroom experiment. Br J Clin Pharmacol 1978;6: Cella D. The Functional Assessment of Cancer Therapy- Anemia (FACT-An) scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 1997;34(3 suppl 2): Gabrilove JL, Cleeland CS, Livingston RB et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life similar to three-times-weekly dosing. J Clin Oncol 21;19: Winningham ML, Nail LM, Burke MB et al. Fatigue and the cancer experience: the state of the knowledge. Oncol Nurs Forum 1994;21: Vogelzang NJ, Breitbart W, Cella D et al. Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol 1997;34(3 suppl 2): Curt GA, Breitbart W, Cella D et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. The Oncologist 2;5: Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin levels for optimal quality of life: results of an incremental analysis. Proc Am Soc Clin Oncol 1999;18:574a. 21 Nortier JWR, Zagari M, Chen Y. Incremental analysis to identify optimal hemoglobin levels to maximize quality of life improvement in anemic cancer patients receiving epoetin alfa. Ann Oncol 2;11:149a. Downloaded from by guest on January 13, 219 CME Access The Oncologist CME Online at: CME.TheOncologist.com