Weekly Epoetin Alfa During Adjuvant Chemotherapy for Breast Cancer: Effect on Hemoglobin Levels and Quality of Life

original

contribution Weekly Epoetin Alfa During Adjuvant Chemotherapy for Breast Cancer: Effect on Hemoglobin Levels and Quality of Life Clifford A. Hudis,1 Charles L. Vogel,2 Julie R. Gralow,3 Denise Williams,4 and the Procrit® Study Group Abstract Purpose: Anemia, fatigue, and diminished quality of life (QOL) often are associated with chemotherapy. In a previous study of patients with early-stage breast cancer and a mean baseline hemoglobin (Hb) level of 12.1 g/dL, Hb decreased by 2.0 g/dL after 4 cycles of adjuvant chemotherapy. The current open-label, nonrandomized, multicenter, prospective, community-based study evaluated the effects of 12-24 weeks of epoetin alfa (40,000 U subcutaneously once weekly initiated at the start of standard adjuvant chemotherapy) in patients with stage I-III breast cancer and baseline Hb levels ≥ 10 g/dL to ≤ 14 g/dL on Hb level, transfusions, and QOL. Patients and Methods: Of 1792 patients enrolled, 1785 were evaluable for safety and 1632 for efficacy. Mean age was 53 years ± 10.7 and mean baseline Hb level was 12.3 g/dL ± 1.0. From baseline levels, epoetin alfa significantly increased Hb (1.3 g/dL ± 1.5; P < 0.05) and improved QOL according to the Linear Analog Scale Assessment (LASA) of energy (5.1 mm ± 27.7), LASA activity (5.1 mm ± 28.2), LASA overall QOL (4.3 mm ± 26.7), and Functional Assessment of Cancer Therapy–Anemia (1.7 points ± 14.0; P < 0.05 in each case). Patients with baseline mild anemia (Hb level >10 g/dL to ≤ 12 g/dL) also had significant improvements from baseline levels in all 3 LASA parameters (P < 0.05). Epoetin alfa was well tolerated; clinically relevant thrombovascular events were reported in 4.3% of patients. Results: In this study, epoetin alfa significantly improved Hb and QOL in mildly anemic patients with early-stage breast cancer receiving adjuvant chemotherapy. However, based on recent studies showing an increased risk of thrombovascular events in patients with cancer treated with erythropoietic agents beyond correction of anemia, treatment with epoetin alfa is not indicated or recommended in patients with cancer and Hb levels > 12 g/dL. Conclusion: Controlled studies are warranted to confirm the safety and efficacy of epoetin alfa therapy in patients with mild anemia receiving chemotherapy. Clinical Breast Cancer, Vol. 6, No. 2, 132-142, 2005 Key words: Anemia, Fatigue, Functional Assessment of Cancer Therapy–Anemia scale, Linear Analog Scale Assessment, Transfusion reductions

Introduction Mild to moderate anemia (hemoglobin [Hb] level of 8-12 g/dL) occurs in as many as 75% of patients with cancer undergo1Breast

Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY 2Cancer Research Network, Plantation, FL 3Medicine/Oncology, Seattle Cancer Care Alliance, WA 4Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ Submitted: Apr 19, 2005; Accepted: Jun 3, 2005; Revised: Jun 7, 2005 Address for correspondence: Clifford A. Hudis, MD, Memorial Sloan-Kettering Cancer Center, Breast Cancer Medicine Service, 1275 York Ave, New York, NY 10021 Fax: 212-639-6483; e-mail: [email protected]

ing chemotherapy or radiation therapy1-3 and often results in debilitating fatigue and weakness, which can impair quality of life (QOL) and functional capacity.4-7 Cumulative decreases in Hb level occur in patients with early-stage breast cancer receiving repeated cycles of adjuvant chemotherapy, with a progressive decrease in Hb observed with each cycle of adjuvant chemotherapy.1,8,9 Moreover, results of a recent chart review showed that 27% of patients with early-stage breast cancer had mild anemia (Hb level 10-11.9 g/dL) before receiving adjuvant chemotherapy.10 In addition, 62% of patients developed moderate to severe anemia (Hb level < 10 g/dL) during chemotherapy.10 De-

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132 • Clinical Breast Cancer June 2005

creases in Hb during chemotherapy have been correlated with greater fatigue, as well as increased cognitive symptoms and reductions in cognitive function.9,11 Studies of QOL in patients with cancer have shown that chemotherapy-related anemia (Hb level < 12 g/dL) is associated with impaired QOL.12-15 In patients with breast cancer who were anemic and had baseline QOL impairment, treatment with weekly recombinant human erythropoietin (ie, epoetin alfa) significantly improved Hb levels and QOL during chemotherapy alone16 or in combination with radiation therapy.17 Current clinical practice guidelines issued by the American Society of Hematology and the American Society of Clinical Oncology recommend the use of epoetin alfa for patients with chemotherapy-related anemia and Hb levels < 10 g/dL.18 For patients with Hb levels ≥ 10 g/dL but < 12 g/dL, the guidelines recommend that the use of epoetin alfa should be determined by clinical circumstances.18 Guidelines from the National Comprehensive Cancer Network issued in 2004 also recommend the use of erythropoietic agents for chemotherapyrelated anemia, supporting the initiation of therapy in patients with Hb levels < 11 g/dL who are symptomatic or who have risk factors.19 The objective of this study was to evaluate the effectiveness (ie, clinical outcomes) and safety of weekly epoetin alfa dosing initiated at the start of adjuvant chemotherapy in a large population of patients with early-stage breast cancer and baseline Hb levels ≥ 10 g/dL to ≤ 14 g/dL.

Patients and Methods Study Design and Evaluations This phase IV, open-label, nonrandomized, multicenter, prospective study was conducted in 343 community and academic institutions throughout the United States from May 2000 through July 2001. The protocol and informed consent form were approved by the appropriate institutional review boards, and the study was conducted in accordance with the Declaration of Helsinki. All patients underwent an initial screening within 14 days of the first dose of epoetin alfa to collect patient demographics: weight; blood pressure; histologic or cytologic confirmation of stage I, II, or III breast cancer; current/previous chemotherapy, radiation therapy and/or hormonal therapy for breast cancer; other concomitant therapy; transfusion history; Eastern Cooperative Oncology Group (ECOG) performance status; and Hb and hematocrit (Hct) levels. Hemoglobin, Hct, and blood pressure were assessed at baseline, weekly until Hb level stabilized, and before each chemotherapy cycle (ie, every 3/4 weeks). Thereafter, monitoring continued at each 3- or 4-week study visit and on study completion or early withdrawal. Patient weight, breast cancer treatment information, and concomitant medications were recorded at baseline, at each study visit, and at study completion or early withdrawal. Transfusion use was assessed before study enrollment and for the entire study duration. Quality of life was evaluated at baseline, after 12 weeks of epoetin alfa therapy, and at study completion or early with-

Figure 1 Dosing of Epoetin Alfa Baseline Hb 10-14 g/dL

Initiate epoetin alfa at 40,000 U SC weekly for 4 weeks

Hb increases ≥ 1 g/dL

Hb increases < 1 g/dL (for patients with BL Hb ≥ 10 to ≤ 12 g/dL)

Continue epoetin alfa at 40,000 U weekly for a maximum duration of 24 weeks

Increase epoetin alfa dose to 60,000 U weekly for 4 additional weeks

Hb increases ≥ 1 g/dL compared with BL

Hb > 15 g/dL on 2 consecutive evaluations

Hb increases by > 1.3 g/dL in a 2-week period

Temporarily withhold epoetin alfa until Hb decreases to ≤ 13 g/dL

Hb decreases ≥ 2 g/dL (for patients with BL Hb > 12 to ≤ 14 g/dL)

Hb increases < 1 g/dL compared with BL

Hb ≤ 15 g/dL

Discontinue epoetin alfa

Continue epoetin alfa 60,000 U weekly for a maximum duration of 24 weeks

Reduce dose by 25% when treatment is resumed, then titrate to maintain desired Hb

Abbreviations: BL = baseline; SC = subcutaneously

drawal using 2 self-report instruments: the Linear Analog Scale Assessment (LASA) and the Functional Assessment of Cancer Therapy (FACT)–Anemia Subscale (FACT-An). The LASA, which has been used extensively in patients with cancer,20-23 was used to determine energy level, ability to perform daily activities, and overall QOL, with patients rating each on a 100-mm scale. A higher LASA score represents better QOL. The FACT-An is a 47-item questionnaire that includes the FACT–General scale, which evaluates physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), and functional well-being (7 items), and an anemia scale (20 items, including 13 related to fatigue).24 The FACT-An has been previously demonstrated to be reliable and valid in patients with cancer with a wide range of Hb levels.15 Scores range from 0 to 188, with higher scores reflecting better well-being. Eligible patients received epoetin alfa 40,000 U subcutaneously weekly for 12-24 weeks, plus supplemental iron (approximately 150-200 mg per day elemental iron) as needed to support erythropoiesis (Figure 1). Dose increases were permitted after 4 weeks, depending on baseline Hb level and response. Total study duration for patients receiving adjuvant chemotherapy only was ≥ 12 weeks to ≤ 24 weeks. Total

Clinical Breast Cancer June 2005 • 133

Epoetin Alfa and Adjuvant Chemotherapy for Breast Cancer Figure 2 Patient Disposition Enrolled (N = 1792)

SAFETY POPULATION Received ≥ 1 dose of epoetin alfa (n = 1785)

EFFICACY POPULATION Met all inclusion/ exclusion criteria, ≥ 1 dose of study drug (n = 1632)

Did not receive ≥ 1 dose of epoetin alfa (n = 7)

Did not meet inclusion/exclusion criteria (n = 153)*

Completed study† (n = 585) Withdrew‡ (n = 1020) Data on completion status missing (n = 27)

tivity to mammalian cell–derived products or serum albumin. Patients who had received a transfusion within 30 days of baseline Hb measurement or who had previously received epoetin alfa or other erythropoietic agents within 6 months of study enrollment were not eligible to participate.

Safety Safety evaluations consisted of adverse event reporting, blood pressure measurement, and clinical laboratory tests (Hb, Hct). Adverse events were summarized by severity, body system, and relationship to epoetin alfa therapy, as well as whether the adverse event led to discontinuation from the study or required other therapeutic intervention. Adverse events were recorded from the first dose of epoetin alfa to 30 days after study completion. Thrombovascular events were classified and analyzed according to World Health Organization Adverse Reaction Terminology (WHO-ART) preferred terms.

Statistical Analysis *Reasons for exclusion from efficacy analysis included patient not receiving an anthracycline chemotherapeutic agent (n = 65), did not meet case report form inclusion/exclusion criteria (n = 26), did not meet criteria check in data (n = 62). †Patients who completed 24 weeks of study visits. ‡Reasons for early withdrawal included receipt of chemotherapy for < 12 weeks (n = 302), patient request (n = 299), investigator request (n = 243), adverse event (n = 35), patient noncompliance (n = 29), sponsor request (n = 14), disease progression (n = 12), lost to follow-up (n = 11), death (n = 9), intercurrent illness (n = 5), other (n = 59), and unknown (n = 2).

study duration for patients receiving adjuvant chemotherapy plus radiation therapy was ≥ 12 weeks to ≤ 34 weeks. If chemotherapy was discontinued but the patient had received ≥ 12 weeks of anthracycline-containing chemotherapy, the patient could continue to receive epoetin alfa at the physician’s discretion until Hb levels were normalized. Patients were deemed to have completed the study if they completed 24 weeks of study visits.

Patients Women who were ≥ 18 years of age and receiving adjuvant chemotherapy (an anthracycline with or without a taxane and with or without radiation) for 12-24 weeks for stage I, II, or III breast cancer were eligible for enrollment if they had Hb levels ≥ 10 g/dL to ≤ 14 g/dL, an ECOG performance status of 0-2, and an estimated life expectancy of ≥ 9 months. Patients with reproductive potential were required to use an adequate contraceptive method and have a negative pregnancy test result within 7 days of the first epoetin alfa dose. Patients also had to be willing and able to complete the LASA and FACT-An questionnaires. All patients provided written informed consent, an additional eligibility criterion. Patients were not eligible to participate if they had uncontrolled or severe cardiovascular disease, including recent (< 6 months before study enrollment) myocardial infarction, uncontrolled hypertension, or congestive heart failure; anemia attributable to factors other than cancer or chemotherapy (ie, iron, vitamin B12, or folate deficiency; hemolysis; or gastrointestinal bleeding); myelodysplastic syndrome; or known sensi-

134 • Clinical Breast Cancer June 2005

Efficacy variables included change in Hb and change in QOL from baseline to final value and the proportion of patients who received a transfusion during months 1, 2, 3, and 4. The efficacy population consisted of the eligible population, defined as all enrolled patients who met the inclusion and exclusion criteria and who received ≥ 1 dose of study drug. Hemoglobin data were analyzed using the last value carried forward (LVCF) and on-treatment approaches to assess the robustness of the results. The QOL variables were analyzed using the on-treatment approach. The LVCF approach imputed missing data by carrying forward the last observed value. The on-treatment approach analyzed data without imputing missing values. As a result, the sample size available from the on-treatment analysis varied over time points and across outcomes of interest. Because efficacy results were similar between the intent-to-treat and eligible populations, only results for the eligible population are presented. The safety population included all enrolled patients who received ≥ 1 dose of study drug. Data were summarized using descriptive statistics for continuous variables and frequency statistics for categoric variables. Analysis of variance (ANOVA) was used to compare change in Hb and mean changes in QOL scores from baseline to weekly visits and last value. The Hb data were analyzed as reported on the case report form (per original protocol), and a post hoc analysis was performed using the Hb data independent of transfusion within the previous 28 days. This was done by setting Hb values to “missing” for 28 days after transfusion. The QOL scores over time also were evaluated using repeated-measures ANOVA. Changes in the percentage of patients who received transfusions from baseline to months 1, 2, 3, and 4 were analyzed using the McNemar χ2 test. Data were analyzed with use of SAS® software or equivalent. A P value ≤ 0.05 was considered statistically significant. Subsequent to the planned analyses described earlier, post hoc analyses were performed to evaluate changes in Hb and QOL stratified by baseline Hb level (ie, Hb ≥ 10 g/dL to ≤ 11 g/dL, > 11 g/dL to ≤ 12 g/dL, > 12 g/dL to ≤ 13 g/dL, or

Clifford A. Hudis et al Table 1 Patient Demographics and Baseline Characteristics (N = 1632) Value

Mean Age ± SD (Years)

53 ± 10.7

Mean Weight ± SD (lbs.)

165.1 ± 38.1

Ethnicity, n (%)

14

13.5

Baseline Hb Final Hb Mean Change in Hb

12.3 12

Mean Hb Level (g/dL)

Parameter

Figure 3 Hemoglobin in Patients Receiving Adjuvant Chemotherapy and Once-Weekly Epoetin Alfa

10 8

White

1265 (77.5)

African-American

177 (10.8)

Hispanic/Latino

117 (7.2)

Asian

43 (2.6)

2

Other/Missing

30 (1.8)

0

6 4

*

1.3 1632

1632

Cancer Stage at Screening Visit, n I

401

II

944

III

208

Not available

79

Patients Transfused £ 6 Months Before Study, n (%)

13 (0.8)

Mean Hb ± SD (g/dL)

12.3 ± 1

Anemic (Hb £ 12 g/dL), n (%)

660 (40.4)

Mean Hb, g/dL Nonanemic (Hb > 12 g/dL), n (%)

11.2 972 (59.6)

Mean Hb, g/dL

13

Mean LASA Score ± SD, mm Energy

61.0 ± 22.7

Activity

62.9 ± 24.2

Overall QOL

66.8 ± 23.2

Mean FACT-An Score ± SD

75.2 ± 14.2

Abbreviation: SD = standard deviation

> 13 g/dL to ≤ 14 g/dL) and baseline anemia status (Hb level ≤ 12 g/dL or > 12 g/dL). As an additional measure of clinical efficacy, the proportion of patients experiencing (if anemic at baseline) or maintaining (if nonanemic at baseline) Hb levels > 12 g/dL at study end was calculated.

Results Patient Demographics and Baseline Characteristics Of the 1792 patients enrolled, 1632 were evaluable for efficacy and 1785 were evaluable for safety (Figure 2). A total of 153 patients evaluable for safety were not included in the efficacy population because it was determined after enrollment that they did not meet all eligibility criteria. Specifically, 65 patients were excluded from the efficacy population because they did not receive an anthracycline chemotherapeutic agent, 26 because they did not meet the case report form eligibility criteria, and 62 because they did not meet criteria for check-

*P < 0.05 versus 0 (current study).

in data. Patient demographics and baseline characteristics are shown in Table 1. At baseline, 660 patients were anemic (Hb level ≤ 12 g/dL) and 972 patients were not anemic (Hb level > 12 g/dL). During the study, patients received chemotherapy for a mean duration of 13.5 weeks ± 6.3. All 1632 patients evaluable for efficacy received anthracycline on study; 706 (43.3%) of these patients received a taxane (paclitaxel or docetaxel) on study for a mean of 10.2 weeks ± 4.6 after study commencement. Of evaluable patients, 44.5% were still receiving chemotherapy at week 13, compared with 14.2% at study completion. Two hundred eighteen of the 1632 patients (13.4%) received hormonal therapy while on study. A total of 1020 patients evaluable for efficacy (62.5%) withdrew from the study before completion (24 weeks on study; Figure 2). The most common reasons for early withdrawal were receipt of chemotherapy for < 12 weeks (29.6% of early withdrawals), patient request (29.3%), and investigator request (23.8%). All other reasons for early withdrawal (adverse events, patient noncompliance, sponsor request, disease progression, loss to follow-up, death, intercurrent or concurrent illness, other, and unknown) occurred in < 6% of patients.

Epoetin Alfa Dose and Schedule The mean weekly dose of epoetin alfa was 37,155 U ± 9368. Three hundred fifty-seven (22%) and 861 (53%) patients required dose increases or dose reductions (including withheld doses), respectively. Reasons for dose increases included Hb increase < 1 g/dL after 4 weeks of epoetin alfa therapy (n = 211; 12.9%) and Hb decrease ≥ 2 g/dL after 4 weeks of epoetin alfa therapy (n = 11; 0.7%). Reasons for dose reductions included Hb increase > 1.3 g/dL in a 2-week period (n = 576; 35.3%), Hb level > 15 g/dL for 2 consecutive weeks (n = 184; 11.3%), Hb increase > 1.3 g/dL in a 2week period plus Hb level > 15 g/dL for 2 consecutive weeks (n = 149; 9.1%), and other reasons (n = 250; 15.3%).

Hematologic Response Epoetin alfa therapy significantly improved mean Hb levels by 1.3 g/dL ± 1.5 (n = 1632) from baseline to final eval-

Clinical Breast Cancer June 2005 • 135

Epoetin Alfa and Adjuvant Chemotherapy for Breast Cancer Figure 4 Hemoglobin (Hb) Profile Over Time 14.5 Mean Hb Level (g/dL)

14.0

*

13.5 13.0

*

12.5

*

*

*

*

*

* *

* *

*

*

12.0 11.5

*

* *

* *

*

*

*

10.0 2

4/5

* * * *

* * * *

Group 1: ≥ 10 to ≤ 11 g/dL Group 2: > 11 to ≤ 12 g/dL Group 3: > 12 to ≤ 13 g/dL Group 4: > 13 to ≤ 14 g/dL

10.5 1

*

*

11.0

Baseline

* * *

7

9/10

13

16/17

19

21/22

24

177 321 425 305

149 246 333 239

116 219 272 202

100 183 248 182

83 146 217 149

Week Group 1 Group 2 Group 3 Group 4

232 428 553 419

231 427 550 416

220 416 531 406

227 425 539 415

216 395 504 393

206 380 499 387

*Levels of Hb are significantly different from baseline at P < 0.005 (analysis of variance and Bonferroni adjustment).

uation in this population of women with early-stage breast cancer and mean baseline Hb levels 12.3 g/dL ± 1.0 (P > 0.05 vs. baseline; Figure 3). The mean increases in Hb level were 0.5 g/dL after 4 weeks of epoetin alfa therapy and 1.0 g/dL after 9 weeks of epoetin alfa therapy (both P < 0.05 vs. baseline). Post hoc analyses of mean weekly Hb levels in patients with baseline Hb levels ≥ 10 g/dL to ≤ 11 g/dL, > 11 g/dL to ≤ 12 g/dL, > 12 g/dL ≤ 13 g/dL, and > 13 g/dL to ≤ 14 g/dL showed a statistically significant increase in Hb level from baseline after 4 weeks of epoetin alfa therapy and at all subsequent time points for all subgroups (P < 0.005; Figure 4). In another post hoc analysis, 78% of patients who were anemic (n = 516) and 91% of patients who were not anemic (n = 882) at baseline exhibited Hb levels > 12 g/dL at study end. Of patients who were not anemic at baseline, Hb levels decreased to < 10 g/dL in only 2% (n = 21) during the study, compared with 16% (n = 104) of those who were anemic at baseline. In a separate post hoc analysis, Hb was analyzed excluding values obtained within 28 days after a transfusion.

Table 2 Comparison of Hemoglobin Change Values Including and Excluding Values Measured Within 28 Days After Transfusion Hb Recorded Time Point

Independent of Transfusion Within 28 Days*

No. of Mean Hb No. of Mean Hb Patients Level ± SD Patients Level ± SD Baseline

1632

12.3 ± 1.0

1632

12.3 ± 1.0

Week 4/5

1606

12.8 ± 1.3

1605

12.8 ± 1.3

Week 9/10

1472

13.3 ± 1.5

1464

13.4 ± 1.5

Week 21/22

713

13.7 ± 1.3

711

13.7 ± 1.3

Study Completion or Withdrawal

1551

13.6 ± 1.4

1543

13.6 ± 1.4

*Hb values measured within 28 days after a red blood cell transfusion were set to missing. Abbreviation: SD = standard deviation

136 • Clinical Breast Cancer June 2005

Results were not different from those of the original analysis; only 28 of 1632 patients (1.7%) received a transfusion on study (Table 2).

Transfusions Thirteen patients (0.8%) had received red blood cell transfusions within 6 months before study commencement. During the study, 28 patients (1.7%) received transfusions (mean, 3.0 U ± 2.0). The mean time to first transfusion was 73 days ± 40, and the mean Hb level before transfusion was 7.4 g/dL ± 0.7.

Quality of Life Parameters Mean final LASA scores for ener-

gy, activity, and overall QOL for the total population improved significantly compared with baseline (5.1 mm ± 27.7, 5.1 mm ± 28.2, and 4.3 mm ± 26.7, respectively; P < 0.05 in each case), although the magnitudes of the changes were not clinically significant (Figure 5).25 Mean FACT-An scores for the total population also significantly increased from baseline to final value (by 1.7 points ± 14.0; P < 0.05), but the change also was not clinically significant (Figure 6).25 The LASA overall QOL scores over time according to anemia status at baseline are shown in Figure 7. Post hoc analyses showed that patients who were anemic at baseline (Hb level ≤ 12 g/dL) had significant improvements in energy, activity, and overall QOL scores after 12 weeks of epoetin alfa therapy and at the final measurement (all P < 0.05). Mean overall QOL was maintained after 12 weeks of epoetin alfa therapy and was improved at final measurement in patients who were not anemic at baseline. Post hoc analyses demonstrated that increases in Hb were significantly correlated with improvements in LASA energy, activity, and overall QOL scores (coefficients of 0.18, 0.18, and 0.16, respectively; all P < 0.0001) in the efficacy population and in all baseline Hb patient subsets (ie, baseline Hb level ≥ 10 g/dL to ≤ 11 g/dL, > 11 g/dL to ≤ 12 g/dL, > 12 g/dL ≤ 13 g/dL, and > 13 g/dL to ≤ 14 g/dL; P < 0.001 for all).

Safety Weekly epoetin alfa therapy was well tolerated in this patient population. The majority of adverse events were mild or moderate in severity, and only 35 of 1020 patients who discontinued epoetin alfa (3.4%) did so because of adverse events. Headache was the most frequently reported adverse event leading to discontinuation (n = 8), followed by hypertension (n = 6; Table 3). The types and frequencies of adverse events reported in this population are not uncommon in patients with cancer receiving chemotherapy. Of 11,651 adverse events, 221 (1.9%) were considered possibly related

Clifford A. Hudis et al Figure 5 Baseline and On-Study QOL Scores for 3 Linear Analog Scale Assessment Domains in Efficacy Population

Table 3 Adverse Events Occurring in ≥ 5% of Patients (N = 1785) Adverse Event

Incidence (%)

80

Mean LASA Score (mm)

Energy Activity Overall QOL

Nausea

41

Granulocytopenia

37

Fatigue

23

Vomiting

22

Alopecia

14

60

Diarrhea

12

55

Headache

11

Constipation

10

Stomatitis

8

Arthralgia

7

Fever

7

Skeletal Pain

7

Anorexia

7

Insomnia

6

Rash

6

75

* 70

* *

65

50

*

1609

1610

1610

1076

Baseline

1077

1076

1484

1484

Week 13

1484

Final

*P < 0.017 using analysis of variance and Bonferroni adjustment.

Figure 6 Mean Baseline and On-Study Functional Assessment of Cancer Therapy–Anemia Scores 80

Mean LASA Score (mm)

* 75

Hot Flushes

6

70

Dyspepsia

6

65

Upper Respiratory Tract Infection

6

Myalgia

6

Coughing

6

Pharyngitis

5

Ulcerative Stomatitis

5

60 55 50

1618

1085

1486

Baseline

Week 13

Final

*P < 0.017 using analysis of variance and Bonferroni adjustment.

Mean LASA Overall QOL Score (mm)

Figure 7 Linear Analog Scale Assessment of Overall QOL Over Time According to Baseline Hemoglobin Level 80 75

All Patients Baseline Hb >10 to ≤12 g/dL (anemic) Baseline Hb >12 to ≤14 g/dL (nonanemic) †

70

†

* *

65

*

*

60 55 50

1610

653 Baseline

957

1076

442 Week 13

634

1484

591

893

Final

*Mean score significantly different versus baseline at P < 0.013 using analysis of variance and Bonferroni adjustment. †Difference significantly different versus baseline at P < 0.013 using paired t test and Bonferroni adjustment.

allergic reaction, pain, and fatigue), cardiovascular events (n = 5), gastrointestinal system events (n = 5), musculoskeletal system events (n = 4), and red blood cell disorder (n = 4). Seventy-seven of the 1785 patients evaluable for safety (4.3%) were diagnosed with clinically relevant thrombovascular events. Of these 77 patients, 22 had baseline Hb levels ≤ 12 g/dL and 55 had baseline Hb levels > 12 g/dL. Clinically relevant thrombovascular events by WHO-ART preferred terms were: thrombophlebitis deep (n = 28), thrombosis (n = 16), pulmonary embolism (n = 9), thrombophlebitis arm deep (n = 9), cerebrovascular disorder (n = 7), thrombophlebitis leg deep (n = 7), embolism blood clot (n = 5), embolism limb (n = 1), embolism arterial (n = 1), myocardial infarction (n = 1), and cardiac arrest (n = 1). The mean time to the development of a clinically relevant thrombovascular event was 48.0 days ± 36.7, and the mean Hb level measured closest to the event was 12.7 g/dL ± 1.4. Eleven patients (0.6%) died on study; none of the deaths were considered related to epoetin alfa.

Discussion to epoetin alfa treatment and 44 (0.4%) were considered probably or very likely related to epoetin alfa. The 6 categories of adverse events most commonly considered related to epoetin alfa were application site reaction (n = 9), body as a whole (n = 5; 1 event each for leg pain, generalized edema,

The results of this large, open-label, nonrandomized, community-based study demonstrate that weekly epoetin alfa at a mean weekly dose of approximately 37,000 U effectively increases or maintains Hb levels in the majority of patients with early-stage breast cancer when administered at the

Clinical Breast Cancer June 2005 • 137

Epoetin Alfa and Adjuvant Chemotherapy for Breast Cancer start of anthracycline-based adjuvant chemotherapy, with a mean Hb increase of 1.3 g/dL from baseline to final evaluation. Of the 660 patients who were anemic at baseline, 516 (78%) exhibited Hb levels > 12 g/dL at study end. Similarly, mean final LASA scores for all domains and mean FACT-An scores improved significantly from baseline, although the magnitude of the changes was not clinically significant.25 Post hoc analyses showed that patients who were anemic at baseline had significant improvements in all LASA domain scores and FACT-An scores. For all evaluable patients, the difference between the percentage of patients receiving chemotherapy at week 13 (44.5%) and study completion (14.2%) may have contributed to the continued improvement in QOL after week 13, at which point increases in Hb began to stabilize. These findings confirm and expand on the results of previous studies evaluating the efficacy of epoetin alfa when administered at the start of chemotherapy in patients with hematologic malignancies26 and breast cancer.9 Straus et al showed that patients with hematologic malignancies and mild anemia (baseline Hb level 10-12 g/dL) who received epoetin alfa at the start of chemotherapy had significant improvements in Hb (P < 0.0001, between-group comparison) and QOL measures (P < 0.03 for all measures, between-group comparison), and decreases in health care resource utilization compared with patients for whom epoetin alfa treatment was delayed until Hb levels decreased to < 9 g/dL.26 In addition, the observed increases in Hb were significantly correlated with QOL improvements. O’Shaughnessy et al described similar results in their exploratory trial showing that weekly epoetin alfa therapy maintained Hb levels in patients with breast cancer undergoing adjuvant anthracycline-based chemotherapy compared with placebo.9 In that study, the majority of patients also were not anemic at baseline (mean baseline Hb level, 12.8 g/dL for patients receiving epoetin alfa; 13.0 g/dL for patients receiving placebo). Patients randomized to receive weekly epoetin alfa generally had higher LASA scores during treatment and at follow-up than patients randomized to receive placebo; patients receiving placebo also had decreases in QOL (including a significant decrease in energy scores) during the treatment phase. In the current study, epoetin alfa was well tolerated. The rate of deaths (0.6%) was similar to that reported in the O’Shaughnessy et al study in patients receiving adjuvant therapy for breast cancer (1.1%).9 There was also a low incidence of thrombovascular events, similar to those seen in the treatment and placebo arms of previously conducted randomized trials.27 Previously conducted studies of patients with breast cancer receiving anthracycline-based adjuvant therapy without epoetin alfa have reported thromboembolic rates ranging from 2% to 10%.28,29 Since this study was undertaken, clinical practice guidelines have been updated to recommend beginning anemia treatment at Hb levels ≤ 10 g/dL or between 10 and 11 g/dL, depending on clinical considerations.18,19 Recent data indicate that the greatest incremental increase in QOL occurs when Hb in-

138 • Clinical Breast Cancer June 2005

creases from 11 g/dL to 12 g/dL,30,31 and treating to a target Hb level of 12 g/dL is recommended by National Comprehensive Cancer Network guidelines19 and the prescribing information for epoetin alfa therapy for patients with cancer.27 However, because Hb levels > 12 g/dL during erythropoietic therapy have been associated with an increased risk of thrombovascular events,32 treatment with epoetin alfa beyond correction of anemia in patients with cancer is not indicated or recommended outside of a clinical trial setting.27 Higher Hb levels and enhanced tumor oxygenation have been associated with improved survival in patients with cancer,33-37 and a possible survival benefit has been suggested in several studies for patients with cancer-related anemia receiving epoetin alfa.36,38 However, data from 2 recent multicenter, double-blind, randomized, placebo-controlled trials in patients with cancer suggest that risks for adverse events may increase if erythropoietic therapy is used beyond anemia correction (ie, treating nonanemic patients and/or treating to target Hb levels > 12 g/dL).39,40 One trial evaluating the effects of weekly epoetin alfa initiated concurrently with chemotherapy in patients with metastatic breast cancer as Hb decreased to ≤ 13 g/dL was stopped early because of a lower 12-month overall survival rate in the epoetin alfa group (P = 0.01) compared with the placebo group, although most of the survival difference observed at 12 months was already present at 4 months and was not considered related to epoetin alfa therapy by study investigators.39 A second trial enrolling patients with carcinoma of the head and neck and mild anemia (Hb level 9-11 g/dL) who received radiation therapy concomitantly with epoetin beta or placebo described similar findings, with patients receiving epoetin beta experiencing a shorter overall survival versus those receiving placebo.40 In this trial, patients received epoetin beta therapy to an Hb level of 14 g/dL. More recently, however, Möbus et al reported the initial results of a prospective randomized trial comparing high-dose, increased-frequency treatment versus conventionally dosed and scheduled sequential chemotherapy in 1284 patients with high-risk nodepositive breast cancer.41 In this study, patients who were randomized to receive dose-dense therapy were further randomized to receive additional treatment with or without epoetin alfa (150 IU/kg 3 times weekly) at the initiation of chemotherapy.41 Overall, patients receiving epoetin alfa experienced no difference in disease-free survival or overall survival compared with those who did not.

Conclusion In our study, 91% of the patients who were not anemic at baseline exhibited Hb levels > 12 g/dL at study end and also maintained QOL. Despite these positive findings, results of the breast cancer trial described earlier and other investigational studies39,40 support the premise that patients with cancer receiving chemotherapy who are not anemic at baseline should not be treated with erythropoietic agents. Until further information is available, the labeling for epoetin

Clifford A. Hudis et al alfa and other erythropoietic agents in the same class has been revised to recommend a target Hb level ≤ 12 g/dL for men and women. Overall, the results of this study showed that epoetin alfa significantly improved Hb and QOL from baseline in mildly anemic patients with early-stage breast cancer receiving adjuvant chemotherapy. Controlled studies are warranted to confirm these findings in patients with mild anemia receiving chemotherapy.

Acknowledgements The authors acknowledge Thomson Scientific Connexions for their assistance in the preparation of this manuscript. This clinical trial (Study PR00-27-012) was sponsored by Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ. Lead Investigators: Martin Abrams, MD, Danbury, CT; Jonathan Abramson, MD, Bay City, MI; John Adams, DO, Arlington, TX; Kent Adler, MD, San Mateo, CA; Mahmoud Afifi, MD, Minot, ND; Fakhiuddin Ahmed, MD, Brooklyn, NY; Harish G. Ahuja, MD, Wausau, WI; Judith A. Albro, Paramus, NJ; Mitchell Alden, DO, Sellersville, PA; Michael Alexander, MD, Santa Cruz, CA; Mohammed Y. Ali, MD, Munster, IN; Ghassan Al-Jazayrly, MD, Glendale, CA; Roy M. Ambinder, MD, Orlando, FL; V.C. Amin, MD, Anderson, IN; John Anagnost, MD, Wilmington, NC; Michael Y. Ashigbi, MD, Tyler, TX; Omar T. Atiq, MD, Pine Bluff, AR; Mary Lou Auchus, MD, Dallas, TX; Craig J. Badolato, MD, Melbourne, FL; Thomas Baeker, MD, Danville, KY; Edward Balaban, DO, Sewickley, PA; Bruce Bank, MD, Elks Grove Village, IL; Bharat H. Barai, MD, Merrillville, IN; Luis R. Barreras, MD, Ft. Lauderdale, FL; Wilbur B. Bassett, Jr, MD, Columbus, GA; Charles L. Beall, MD, Morgantown, WV; J. Thaddeus Beck, MD, Springdale, AR; Elliot M. Belenkov, MD, New York, NY; Donna A. Bell, Wakefield, RI; Dan BenZeev, MD, Walnut Creek, CA; Michael Berkovic, MD, Madison Heights, MI; Dennis Berman, MD, West Chester, PA; Utpal K. Bhanja, MD, Zanesville, OH; Karin Bigman, MD, Ormond Beach, FL; Roger T. Biss, MD, Latham, NY; Nanda Biswas, MD, Victorville, CA; Kenneth Blankstein, MD, Flemington, NJ; Douglas Blayney, MD, Glendora, CA; Virginia F. Borges, MD, Boston, MA; Linda D. Bosserman, MD, Pomona, CA; Cordell J. Bott, MD, Provo, UT; Gino C. Bottino, MD, Mt. Kisco, NY; L. Eamonn Boyle, MD, York, PA; Ranga Brahmamdam, MD, Cincinnati, OH; Elizabeth J. Brate, Middletown, OH; William Brinkley, MD, Salisbury, NC; Kathleen Briscoe, MD, Irvine, CA; Paula Broadway, Marion, AR; Marcia J. Browne, MD, Wellesley, MA; Patricia Burns, MD, Stonybrook, NY; Gary V. Burton, MD, Shreveport, LA; Atul Butala, MD, Utica, NY; Patrick Byrne, MD, Fairfax, VA; Vincent Caggiano, MD, Sacramento, CA; Elber Camacho, MD, Palm Springs, CA; Laura C. Campbell, MD, Shreveport, LA; Luis Campos, MD, Houston, TX; Salvadore Caputto, MD, New Orleans, LA; Mark Carlson, MD, Lincoln, NE; Linda Carmosino, MD, East Meadow, NY; Jean M. Carrellas, Wakefiled, RI; Jennifer H. Caskey, MD, Wheat Ridge, CO; William Cathcart-Rake, MD, Salina, KS; Majd Chahin, MD, Beaufort,

SC; Kerry E. Chamberlain, DO, Largo, FL; Veena Charu, MD, Anaheim, CA; Sant P. Chawla, MD, Los Angeles, CA; Alice P. Chen, MD, Corpus Christi, TX; David Chernicoff, DO, Harrisburg, PA; Gurdeep Chhabra, MD, Leonardtown, MD; Bernard Chinnasami, MD, High Point, NC; Jennifer Choate, MD, Soquel, CA; Janak Choksi, MD, Burlington, NC; Anthony Ciarolla, MD, Long Beach, CA; Patrick Cobb, MD, Billings, MT; Everardo Cobos, MD, Lubbock, TX; Paul Coluzzi, MD, Orange, CA; John D. Conroy, Jr, MD, Lemoyne, PA; Javier Corral, MD, El Paso, TX; John J. Costanzi, MD, Austin, TX; Mark Coughenour, MD, Everett, WA; Debbie Creekbaum, Monroe, OH; Jennie R. Crews, MD, Greenville, NC; Edward B. Crowell, MD, Morgantown, WV; William Cunningham, MD, Springfield, MO; Snehal A. Damle, MD, Portsmouth, VA; Sheldon Davidson, MD, Northridge, CA; Cathy Deen, RN, Camarillo, CA; Michael DeLeo, Jr, MD, Pittsfield, MA; Salvatore A. DelPrete, MD, Stamford, CT; Michael DeMattia, DO, Mt. Clemens, MI; Eknath Deo, MD, Long Beach, CA; Francisco H. Dexeus, MD, Enid, OK; Robert F. Dobrzynski, MD, Alexandria, VA; Gary Dosik, MD, Encino, CA; Philip B. Dreisbach, MD, Rancho Mirage, CA; David Dresdner, MD, St. Petersburg, FL; Mark Druck, MD, Jersey City, NJ; John R. Dunn, MD, Dothan, AL; Janice P. Dutcher, MD, Bronx, NY; John Eckenrode, MD, Dearborn, MI; Peter D. Eisenberg, MD, Greenbrae, CA; James K. Ellis, MD, Gulfport, MS; Craig Englund, MD, Crystal River, FL; Hilal Fanasch, MD, Beaumont, TX; Tzann T. Fang, MD, Bakersfield, CA; Susan Faulkner, Middletown, OH; John Feigert, MD, Arlington, VA; Lorne D. Feldman, MD, Los Angeles, CA; Stuart Feldman, MD, White Plains, NY; Ira E. Felman, MD, Montebello, CA; Eduardo Fernandez, MD, Willingboro, NJ; Barry Fernbach, MD, Ridgewood, NJ; Mark R. Fesen, MD, Hutchinson, KS; Ellioth Fishkin, MD, Elizabeth, NJ; Donald Fleming, MD, Louisville, KY; Pamela Foley, Wakefield, RI; Robert Folman, MD, Trumbull, CT; Minch K. Fong, MD, Mission Viejo, CA; Cynthia Forsthoff, MD, Long Beach, CA; Nashat Y. Gabrail, MD, MRCP, Canton, OH; Kirit V. Gala, MD, San Gabriel, CA; Elaine Galindez, MD, Hixson, TN; Eugenio Galindo, MD, McAllen, TX; Isosceles D. Garbes, MD, West Seneca, NY; Anna Gattani, MD, New York, NY; Lloyd G. Geddes, Jr., MD, Decatar, GA; Sebastian George, MD, Rancho Mirage, CA; Hassan Ghazal, MD, Hazard, KY; Ahmad N. Gill, MD, Aiken, SC; John A Glaspy, MD, MPH, Los Angeles, CA; Dana Glenn, MD, San Diego, CA; Thomas Godfrey, MD, Loma Linda, CA; John Gohmann, MD, Lexington, KY; Robert Goldberg, MD, Pomona, NY; Gerald Goldklang, MD, Riverdale, GA; Wendell J. Goodwin, MD, Springfield, MO; Cary Gota, MD, Los Angeles, CA; Carol Grabowski, MD, Minneapolis, MN; Generosa Grana, MD, Voorhees, NJ; Ellsworth Grant, MD, Los Angeles, CA; Paul A.C. Greenberg, MD, New York, NY; Susan Greenberg, MD, Little Silver, NJ; John Griffin, MD, Plattsburgh, NY; Howard M. Gross, MD, Dayton, OH; Steven Gruenstein, MD, New York, NY; Esteban R. Guevara, MD, Sheboygan, WI; Tami Haburjak, Naples, FL; Julio Hajdenberg, MD, Tarpon Springs, FL; Bohdan E. Halibey, MD, Newton, NJ; Gerrie Michelle Hand,

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Epoetin Alfa and Adjuvant Chemotherapy for Breast Cancer MD, Rocky Mount, NC; John G. Hankins, MD, Birmingham, AL; Vincent L. Hansen, MD, Ogden, UT; Lori Updyke Hartman, Dothan, AL; William Heim, MD, Scranton, PA; Charles Henderson, MD, Atlanta, GA; Carolyn B. Hendricks, MD, Bethesda, MD; David H. Henry, MD, Philadelphia, PA; John A. Hersman, MD, Renton, WA; Andrew A. Hertler, MD, Waterville, ME; William J. Hicks, MD, Columbus, OH; Robert Hirsch, MD, Aventura, FL; Karen Hoelzer, MD, Springfield, IL; Lawrence Holt, MD, Myrtle Beach, SC; Richard C. Horns, Jr, MD, Rancho Cucamonga, CA; Robert Horowitz, MD, York, ME; Everard Hughes, MD, Newton, KS; Sang Huh, MD, Terre Haute, IN; Edgar Hull, MD, Pascagoula, MS; Atif Hussein, MD, Weston, FL; Laura Hutchins, MD, Little Rock, AR; Nicholas Iannotti, MD, Port St. Lucie, FL; Roger Inhorn, MD, St. Louis, MO; Richard Ishmael, MD, Midwest City, OK; Vasu Iyengar, MD, Ocoee, FL; Mohammad Jahanzeb, MD, Boca Raton, FL; M.M. Javle, MD, Corning, NY; Haresh S. Jhangiani, MD, Fountain Valley, CA; Madhu Jodhani, MD, Yuba City, CA; Thomas R. Johnson, MD, Johnson City, TN; C. Michael Jones, MD, Germantown, TN; Theresa Jones, Dothan, AL; Playkil J. Joseph, MD, Cranston, RI; Robert Joseph, MD, Westlake, CA; Harshvadan P. Joshi, MD, Columbus, GA; Gracy Joshua, MD, Lake Worth, FL; Walt A. Kagan, MD, Quincy, MA; Alfred Kalman, MD, Tamarac, FL; M.K. Kamal, MD, Ocala, FL; Susan Kambhu, MD, Omaha, NE; Carsten E. Kampe, MD, Austin, TX; Richard Karchmer, MD, Medford, OR; Frederic C. Kass, MD, Santa Barbara, CA; Suresh B. Katakkar, MD, Tucson, AZ; Harvey I. Katzen, MD, Clinton, MD; Douglas Kaufman, MD, San Pablo, CA; Alex Kawana, MD, Los Angeles, CA; Mark M. Keating, MD, Altoona, PA; Peter S. Kennedy, MD, Los Angeles, CA; Alan W. Keogh, DO, Upland, PA; Abbas Khalil, MD, FACP, Lima, OH; Hany R. Khalil, MD, Simi Valley, CA; Rajiu Khanna, MD, Beckley, WV; Masoud KhorsandSahbaie, MD, Roswell, NM; Brian Kim, MD, Savannah, GA; Gerrit Kimmey, MD, Huntington, WV; Judith Kleinerman, MD, Taunton, MA; Marlon B. Kleinman, MD, Skokie, IL; Kevin Knopf, MD, Annapolis, MD; Victor Koo, MD, Boynton Beach, FL; Michael A. Kosmo, MD, Poway, CA; Yamil Kouri, MD, Methuen, MA; Gabor Kovacs, MD, Laguna Beach, CA; Nora Ku, MD, Redondo Beach, CA; Kapisthalam S. Kumar, MD, New Port Richey, FL; B.D. Kundaria, MD, Santa Maria, CA; John E. Kurnick, MD, Downey, CA; Rosemary LambertFalls, MD, West Columbia, SC; Amy S. Lang, MD, San Antonio, TX; Robert Langdon, Jr, MD, Omaha, NE; Leslie A. Laufman, MD, Columbus, OH; John Laurie, MD, Grand Forks, ND; Ronald Lawson, MD, Memphis, TN; Sheila Lemke, MD, Syracuse, NY; Robert Levenson, MD, Seattle, WA; Janet S. Levick, MD, Teaneck, NJ; Jedd Levine, MD, Torrington, CT; James Liebmann, MD, Albuquerque, NM; Tiberio Lindgren, MD, Tustin, CA; Kaye A. Linke, MD, Phoenix, AZ; Joseph P Litam, MD, McAllen, TX; Randal Liu, MD, Honolulu, HI; Marian Llenado-Lee, MD, Dayton, OH; Dennis A Lowenthal, MD, Summit, NJ; Susan Luedke, MD, St. Louis, MO; Alice M. Luknic, MD, Denver, CO; Barry D. Luskey, MD, Savannah, GA; Siobhan Maher, Wakefield, RI;

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Thomas Maher, MD, Syracuse, NY; Tariq Mahmood, MD, Orange, CA; David E. Mann, Jr, MD, Pensacola, FL; Robert March, MD, New City, NY; Carmine Marchioli, MD, DuBois, PA; Mitchell D. Martin, MD, Knoxville, TN; Mohammed Masri, MD, Waterloo, IA; Michael D. Masterson, MD, Thousand Oaks, CA; Idelfia Matre, MD, Palm Harbor, FL; H. Marshall Matthews, MD, Sheboygan, WI; Philomena McAndrew, MD, Los Angeles, CA; John McCann, MD, Springfield, MA; Robert D. McCroskey, MD, Puyallup, WA; Rosemary McIntyre, MD, Oxnard, CA; Elisabeth A. McKeen, MD, West Palm Beach, FL; John McKeown, MD, Tinley Park, IL; Rick G McKinney, DO, Oklahoma City, OK; Becki Melton, MD, Ormand Beach, FL; Michael Messino, MD, Asheville, NC; Luis Meza, MD, Lafayette, LA; John C. Michalak, MD, Sioux City, IA; John Migas, MD, Normal, IL; Gerald Miletello, MD, Baton Rouge, LA; Becky Miller, MD, Los Angeles, CA; Robert A. Minow, MD, Los Alamitos, CA; Eduardo Miranda, MD, Laredo, TX; Houshang Moayeri, MD, Huntington Beach, CA; Iman E. Mohamed, MD, Toledo, OH; Timothy Moore, MD, Columbus, OH; Duane P. Moores, MD, Brunswick, GA; Gordon L. Morris MD, Charlottesville, VA; Robert A. Moss, MD, Fountain Valley, CA; Elizabeth F. Mullen, Wilmington, DE; Brian Murphy, MD, Sandusky, OH; Seetha Murukutla, MD, Staten Island, NY; Johnny Nacilla, MD, Cullman, AL; L. Stuart Nagasawa, MD, Mission Viejo, CA; Vir K. Nanda, MD, Apple Valley, CA; Screenivasa Nattam, MD, Fort Wayne, IN; Naim T. Nazha, MD, Northfield, NJ; James A. Neidhart, MD, Farmington, NM; Harvey W. Neitlich, MD, Brockton, MA; Alan B. Newman, MD, San Francisco, CA; Bichlien Nguyen, MD, Fountain Valley, CA; D. Anda Norbergs, MD, Palm Harbor, FL; Donald W. Northfelt, MD, Rancho Mirage, CA; Mohan Nuthakki, MD, Troy, OH; Gregg A. Olsen, MD, Sherman Oaks, CA; Allan Orenstein, MD, Inglewood, CA; Gregory L. Ortega, MD, Orange City, FL; Stuart Packer, MD, Langhorne, PA; Phatama Padavanija, MD, Montgomery, AL; Robert Palmer, MD, Columbus, GA; Steven Papish, MD, Morristown, NJ; Susan Paramonte, Staten Island, NY; Susan Partyka, DO, Scottsdale, AZ; Atul Patel, MD, Dalton, GA; Dhimant R. Patel, MD, Rhinelander, WI; Girabala Patel, MD, Fullerton, CA; Asim R. Pati, MD, Spartanburg, SC; Christopher R. Perkins, MD, Fresno, CA; Michael C. Perry, MD, Columbia, MO; Paul J. Petruska, MD, St. Louis, MO; Sigurdur Petursson, MD, Butler, PA; Kavitha Pinnamaneni, MD, Lufkin, TX; Andrew Pippas, MD, Lakeland, FL; Elizabeth Plaza, Norwood, NJ; Timothy S. Pluard, MD, St. Charles, MO; Ester Pollard, MD, Corpus Christi, TX; William J. Popovic, MD, Belleville, IL; Cary Presant, MD, West Covina, CA; H. Alejandro Preti, MD, Houston, TX; Dennis Priebat, MD, Washington, DC; Victor M. Priego, MD, PC, Bethesda, MD; Sarode K. Pundaleeka, MD, Joliet, IL; Prabhjit S. Purewal, MD, Stockton, CA; Chitra Rajagopal, MD, Olney, MD; Thomas Rakowski, MD, Midland Park, NJ; Joseph Ramek, MD, New York, NY; Raj Rangineni, MD, St. Joseph, MO; Lynn Herbert Ratner, MD, New York, NY; Pinjai Ravichander, MD, Taylors, SC; Lori Ann Rebello, Wakefield, RI; Rohini Reganti, MD, West

Clifford A. Hudis et al Burlington, IA; Ronald Reimer, MD, Bremerton, WA; David A. Rinaldi, MD, Lafayette, LA; Rosalba Rodriguez, MD, Chula Vista, CA; Roslyn Romanowski, MD, Williamsville, NY; Stanley H. Rossman, MD, Van Nuys, CA; Ivan Rothman, MD, Rockville Centre, NY; Rene Rothstein-Rubin, MD, Philadelphia, PA; Jon P. Rubach, MD, Mesa, AZ; Richard H. Ruben, MD, Topeka, KS; Martin Rubenstein, MD, Campbell, CA; Dana Russell, Leonardtown, MD; Fred Saleh, MD, San Diego, CA; Marc Saltzman, MD, Miami Shores, FL; Joyce Samuel, MD, Chicago, IL; Shamel Sanani, MD, Mission Hills, CA; Ravi P. Sarma, MD, Snellville, GA; Paul Schaefer, MD, Toledo, OH; Richard Scher, DO, Red Bank, NJ; Michael Schleider, MD, Englewood, NJ; Michael Schlutz, MD, Newport Beach, CA; Lee S. Schwartzberg, MD, Memphis, TN; Kala Seetharaman, MD, Worcester, MA; Milton Seiler, MD, New Orleans, LA; Nik M. Shah, MD, Parkersburg, WV; Ramesh K. Shah, MD, Tampa, FL; Harvey B. Sher, MD, Jacksonville, FL; Daniel R. Shirey, MD, Evansville, IN; Mark Shparber, MD, Fall River, MA; Robert Siegel, MD, Washington, DC; Peter Silberstein, MD, Mason City, IA; Justino Silvestre, MD, Port Charlotte, FL; Joginder Singh, MD, Waterloo, IA; Cheryl A. Skinner, MD, Middletown, OH; Dennis Slater, MD, Norwich, CT; Evan Slater, MD, Ventura, CA; Clyde Smith, MD, Jackson, TN; Gregory W. Smith, MD, Indianapolis, IN; James l. Smythe, MD, Wakefield, RI; Raman Sood, MD, Dunkirk, NY; Joseph Sparano, MD, Bronx, NY; Jonathan Sporn, MD, Farmington, CT; Kellie Sprague, MD, Boston, MA; Thomas Stanton, MD, Petaluma, CA; Cynthia D. Starr, MD, Phillipsburg, NJ; Bruce K. Stechmiller, MD, Gainesville, FL; Thomas Steffens, MD, Concord, NC; Ron Steis, MD, Roswell, GA; Jason Stern, DO, Mayfield Heights, OH; Donald K. Strickland, MD, Memphis, TN; Mark Stutz, MD, St. Louis, MO; Nancy Sun, MD, Syosset, NY; Forrest Swan, Jr, MD, Abingdon, VA; Joseph Szumowski, MD, Pleasanton, CA; Gary F. Tansino, MD, Meriden, CT; Steven Tapuzoglou, MD, Warren, MI; Simon Tchekmedyian, MD, Long Beach, CA; Daniel T. Tell, MD, Colorado Springs, CO; Terenig Terjanian, MD, Staten Island, NY; Merry L. Tetef, MD, Irvine, CA; Shanti Thomas, MD, Dearborn, MI; Irwin W. Tischler, DO, Mesa, AZ; John Trauscht, MD, Missoula, MT; Malcolm Trimble, MD, Jackson, MI; Antonio Trindade, MD, Lakeland, FL; R. Douglas Trochelman, MD, Akron, OH; Dean G. Tsarwhas, MD, Libertyville, IL; Loren Tschetter, MD, Sioux Falls, SD; Cesar Tula, MD, Laredo, TX; Rambabu Tummala, MD, Tavares, FL; Mayank J. Vakil, MD, West Covina, CA; Carol Van Haelst, MD, Kirkland, WA; Mohammad A. Varghai, MD, Lyndhurst, OH; R. S. Vasan, MD, Van Nuys, CA; Clarence B. Vaughn, MD, Southfield, MI; Joseph D. Verdirame, MD, Omaha, NE; Mary Jo Villar, DO, Miami, FL; Charles L. Vogel, MD, Plantation, FL; Plyapong Vongkovit, MD, Hickory, NC; Jerry K. Wada, MD, Glendale, CA; Brian K. Walker, MD, Naples, FL; Sabina R. Wallach, MD, LaJolla, CA; John Waples, MD, Huntsville, AL; Jeffrey Wasser, MD, Manchester, CT; R. Timothy Webb, MD, Hot Springs, AR; Kathryn Weichert, MD, Cincinnati, OH; Stuart Weiner, DO, Flint, MI; Peter Weiss, MD, Chesterfield, MO; Steven Weiss,

MD, Coral Springs, FL; William H. Whaley, MD, Atlanta, GA; Jack O. Williams, MD, Evansville, IN; Byron Wilson, MD, Castro Valley, CA; Bozena Witek, MD, Chicago, IL; Howard Wold, MD, Alexandria, LA; Timothy Wozniak, MD, Wilmington, DE; Sharon J. Yee, MD, Arcadia, CA; Timothy Yeh, MD, Brainerd, MN; Dal Yoo, MD, Washington, DC; Peter Yu, MD, Sunnyvale, CA; Furhan Yunus, MD, Memphis, TN; Lee Zehngebot, MD, Winter Park, FL; Richard Zelkowitz, MD, Norwalk, CT.

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