Oncologist. The. Symptom Management and Supportive Care

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1 The Oncologist Symptom Management and Supportive Care The Effectiveness of Darbepoetin Alfa Administered Every 3 Weeks on Hematologic Outcomes and Quality of Life in Older Patients With Chemotherapy-Induced Anemia RALPH BOCCIA, a TOM LILLIE, b DIANNE TOMITA, b LODOVICO BALDUCCI c a Georgetown University/Center for Cancer and Blood Disorders, Bethesda, Maryland, USA; b Amgen Inc., Thousand Oaks, California, USA; c H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA Key Words. Darbepoetin alfa Chemotherapy Anemia Hemoglobin ABSTRACT Chemotherapy-induced anemia (CIA) may substantially impact the health-related quality of life (HRQoL) of older cancer patients. This exploratory analysis evaluated the effect of darbepoetin alfa administered as a fixed dose (300 g) every 3 weeks (Q3W) on hematologic outcomes, HRQoL, and safety in older (>65 years old) versus younger (<65 years old) patients with CIA (hemoglobin <11g/dl). Patients were categorized by age at screening: <65, >65 to <70, >70 to <75, >75 to <80, and >80 years old. Patients who received at least one dose of darbepoetin alfa were included in the analysis; of 1,493 patients, 724 were >65 years old. Age did not appear to influence hematologic outcomes after treatment with darbepoetin alfa; in all age categories, similar percentages of patients (78% 80%) achieved the target hemoglobin in approximately the same time (4 5 weeks). Also, the percentage of patients in each age category who received RBC transfusions was reduced from 10% 13% in month 1 to 2% 4% in month 4. Although younger patients reported the greatest improvement in HRQoL scores, approximately one half in each older age category reported clinically significant improvement in fatigue, and improvement in the Energy and Overall Health Assessment and Work Productivity and Activity Impairment scales. There were no treatment-related deaths. Treatment-related thromboembolic events were reported by <1% of patients <65 years old and <1% of patients >65 to <70 and >70 to <75 years old. Darbepoetin alfa Q3W appeared well tolerated and effective for treating older patients with CIA. The Oncologist 2007;12: Disclosure of potential conflicts of interest is found at the end of this article. INTRODUCTION Anemia is a common complication for patients with cancer receiving myelosuppressive chemotherapy [1] and is associated with a number of symptoms that may adversely impact health-related quality of life (HRQoL). Fatigue is the most debilitating symptom of chemotherapy-induced anemia (CIA) and affects patients physical and emotional well-being as well as their ability to perform daily activities [2 5]. CIA may be particularly detrimental to the overall health and physical functioning of older patients ( 65 years old). Regardless of whether they have cancer, anemia in older patients is an independent risk factor for death, clinical complications such as cardiovascular Correspondence: Ralph Boccia, M.D., Georgetown University/Center for Cancer and Blood Disorders, 6420 Rockledge Drive, Bethesda, Maryland 20817, USA. Telephone: ; Fax: ; rboccia@ccbdmd.com Received December 20, 2006; accepted for publication February 11, AlphaMed Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

2 Boccia, Lillie, Tomita et al. 585 disease, and functional dependence (reviewed in [6]). Studies have shown that physical decline occurs in older individuals even if their hemoglobin levels are above the World Health Organization (WHO) criteria for anemia [7, 8] (defined as 12 g/dl for women and 13 g/dl for men). Likewise, older individuals have fewer disabilities and better physical performance and muscle strength if their hemoglobin levels are 2 g/dl above the WHO cutoff level for anemia [9]. CIA can be treated with the erythropoiesis-stimulating agents (ESAs), darbepoetin alfa and epoetin alfa, which increase hemoglobin levels and reduce the requirement for RBC transfusions, thus alleviating fatigue and improving patients HRQoL [10 13]. A number of clinical trials have evaluated the efficacy and safety of ESAs in patient populations that included a large percentage of patients 65 years old. However, few studies have focused on the treatment of CIA specifically in older patients. One small study compared hemoglobin concentrations in patients 70 years old (n 20) with patients 70 years old (n 20) after treatment with recombinant human erythropoietin (rhuepo) [14], but the effects of increasing hemoglobin on HRQoL were not investigated. Another small study (n 10) showed that increasing hemoglobin levels with rhuepo in CIA patients 65 years old improved their cognitive functions [15]. Darbepoetin appeared to be effective and well tolerated in patients with CIA when administered every 3 weeks (Q3W) [16 19], a dosing schedule that may reduce the number of clinic visits for patients and their caregivers. The objective of this exploratory analysis was to examine the effectiveness and safety of a fixed dose of darbepoetin alfa (300 g with an increase to 500 g if required) administered Q3W in different subsets of older patients ( 65 to 70, 70 to 75, 75 to 80, and 80 years old) versus younger patients ( 65 years old) with CIA. This is a new stratified analysis of data from the total study population (n 1,493) that have been published previously [16]. We assessed the effectiveness of darbepoetin alfa Q3W in achieving a hemoglobin concentration 11 g/dl and maintaining hemoglobin within the range recommended by evidence-based guidelines (11 13 g/dl [20 22]), the incidence of RBC transfusions, and changes in patient-reported outcomes that included fatigue, energy, and the effect of anemia and/or treatment with darbepoetin alfa on work productivity and ability to perform daily activities. To our knowledge, this is the first analysis of the effects of an ESA on clinical outcomes in a large population of older patients (n 724) with CIA. PATIENTS AND METHODS Patient Population The study protocol was approved by the institutional review board (IRB) of each participating site, and all patients provided a written, IRB-approved informed consent before study-related procedures were initiated. Patients were eligible for this study if they were 18 years old, had a nonmyeloid malignancy, were receiving at least eight additional weeks of chemotherapy, and were anemic (hemoglobin 11 g/dl) as a result of cancer and chemotherapy. Patients were excluded if they had inadequate renal and liver function, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndromes, unstable cardiac disease, active bleeding, active systemic or chronic infection, severe active chronic inflammatory disease, other hematologic disorders associated with anemia, uncontrolled hypertension, iron or other nutritional deficiencies, HIV, a history of pure red cell aplasia, or a history of positive antibody response to any erythropoietic agent. Patients were also excluded if they had previously enrolled in the study, had planned elective surgeries during the study period, had had RBC transfusions within 2 weeks of screening, had had erythropoietic therapy within 4 weeks of screening, had used drugs or devices not approved by the U.S. Food and Drug Administration for any indication within 30 days of screening, were pregnant or lactating, or had known hypersensitivity to mammalian cell derived products. Study Design In this multicenter, 16-week, single-arm, open-label study, darbepoetin alfa (Aranesp, Amgen Inc., Thousand Oaks, CA) was administered by s.c. injection to cancer patients with CIA at a fixed dose of 300 g Q3W. Patients received darbepoetin alfa for 13 weeks, with a follow-up visit at week 16. During the study, the dose of darbepoetin alfa was titrated to achieve a hemoglobin concentration 11 g/dl and maintain hemoglobin within the range of g/dl (as recommended by evidence-based guidelines [20 22]). The dose was reduced by 25% if the hemoglobin concentration increased 1 g/dl in a 2-week period, was withheld if hemoglobin exceeded 13 g/dl (but was reinitiated at a dose approximately 25% below the previous dose if hemoglobin fell to 12 g/dl), and was increased to 500 g Q3W if, after 6 weeks, hemoglobin concentration remained 10 g/dl and the increase from baseline was 1 g/dl. Physicians could exercise discretion regarding dose increases if the hemoglobin concentration was 10 g/dl but below the baseline hemoglobin concentration; however, the dose was not increased if hemoglobin was within the target range (

3 586 Darbepoetin Alfa in Older Patients with CIA Table 1. Patient demographics and baseline characteristics Patients by age category (years) Characteristic <65 (n 769) >65 to <70 (n 210) >70 to < 75 (n 205) >75 to < 80 (n 194) >80 (n 115) Women, n (%) 529 (69) 118 (56) 105 (51) 96 (49) 58 (50) Race, n (%) White 565 (73) 183 (87) 164 (80) 161 (83) 105 (91) Black 121 (16) 19 (9) 24 (12) 20 (10) 8 (7) Hispanic 52 (7) 6 (3) 7 (3) 13 (7) 2 (2) Asian 16 (2) 2 (1) 4 (2) 0 (0) 0 (0) Other 15 (2) 0 (0) 6 (3) 0 (0) 0 (0) Age (years) Mean (SD) 52.1 (9.1) 67.0 (1.4) 72.2 (1.4) 77.0 (1.5) 83.1 (3.1) Primary tumor type Breast 319 (41) 53 (25) 28 (14) 29 (15) 10 (9) Gastrointestinal 167 (22) 57 (27) 50 (24) 47 (24) 39 (34) Hematologic a 80 (10) 36 (17) 36 (18) 36 (19) 28 (24) Lung 77 (10) 22 (10) 39 (19) 27 (14) 6 (5) Gynecologic 36 (5) 10 (5) 11 (5) 4 (2) 7 (6) Genitourinary 35 (5) 16 (8) 31 (15) 32 (16) 21 (18) Other b 55 (7) 16 (8) 10 (5) 19 (10) 4 (3) Disease stage, n (%) I 43 (6) 6 (3) 3 (1) 8 (4) 0 (0) II 142 (18) 27 (13) 18 (9) 29 (15) 16 (14) III 176 (23) 46 (22) 56 (27) 34 (18) 27 (23) IV 335 (44) 111 (53) 99 (48) 100 (52) 61 (53) Metastases, n (%) 330 (43) 101 (48) 99 (48) 109 (56) 62 (54) Patients receiving platinumcontaining 258 (34) 68 (32) 76 (37) 64 (33) 33 (29) chemotherapy, n (%) Baseline Hb (g/dl), mean (SD) n 10.1 (0.7) (0.7) (0.7) (0.7) (0.6) 108 Patients with baseline 238 (31) 65 (31) 67 (33) 57 (29) 35 (30) Hb 10 g/dl, n (%) Patients with missing Hb or Hb within 28 days of a transfusion 66 (8) 13 (6) 16 (7) 11 (6) 7 (6) a May include acute and chronic lymphocytic leukemia, non-hodgkin s lymphoma, Hodgkin s disease, multiple myeloma, and other lymphoma. b May include bone sarcoma, soft tissue sarcoma, melanoma, head and neck (squamous cell carcinoma), and other tumors. Abbreviations: FACT-F, Functional Assessment of Cancer Therapy Fatigue; Hb, hemoglobin; SD, standard deviation. g/dl). Hemoglobin concentrations were measured weekly (before dosing with darbepoetin alfa) and at the end of the study. Patient-reported outcomes were measured at baseline, during each clinic visit (Q3W), and at the end of the study. Patients answered 13 questions related to the Functional Assessment of Cancer Therapy Fatigue (FACT-F) scale [23]. Two other patient-reported outcomes were measured using an 11-point scale (0 10). These included the Energy and Overall Health Assessment (EOHA) scale, which consisted of three questions pertaining to energy (0 no energy at all to 10 a great deal of energy), overall health (0 worst possible to 10 perfect health), and ability to do everything (0 able to do nothing to 10 able to do everything), and Work Productivity and Activity Impairment (WPAI) scale, which consisted of two questions pertaining to impairment in work productivity (0 anemia and/or its treatment had no effect on my work to 10 anemia and/or

4 Boccia, Lillie, Tomita et al. 587 Table 2. Hemoglobin-based endpoints Patients by age category (years) Characteristic <65 (n 769) >65 to <70 (n 210) >70 to <75 (n 205) >75 to <80 (n 194) >80 (n 115) Achievement of target Hb ( 11 g/dl) a Patients who achieved 79 (76, 82) (72, 83) (75, 86) (72, 84) (72, 87) 114 target Hb, crude percent (95% CLs) n K-M time to target Hb, weeks 4.0 (4.0, 5.0) 5.0 (4.0, 6.0) 4.0 (4.0, 5.0) 5.0 (3.0, 6.0) 4.0 (3.0, 6.0) (95% CLs) Maintenance of target Hb Mean (standard deviation) Hb 11.6 (0.8) (0.8) (0.9) (0.8) (0.9) 92 (g/dl) after achieving target n Patients maintaining Hb after achieving target, n (%) b,c 11 g/dl 143 (24) 36 (22) 41 (25) 31 (21) 24 (26) g/dl 443 (73) 119 (73) 117 (71) 116 (76) 63 (68) 13 g/dl 20 (3) 9 (5) 6 (4) 5 (3) 5 (5) Patients who had a hematopoietic response Crude percent (95% CLs) n 64 (61, 68) (57, 70) (56, 70) (52, 67) (54, 72) 108 K-M percent (95% CLs) 73 (69, 77) 72 (65, 79) 100 (100, 100) 73 (65, 81) 73 (63, 82) a Not including patients with baseline hemoglobin 11 g/dl. b Including patients who had hemoglobin values 11 g/dl. c Based on the number of patients who achieved the target hemoglobin level or who had a hemoglobin level 11 g/dl at baseline. Abbreviations: CLs confidence limits; Hb, hemoglobin; K-M, Kaplan-Meier. its treatment completely prevented me from working) and regular activity (0 anemia and/or its treatment had no effect on my daily activities to 10 anemia and/or its treatment completely prevented me from doing my daily activities) in the past 7 days. Efficacy Endpoints The objective of this exploratory analysis was to assess the efficacy and safety of darbepoetin alfa (300 g Q3W) by age category. Patients were categorized according to their age at screening: 65, 65 to 70, 70 to 75, 75 to 80, and 80 years old. The primary endpoints were the percentage of patients who achieved the target hemoglobin concentration ( 11 g/dl, in the absence of an RBC transfusion within the preceding 28 days) and the percentage of these patients who maintained a mean hemoglobin concentration of g/dl after achieving the target concentration. Secondary endpoints included the percentage of patients who received RBC transfusions, percentage of patients who had a hematopoietic response (either a 2-g/dl increase in hemoglobin from baseline or hemoglobin 12 g/dl in the absence of an RBC transfusion within the previous 28 days), change in hemoglobin concentration from baseline, and change in patient-reported outcomes from baseline. Safety Endpoints Only serious adverse events and serious treatment-related adverse events were collected; events that occurred on or after the first dose of darbepoetin alfa and on or before the end of the study were summarized according to the affected body system and by the preferred term within the body system using the Medical Dictionary for Regulatory Activities [24]. The presence of antibodies to darbepoetin alfa was assessed at the beginning and end of the study. Statistical Analysis This exploratory analysis included all patients who were correctly consented and who received at least one dose of darbepoetin alfa. Patients were categorized according to their age and baseline hemoglobin concentration ( 10 or 10 g/dl). Baseline demographics and clinical characteristics were summarized by number and percentage for categorical variables and mean (standard deviation) for continuous variables. Hemoglobin-based endpoints were calculated using the last value carried forward (LVCF) ap-

5 588 Darbepoetin Alfa in Older Patients with CIA proach (missing hemoglobin values or hemoglobin values within 28 days of an RBC transfusion were imputed using the previous value) and an available data approach (no imputation). The numbers and percentages of patients who achieved the target hemoglobin concentration, who had a hematopoietic response by the end of the study, who had a change in hemoglobin, and who received at least one RBC transfusion were calculated (with 95% confidence limits [CLs]). The time to target hemoglobin was calculated using the Kaplan-Meier (K-M) method. Patient-reported outcomes were calculated using available data from patients who received at least one dose of darbepoetin alfa and who completed, or partially completed, both the baseline and at least one subsequent questionnaire. FACT-F scores were calculated as the sum of 13 items, multiplied by 13, and divided by the number of items answered. Mean changes in WPAI scores were multiplied by 1. Thus, improvement in all HRQoL scores is represented as a positive change from baseline; worsening of scores is represented as a negative change from baseline. All statistical analyses were done using SAS version 8.2 (SAS Institute, Cary, NC). RESULTS Patient Characteristics The total study population comprised 1,501 patients from 230 sites. The primary analysis set included 1,493 patients who were properly consented and received at least one dose of darbepoetin alfa (Table 1). Most patients were white, and 51% were 65 years old. The percentage of women was 69% in the 65-years-old age category and only 50% in the 80-years-old age category. As expected, breast cancer was the most common tumor type in younger patients, and the incidence of genitourinary and hematologic malignancies increased with age. The percentages of patients with disease stage I, II, III, or IV were similar among age categories. However, no patients in the 80-years-old age category had stage I disease. Similar percentages of patients in each age category received platinum-based chemotherapy (Table 1); the type and utilization of other chemotherapy agents were consistent across all age categories (not shown). Baseline hemoglobin concentrations were similar across all age groups. Between 22% and 29% of the patients within each age category did not complete the study. The reasons for discontinuation were similar among age categories and included administrative decision (2% 5%), withdrawal of consent (3% 6%), adverse event (1% 3%), and death (4% 6%). Darbepoetin Alfa Dosing Use of darbepoetin alfa was similar among age categories, in the range of g per week. Changes in dose were also similar among age categories: 36% 41% had a dose increase, 13% 17% had more than one dose withheld, and 19% 23% had a dose decrease. Efficacy Endpoints Hemoglobin-Based Endpoints A similar percentage of patients (78% 80%) in each age category achieved the target hemoglobin ( 11 g/dl) by the end of the study, and the K-M estimated median time to achieve the target hemoglobin was 4 5 weeks (Table 2). By week 16, the mean hemoglobin concentration in all age categories was within the target range of g/dl (Fig. 1). Both the mean hemoglobin after achieving the target concentration and the percentage of patients who maintained hemoglobin within the target hemoglobin range were similar among age categories (Table 2). Transfusions Within each age category, fewer patients with baseline hemoglobin 10 g/dl received transfusions from week 5 to the end of the study compared with patients with baseline hemoglobin 10 g/dl; this difference was significant for patients 65 years old (Fig. 2A). For patients in the 80- years-old category, the difference between the two baseline hemoglobin groups was only three percentage points. The percentages of patients with baseline hemoglobin 10 g/dl who received transfusions were similar among age categories; however, for patients with a baseline hemoglobin level 10 g/dl, transfusion requirements appeared to vary with age. For all age categories, darbepoetin alfa reduced the percentage of patients who received transfusions between the first month (month 1) and the last month (month 4) of the study by three- to sixfold (Fig. 2B). Patient-Reported Outcomes HRQoL scores reported at baseline are shown in Table 3. In general, age did not appear to influence mean baseline FACT-F, EOHA, or WPAI scores, all of which were within the low-to-mid range of their respective scales. Age appeared to have a small to moderate effect on mean baseline scores for work productivity, with the lowest mean scores in the 80-years-old age category. Age appeared to have an impact on the mean change in FACT-F scores during the study (Fig. 3). Although patients in each age category achieved similar mean hemoglobin concentrations, improvements in FACT-F scores were lower with each incremental increase in the age of patients

6 Boccia, Lillie, Tomita et al. 589 (Fig. 3A). By week 16, all age categories, except the 80 category, had significant mean improvements in scores from baseline; however, only the 65 and 65 to 70 age categories had a clinically significant ( 3-point change [25]) mean improvement in scores. A high percentage of patients 65 years old reported a 3-point improvement in FACT-F scores from baseline (Fig. 3B). As the age of patients increased, the percentage who achieved a 3-point improvement in FACT-F decreased. Age also appeared to influence change in EOHA outcomes by the end of the study (Fig. 3C). Although patients in each age category reported improvement in these outcomes, increasing age appeared to reduce the mean change in energy, ability to do everything, and overall health. Only the 65 and 65 to 70-years-old age categories had significant mean improvements in scores from baseline, with the 65-years-old age category having clinically significant ( 10% increase) mean improvements in scores for energy and ability to do everything (Fig. 3C). Patients in each age category also reported improvement in WPAI scores, and mean changes in scores did not appear to be dependent on age (Fig. 3D). Each age category (except the 70 to 75 age category) had a significant mean improvement from baseline in regular activity; only patients 65 years old had a significant mean improvement from baseline in work productivity. Safety The number of patients in each age category who reported at least one serious adverse event is shown in Table 4. The most commonly reported serious adverse events were febrile neutropenia, pneumonia, pyrexia, and dehydration, and none of these were reported to have been caused by treatment with darbepoetin alfa. Treatment-related serious adverse events were reported by patients in the 65, 65 to 70, and 70 to 75 age categories (Table 4). Treatmentrelated thromboembolic events were reported by three patients in the 65 age category, and one patient in each of the 65 to 70 and 70 to 75 age categories (Table 4). A similar percentage of patients in each age category did not complete the study (Table 4). The percentages of deaths were in the range of 7% 8%. Most deaths were a result of disease progression and none were related to treatment with darbepoetin alfa. Assay results for neutralizing antibodies to darbepoetin alfa were available for 1,169 patients; none developed neutralizing antibodies during the study. DISCUSSION This exploratory analysis indicates that a fixed dose of darbepoetin alfa administered Q3W appears to be effective and Figure 1. Hemoglobin concentration over the study period. Mean hemoglobin concentration at baseline, week 7, and week 16 for each age category. The shaded area represents the target hemoglobin range (11 13 g/dl) recommended by current evidence-based guidelines. Available data approach; bars represent 95% confidence limits (CLs). Figure 2. Patients receiving RBC transfusions. (A): Effect of baseline hemoglobin ( 10 g/dl versus 10 g/dl) on percentage of patients who received RBC transfusions. (B): Percentage of patients receiving RBC transfusions in month 1 and month 4 of the study. Bars represent 95% confidence limits (CLs). Abbreviation: EOTP, end of treatment period. well tolerated in younger ( 65 years old) and older ( 65 years old) cancer patients with CIA. Interestingly, the age

7 590 Darbepoetin Alfa in Older Patients with CIA Table 3. Baseline quality-of-life scores Baseline Quality-of-Life Scores a, mean (standard deviation) n] <65 (n 769) >65 to <70 (n 210) Patients by age category (years) >70 to <75 (n 205) >75 to <80 (n 194) >80 (n 115) FACT-F 27.4 (12.1) (13.0) (12.9) (12.4) (11.3) 101 Energy and Overall Health Assessment Energy 4.7 (2.1) (2.3) (2.4) (2.2) (2.1) 101 Ability to do everything 4.5 (2.4) (2.4) (2.6) (2.5) (2.4) 101 Overall health 5.4 (2.2) (2.2) (2.3) (2.2) (2.2) 101 Work Productivity and Activity Impairment Work productivity 3.8 (3.1) (3.5) (3.1) (3.1) (2.6) 26 impairment Regular activity impairment 4.4 (2.9) (3.2) (2.9) (3.0) (2.8) 94 a Available data approach. Abbreviation: FACT-F, Functional Assessment of Cancer Therapy Fatigue. of patients did not appear to influence hematologic outcomes: the percentages of patients who achieved the target hemoglobin and maintained hemoglobin within the recommended range (11 13 g/dl) were similar, and the times to achieve the target hemoglobin were approximately the same in each of the older and younger age categories. Also, the percentages of patients who received RBC transfusions during the study and who experienced reductions in RBC transfusions after treatment with darbepoetin alfa were similar in all age categories. Our results support the conclusions of a small study of older patients ( 70 years old) with CIA in which age did not appear to impact hematologic outcomes after treatment with ESAs [14]. In the present analysis, younger patients reported the greatest improvement in HRQoL scores after treatment with darbepoetin alfa. However, substantial improvement in HRQoL was also reported by older patients; approximately one half of patients in each of the older age categories reported clinically significant improvement in FACT-F scores, and the majority of older patients reported improvement in EOHA and WPAI scores. Despite the similarities in hematologic outcomes among all age categories, we observed a trend toward less improvement in HRQoL as the age of this patient population increased. Because of continuing concern about the appropriate maximum hemoglobin level for patients with CIA, product labels currently recommend a ceiling hemoglobin level of 13 g/dl. These concerns resulted from the outcomes of two clinical trials of patients with breast [26] or head and neck [27] cancer that found a higher risk for thromboembolic events and shorter survival in patients treated with epoetin; those trials allowed hemoglobin levels to increase up to 14 g/dl [26] or 15 g/dl [27], levels which are above the recommended threshold level. In the present study, darbepoetin alfa was dosed using strict titration rules to maintain hemoglobin levels between 11 g/dl and 13 g/dl, consistent with current recommendations [20 22]; there were no treatment-related deaths, and 1% of patients in the 65, 65 to 70, and 70 to 75 age categories reported treatmentrelated thromboembolic events. The analysis presented here does have some limitations. First, age groups were selected post hoc. Second, it was not designed to prospectively compare outcomes in older versus younger patients with CIA, and the tools used to record HRQoL may not have been appropriate for older patients. For example, assessment of change in work productivity was not ideal for older patients since only 17 and 7 patients in the 75 to 80 and 80 age categories, respectively, reported changes in this measure. A more reliable tool to determine change in HRQoL in these older cancer patients would be a comprehensive geriatric assessment, such as the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) tools. These tools measure functional dependence, which is associated with shorter survival, lower tolerance to cytotoxic chemotherapy, and frailty (reviewed in [28]). Third, this analysis did not differentiate between fit and frail older patients, and frailty may have a significant effect on the health outcomes of older individuals [29]. Last, tumor type, disease stage, and comorbid disease may have affected responses to HRQoL questionnaires. The older population of the U.S. is expected to be approximately 13% of the total population by 2010, and a significant proportion of these patients will likely develop

8 Boccia, Lillie, Tomita et al. 591 Figure 3. Health-related quality-of-life scores. (A): Change in Functional Assessment of Cancer Therapy Fatigue (FACT-F) scores. (B): Percentage of patients with a 3-point change in FACT-F score. (C): Change in scores for energy, ability to do everything, and overall health. (D): Change in scores for work productivity and regular activity. Available data approach with 95% confidence limits (CLs). Table 4. Safety data <65 (n 769) >65 to <70 (n 210) Patients by age category (years) >70 to <75 (n 205) >75 to <80 (n 194) >80 (n 115) Patients who had serious 189 (25) 60 (29) 66 (32) 58 (30) 42 (37) adverse events, n (%) Patients who had serious 6 (1) 3 (1) 1 ( 1) 0 (0) 0 (0) treatment-related adverse events, n (%) Vascular disorders 3 ( 1) 1 ( 1) 1 ( 1) 0 (0) 0 (0) Deep vein thrombosis 2 ( 1) 1 ( 1) 1 ( 1) 0 (0) 0 (0) Phlebothrombosis 1 ( 1) 0 (0) 0 (0) 0 (0) 0 (0) Cardiac disorders 0 (0) 1 ( 1) 0 (0) 0 (0) 0 (0) Acute myocardial infarction 0 (0) 1 ( 1) 0 (0) 0 (0) 0 (0) Nervous system disorders 2 ( 1) 0 (0) 0 (0) 0 (0) 0 (0) Cerebral artery occlusion 1 ( 1) 0 (0) 0 (0) 0 (0) 0 (0) Cerebrovascular accident 1 ( 1) 0 (0) 0 (0) 0 (0) 0 (0) Respiratory, thoracic, and 1( 1) 1 ( 1) 0 (0) 0 (0) 0 (0) mediastinal disorders Pulmonary embolism 1 ( 1) 1 ( 1) 0 (0) 0 (0) 0 (0) Patients who discontinued 185 (24) 50 (24) 46 (22) 57 (29) 25 (22) study, n (%) Patients who died 52 (7) 15 (7) 15 (7) 15 (8) 9 (8) Adverse events 13 (2) 3 (1) 3 (1) 6 (3) 2 (2)

9 592 Darbepoetin Alfa in Older Patients with CIA cancer and CIA. Future prospective studies using appropriate assessment tools to monitor HRQoL during treatment with ESAs are warranted in this important patient population. ACKNOWLEDGMENTS The authors wish to thank the investigators, study coordinators, and participants at each of the institutions for their contributions to this study. We thank Kathryn Boorer, Ph.D., for assistance with writing this manuscript, Joe Murray, M.S., for statistical assistance, and Ben Frierson, M.B.A., and Matt Ness for programming support. This study and this analysis were sponsored by Amgen Inc., Thousand Oaks, California (Study No ). DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST R.B. owns stock in and is on the speakers bureau for Amgen. D.T. and T.L. own stock in Amgen. L.B. has acted as a consultant for Amgen. REFERENCES 1 Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: Incidence and treatment. J Natl Cancer Inst 1999;91: Cella D. 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