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Efficacy of Pegfilgrastim and Darbepoetin Alfa As Hematopoietic Support for Dose-Dense Every-2-Week Adjuvant Breast Cancer Chemotherapy

From the Dana-Farber Cancer Institute; Brigham & Women's Hospital; Massachusetts General Hospital; Beth Israel Deaconess Medical Center; and Harvard Medical School, Boston, MA

Address reprint requests to Harold J. Burstein, MD, PhD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: hburstein{at}partners.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Dose-dense, every-2-week adjuvant chemotherapy using doxorubicin/cyclophosphamide (AC; 60/600 mg/m² every 2 weeks x four cycles) followed by paclitaxel (175 mg/m² every 2 weeks x four cycles), requiring filgrastim on days 3 through 10 of each cycle has been shown to improve survival compared with every-3-week treatment schedules but is associated with greater risk of RBC transfusion (13%). The role of long-acting hematopoietic growth factors in facilitating every-2-week chemotherapy and minimizing hematologic toxicity has not been established.

PATIENTS AND METHODS: Women with stage I to III breast cancer received dose-dense AC paclitaxel as neoadjuvant or adjuvant chemotherapy. Patients received pegfilgrastim 6 mg subcutaneous (SQ) on day 2 of each cycle. Darbepoetin alfa was initiated at 200 µg SQ every 2 weeks for hemoglobin 12 g/dL, and administered thereafter, according to a preplanned algorithm. The primary end points were to evaluate the percentage of patients with febrile neutropenia and the percentage of patients requiring RBC transfusion.

RESULTS: Among 135 women treated on this single arm study, there were two cases of febrile neutropenia (incidence 1.5%). No patients received RBC transfusion. Darbepoetin alfa therapy was initiated in 92% of patients. The modest leukocytosis seen during paclitaxel cycles was attributable, in part, to corticosteroid premedication. Other toxicity and dose-delivery were similar to dose-dense AC paclitaxel in Cancer and Leukemia Group B 9741.

CONCLUSION: Pegfilgrastim and darbepoetin alfa are effective and safe in facilitating every-2-week AC paclitaxel, minimizing rates of febrile neutropenia and RBC transfusion.

	INTRODUCTION

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Intensive adjuvant breast cancer chemotherapy regimens based on anthracycline and taxane therapy are associated with substantial risk of myelosuppression and anemia. Historically, the time to recovery of the neutrophil count has been the schedule-limiting factor in crafting adjuvant chemotherapy regimens. Thus, regimens such as doxorubicin plus cyclophosphamide (AC) or sequential AC followed by paclitaxel were developed on every-3-week schedules to allow adequate bone marrow, and, in particular, neutrophil recovery.¹ The emergence of myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) allowed for accelerated bone marrow recovery, and enabled the design of clinical trials that tested the importance of treatment scheduling as part of adjuvant chemotherapy for early-stage breast cancer.

Cancer and Leukemia Group B (CALGB) 9741 was one such trial.² It compared AC paclitaxel given on the traditional every 3 week schedule against an accelerated, dose-dense schedule consisting of the same chemotherapy dose and cycle number, but with cycles given every 2 weeks instead of every 3 weeks. To facilitate the dose-dense schedule, patients receiving every-2-week therapy received G-CSF support, consisting of filgrastim administered subcutaneously on days 3 through 10 at 5 µg/kg of each treatment cycle.³ The first results of CALGB 9741 indicate that the accelerated dose-dense schedule improved disease-free and overall survival among women with lymph node–positive breast cancer. The toxicity experience for patients receiving every 2 week or every 3 week treatment was generally similar. Because of the use of filgrastim in CALGB 9741, neutropenia and febrile neutropenia were less common in the dose-dense treatment arms; the rate of febrile neutropenia was 2% to 3% among patients receiving G-CSF.

Advances in biotechnology led subsequently to the development of long-acting hematopoietic growth factors. Pegfilgrastim, a pegylated version of filgrastim, was designed to have a longer half-life and thus, facilitate less frequent dosing. In randomized trials, pegfilgrastim administered once every 3 weeks provided equivalent myeloid support as filgrastim when given to patients receiving intensive adjuvant chemotherapy.⁴ Given the long half-life of pegfilgrastim, it has not been clear whether treatment intervals shorter than 21 days were feasible or desirable. Recent pharmacologic data suggest that by day 12 following intensive chemotherapy, residual levels of pegfilgrastim are subtherapeutic.^5,6 Furthermore, because pegfilgrastim is cleared by binding to G-CSF receptors found on myeloid bone marrow elements and neutrophils, the recovery of neutrophil counts to levels in excess of 1,000/µL is associated with subtherapeutic levels of pegfilgrastim. Thus, it seemed possible that pegfilgrastim could be safely and effectively used to support an every 2 week chemotherapy cycle, with the attendant convenience compared with short-acting filgrastim of once per cycle dosing. However, clinical data demonstrating the feasibility of this regimen in support of dose-dense AC paclitaxel were not available.

Another finding in CALGB 9741 was a greater risk of anemia and a greater incidence of RBC transfusion among patients receiving dose-dense AC paclitaxel.² Although parameters for RBC transfusion were not articulated in that protocol, 13% of patients receiving dose-dense AC paclitaxel received transfusions. This percentage was higher than for other treatment arms in the study, and higher than historically seen in other adjuvant chemotherapy trials. Erythropoietic agents were permitted on CALGB 9741, but the protocol did not specify which patients should receive such hematologic support.

Because of the widespread acceptance of dose-dense AC paclitaxel as an adjuvant chemotherapy regimen, we sought to evaluate the use of long-acting hematopoietic growth factors in support of the regimen. We developed a phase II trial to determine whether long-acting pegfilgrastim could be safely and effectively substituted for short-acting filgrastim in support of every-2-week chemotherapy. We also sought to determine whether a planned algorithm for use of the long-acting erythropoietic growth factor, darbepoetin alfa,⁷ given on an every-2-week schedule,⁸ could mitigate the need for RBC transfusion in patients receiving dose-dense AC paclitaxel. If successful, the use of the growth factors offered the convenience of once-per-cycle dosing of both myeloid and erythroid growth factor support.

	PATIENTS AND METHODS

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Protection of Human Subjects
Patients were treated at the Dana-Farber Cancer Institute (Boston, MA) and member institutions of the Dana-Farber/Harvard Cancer Center (Boston, MA), including Massachusetts General Hospital (Boston, MA) and Beth Israel Deaconess Medical Center (Boston, MA), and affiliated community hospitals. The study was approved by the Scientific Review Committee and Human Protection Committee for Dana-Farber/Harvard Cancer Center, and by the institutional review boards at participating community hospitals. All patients provided written informed consent for protocol-based treatment.

Eligibility
Patients were enrolled in the study between July 2003 and May 2004. Eligible patients had stage I to III breast cancer as defined by the American Joint Committee on Cancer sixth edition, and were deemed appropriate for dose-dense adjuvant chemotherapy by their treating oncologist. Patients could not have received prior chemotherapy or radiation therapy, be pregnant or nursing, or have a history of hyperviscosity syndrome, bone marrow disorders such as sickle cell disease, thalassemia or myelodysplasia, immunodeficiency states, previous exposure to G-CSF or erythropoietic agents, concurrent lithium use, RBC transfusion within the previous 4 weeks, antibiotic use within the previous 72 hours, or other concurrent illness such as active infection, heart failure, or psychiatric illness that might limit treatment compliance. Patients were required to have normal organ function, defined as follows: absolute neutrophil count (ANC) 1,500/µL, hemoglobin (Hgb) 9 gm/dL, platelets 100,000/µL, AST and ALT 1.5 times the upper limits of normal, left ventricular ejection fraction 50%, and bilirubin, creatinine, prothrombin time, and partial prothrombin time within institutional normal limits.

Treatment Plan
Chemotherapy. The chemotherapy regimen was the same used in arm 4 of CALGB 9741: doxorubicin 60 mg/m² intravenous pyelography and cyclophosphamide 600 mg/m² intravenous bolus (IVB) (AC) once every 2 weeks x four cycles followed by paclitaxel 175 mg/m² IVB once every 2 weeks x four cycles. The chemotherapy dose was determined by actual body weight on the day of treatment for each cycle. The protocol was generally intended for adjuvant therapy—that is, following definitive breast surgery. However, patients could receive neoadjuvant chemotherapy treatment at the same doses and schedules as above. In such instances, patients could receive four cycles of dose-dense AC with or without four cycles of dose-dose paclitaxel as preoperative therapy. Patients receiving preoperative AC x four could receive adjuvant (ie, postoperative) paclitaxel x four cycles. Patients could not receive concurrent radiation therapy or trastuzumab.

Early in the course of treatment, we observed elevated ANCs on day 1 of treatment cycles during the paclitaxel phases of therapy. We hypothesized that this leukocytosis might be caused in part by the oral corticosteroid premedication given 12 and 6 hours before paclitaxel therapy. To test this hypothesis, we amended the protocol in March 2004 to evaluate a cohort of patients not receiving oral steroid premedication. Thus, patients in cohort A represent the originally planned cohort of 109 patients treated with oral corticosteroid premedication. Patients in cohort B represent an additional group of 26 women who received oral steroid premedication before cycle five (this first dose of paclitaxel) but not before cycles six, seven, or eight provided they did not experience paclitaxel-related hypersensitivity.

Schedule and dose modifications. Treatment with AC or paclitaxel was held for ANC less than 1,000/µL or a platelet count of less than 100,000/µL on the scheduled day of treatment, and given as soon as reasonably possible once the ANC or platelet count recovered to allow treatment. Patients with febrile neutropenia were given a 25% dose reduction during the same remaining cycles of the same chemotherapy. Patients with gastrointestinal toxicity in excess of grade 1 had chemotherapy held until symptoms resolved to grade 0 or 1. Patients with grade 4 gastrointestinal toxicity had chemotherapy dose(s) reduced by 25% at the time of retreatment. Patients were taken off study for symptomatic cardiac toxicity, or grade 3 neurotoxicity associated with paclitaxel. Other grade 2 or 3 treatment-related nonhematologic toxicity had to resolve to grade 0 or 1 before retreatment. Patients requiring treatment delay of more than 3 weeks or with other grade 4 treatment-related nonhematologic toxicity were taken off study.

Patients were additionally to be taken off study for tumor recurrence or progression, voluntary withdrawal of consent, chemotherapy delays of more than 5 weeks because of treatment-related toxicity, or general or specific changes in the patient's condition that rendered the patient unacceptable for further treatment in the judgment of the investigator.

Supportive measures. Patients received appropriate hydration and antiemetic therapy according to standard institutional practices. To minimize hypersensitivity reactions associated with paclitaxel, patients in cohort A were premedicated before each cycle with dexamethasone 20 mg orally (PO) taken approximately 12 and 6 hours before infusion, diphenhydramine 25 mg IV/PO 30 to 60 minutes before infusion, and ranitidine (or equivalent) 50 mg IV or 150 mg PO 30 to 60 minutes before infusion. Patients in cohort B received this same premedication regimen before their first dose of paclitaxel (cycle 5). If the patient did not experience hypersensitivity reactions with that cycle, the oral dexamethasone premedication was omitted from subsequent paclitaxel cycles, and patients were premedicated with dexamethasone 10 mg IV 30 to 60 minutes before paclitaxel infusion.⁹ Patients were prohibited from receiving prophylactic antibiotics while on study. Patients who, during the course of treatment, had evidence of iron, folate, or B12 deficiency were to receive appropriate repletion therapy.

Pegfilgrastim. Pegfilgrastim was administered 6 mg subcutaneously (SQ) on day 2 of each treatment cycle, approximately 24 hours after chemotherapy. There were no dose or schedule modifications.

Darbepoetin alfa. Hgb levels were checked on day 1 of each chemotherapy cycle. Darbepoetin alfa 200 µg SQ every 2 weeks was administered to patients with Hgb less than 12 g/dL. Once initiated, darbepoetin alfa was administered on day 1 of each chemotherapy cycle, on the basis of that day's Hgb, according to the following algorithm (Fig 1): Hgb 10 to 12 g/dL, 200 µg SQ; Hgb less than 10 g/dL, 300 µg SQ; Hgb more than 12 g/dL, darbepoetin alfa held. When a patient had initiated darbepoetin alfa and subsequently had darbepoetin alfa held for Hgb more than 12 g/dL, darbepoetin alfa was restarted at 150 µg SQ on day 1 if the Hgb fell to 12 g/dL or less (ie, 75% of previous treatment level).

View larger version (16K): [in this window] [in a new window]   Fig 1. Darbepoetin alfa algorithm. Hgb, hemoglobin; SQ, subcutaneously.

RBC transfusion. The decision to offer RBC transfusion was left to the discretion of the treating clinician, but, consistent with American Society of Clinical Oncology and institutional guidelines, was generally reserved for patients with Hgb less than 10 g/dL.

Analytic Plan
End points and analyses. The initial accrual goal of the study was 109 patients to obtain 100 patients assessable for febrile neutropenia and RBC transfusion. Sample size and power calculations were determined prospectively as follows. The first primary end point of the study was to evaluate the utility of pegfilgrastim by estimating the percent of patients having febrile neutropenia defined by the National Comprehensive Cancer Network and Infectious Diseases Society of America as a single oral temperature of 38.3°C (101°F) or a temperature of 38.0°C (100.4°F) for 1 hour, with ANC less than 500 µ/L.¹⁰ A true rate of febrile neutropenia of 10% was considered unacceptable and a true rate of 3% considered acceptable on the basis of experience in CALGB 9741. Pegfilgrastim was deemed useful if no more than four patients among the first 100 eligible patients had febrile neutropenia. With this decision rule, a cumulative binomial calculation yielded an 82% chance of deeming pegfilgrastim useful, if the true proportion of patients with febrile neutropenia was 3%, and to have a 2% chance of deeming it useful, if the true proportion with febrile neutropenia was 10%.

The second primary end point was to determine the acceptability of the darbepoetin alfa algorithm by estimating the percentage of patients needing RBC transfusions: a true rate of 5% was considered acceptable and a true rate of 13% was considered unacceptable. The darbepoetin alfa algorithm was considered acceptable if no more than seven patients received RBC transfusions. With this decision rule, a cumulative binomial calculation yielded an 87% chance of considering the darbepoetin alfa algorithm acceptable, if the true proportion of patients needing RBC transfusions was 5%, and a 4% chance, if the true proportion was 13%.

Planned secondary end points were to characterize: the percentage of patients completing four cycles of dose-dense AC and eight cycles of dose-dense (neo)adjuvant chemotherapy on an every-2-week schedule with pegfilgrastim and darbepoetin alfa support; the incidence of hematologic toxicity; the change in Hgb from baseline at each cycle and at the end of treatment; the percentage of patients with normal Hgb or mild, moderate, or severe anemia defined according to the National Cancer Institute (NCI) anemia severity scale at monthly intervals and the end of treatment; the percentge of patients who received darbepoetin alfa according to the planned treatment algorithm; the percentage of darbeopoetin alfa-treated patients who achieved a hematopoietic response defined as either (1) rise in Hgb by more than 2 g/dL (based on the Hgb level at which darbepoetin alfa was initiated), or (2) a Hgb more than 12 g/dL at any cycle; the incidence of nonhematologic toxicities associated with dose-dense therapy; and the incidence of chemotherapy dose delays and/or reductions, the percentage of patients receiving at least 85% of planned chemotherapy doses, and the average chemotherapy cycle length.

The protocol was amended to include an additional cohort of 25 patients who would receive oral premedication with dexamethasone to determine if the use of intravenous dexamethasone would lower the cycle 6 day 1 ANC counts. Based on evaluation of the first 31 patients enrolled on the study at the time of the amendment, the sample size for cohort B was calculated assuming a minimum of the 30 patients in cohort A who had received at least six cycles of treatment. The enrollment of 25 patients in cohort B (and 30 patients in cohort A) would provide at least 80% power to detect a difference in ANC between cycles five and six, comparing patients in cohorts A and B. The calculation assumed that the standard deviation of the difference in ANC between cycles five and six would be no bigger than the estimate of standard deviation of cycle six ANC (as observed at the time of the amendment). To test the hypothesis regarding the effect of oral dexamethasone premedication on ANC counts, an analysis was planned to compare cycle 5 day 1 ANC minus cycle 6 day 1 ANC between patients in cohort B (who received oral dexamethasone premedication) and patients in cohort A, using a two-sided Wilcoxon rank sum test.¹¹

Toxicity reporting. Toxicity was recorded using the NCI Common Toxicity Criteria, version 3, (http://ctep.cancer.gov/reporting/ctc.html). Anemia was also graded according to the NCI anemia scale.¹²

	RESULTS

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Altogether 135 women were entered onto study, 109 in cohort A and 26 in cohort B (two patients registered simultaneously on the last day). A total of 1,005 treatment cycles were administered on study. The median patient age was 48 years (range, 28 to 71 years). Patients had stage I (13%), II (62%), or III (24%) breast cancer. Though patients were eligible to receive neoadjuvant chemotherapy, all study treatment was given as adjuvant therapy after surgery. Five patients came off study for treatment-related reasons. One had grade 3 neuropathy, a protocol-defined stopping point. The others had grade 2 neuropathy (n = 4) or grade 2 hypersensitivity to paclitaxel (n = 1, in cohort A) and chose to end therapy before concluding all eight cycles.

Rates of Febrile Neutropenia and RBC Transfusion
Only two patients (1.5%) reported febrile neutropenia. Both occurrences were during AC chemotherapy. The patients recovered without complication and went on to conclude AC chemotherapy with the planned 25% dose reduction before continuing on to paclitaxel chemotherapy. No patients received RBC transfusion.

Hematologic Toxicity
ANC and Hgb levels were determined on day 1 of each treatment cycle, and a post-treatment level was drawn 4 to 8 weeks after completing chemotherapy. The incidence of nonfebrile grade 3 or 4 neutropenia was extremely low, affecting only four patients (3%). The mean day 1 ANC ranged from 4,600 to 7,830 µ/L during AC treatment, and from 11,480 to 16,120 µ/L during paclitaxel therapy. Figure 2 shows the day 1 ANC by cohort at baseline, each treatment cycle, and post-treatment. The omission of oral steroid premedication before cycles six through eight for patients in cohort B attenuated the increase in day 1 ANC observed during the paclitaxel phase of treatment. The difference in day 1 ANC between cycles five and six was significantly lower for patients in cohort B than in cohort A, (P = .001), and, in fact, was in the opposite direction overall. Post-treatment levels appeared to normalize, consistent with prior historic experience following adjuvant chemotherapy.

View larger version (12K): [in this window] [in a new window]   Fig 2. Absolute neutrophil counts (ANC) by cohort (effect of steroid premedication). The boxes are drawn from the 25% to 75% quartiles, the horizontal line represents the median, and the whiskers are drawn out to 1.5*interquartile range (considered extreme values); individual lines represent outliers. Patients in cohort A received oral corticosteroid premedication before each paclitaxel cycle (cycles 5 to 8), whereas, those in cohort B received corticosteroid premedication before cycle five but not thereafter. Numbers in parentheses indicate number of assessable patients in cohorts A/B.

View larger version (14K): [in this window] [in a new window]   Fig 3. Day 1 hemoglobin (Hgb) levels. The boxes are drawn from the 25% to 75% quartiles, the horizontal line represents the median, and the whiskers are drawn out to 1.5*interquartile range (considered extreme values); individual lines represent outliers. Numbers in parentheses indicate number of assessable patients.

View larger version (12K): [in this window] [in a new window]   Fig 4. Darbepoetin alfa utilization. Percentage of patients receiving darbepoetin alfa administered per the planned algorithm for each treatment cycle. The solid line indicates the cumulative percentage over cycles of patients who started darbepoetin alfa therapy; the dashed line denotes the actual percentage of patients receiving darbepoetin alfa on any given treatment cycle.

	DISCUSSION

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It has been questioned whether all cycles of dose-dense AC paclitaxel require G-CSF support. Our data do not address that question. A single anecdotal experience from our trial cautions that withholding pegfilgrastim during paclitaxel therapy may lead to inadequate neutrophil recovery. It is not known how to identify patients in whom G-CSF support may be safely omitted. Our trial defines rates of planned dose on time and of treatment delays that can be used by other investigators in subsequent studies to determine whether G-CSF treatment can be withheld while still delivering adjuvant chemotherapy in a timely manner. We did explore the contributors to the leukocytosis observed during paclitaxel treatment. The experience of patients in cohort B, who did not receive oral corticosteroid premedication with paclitaxel at cycles 6, 7, and 8, suggests that a significant proportion of the rise in ANC can be attributed to the use of steroids.

Our data include comprehensive analyses of dose delivery and treatment delay for every-2-week AC paclitaxel therapy. For patients receiving dose-dense AC paclitaxel in CALGB 9741, treatment delays affected 6% of cycles, while dose reductions affected 3% (doxorubicin) to 5% (cyclophosphamide and paclitaxel) of patients.² We report dose delays in 4.9% of cycles, with dose reductions affecting fewer than 2% of patients. In CALGB 9741, 15% of the delays were caused by hematologic toxicity, whereas, fewer than 2% of delays in our trial were caused by hematologic toxicity. Thus, we believe our experience with long-acting growth factors compares favorably to dose-delivery outcomes in CALGB 9741.

The optimal role for erythropoietic agents in management of chemotherapy-induced anemia and fatigue remains an area of intense research. Multiple randomized trials have demonstrated that planned initiation of erythropoietins such as darbepoetin alfa has been shown to maintain Hgb levels, reduce the need for RBC transfusion, and enhance quality of life,^13,14,15 including among breast cancer patients.¹⁶ Current data suggest that Hgb in the range of 11 to 12 g/dL appears optimal for realizing gains in quality of life with erythropoietic therapy.^17,18 For these reasons, current guidelines from the National Comprehensive Cancer Network suggest maintaining Hgb in the range of 11 to 12 g/dL as the target for treatment of chemotherapy-induced anemia.¹⁹ Because of the low rate of RBC transfusion, and the successful titration of Hgb to recommended target ranges, our experience suggests that darbepoetin alfa given every 2 weeks on a planned algorithm provides effective erythropoietic support for patients receiving dose-dense adjuvant AC paclitaxel.

A limitation of the current trial is a lack of cost or cost-effectiveness data. We believe that the every-2-week treatment programs offer substantial clinical convenience to patients over more frequent dosing of hematopoietic growth factors. However, formal cost analyses were not available.

In summary, we have demonstrated that long-acting, every-2-week growth factors provide effective hematologic support for breast cancer patients receiving dose-dense, every-2-week chemotherapy with AC paclitaxel. This treatment program offers the convenience of once-per-cycle dosing of pegfilgrastim and darbepoetin alfa and has become the standard supportive regimen for patients at our institutions.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Harold J. Burstein Amgen (A) Amgen (A) Leroy M. Parker Amgen (A) Amgen (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	NOTES

 
Supported in part by a research grant-in-aid from Amgen.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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2. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003[Abstract/Free Full Text]

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4. Siena S, Piccart MJ, Holmes FA, et al: A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily Filgrastim in patients with stage II-IV breast cancer. Oncol Rep 10:715-724, 2003[Medline]

5. George S, Yunus F, Case D, et al: Fixed-dose pegfilgrastim is safe and allows neutrophil recovery in patients with non-Hodgkin's lymphoma. Leuk Lymphoma 44:1691-1696, 2003[Medline]

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8. Schwartzberg LS, Yee LK, Senecal FM, et al: A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist 9:696-707, 2004[Abstract/Free Full Text]

9. Bookman MA, Kloth DD, Kover PE, et al: Intravenous prophylaxis for paclitaxel-related hypersensitivity reactions. Semin Oncol 24:S19-13-S19-15, 1997 (suppl 6)

10. Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730-751, 2002[CrossRef][Medline]

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12. Groopman JE, Itri LM: Chemotherapy-induced anemia in adults: Incidence and treatment. J Natl Cancer Inst 19:1616-1634, 1999

13. Littlewood TJ, Bajetta E, Nortier JWR, et al: Effects of epoetin alfa on hematological parameters and quality of life in cancer patients receiving non-platinum chemotherapy: Results of a randomized, double-blind, placebo controlled trial. J Clin Oncol 19:2865-2874, 2001[Abstract/Free Full Text]

14. Seidenfeld J, Piper M, Flamm C, et al: Epoetin treatment of anemia associated with cancer therapy: A systematic review and meta-analysis of controlled clinical trial. J Natl Cancer Inst 93:1204-1214, 2001[Abstract/Free Full Text]

15. Vansteenkiste J, Pirker R, Massuti B, et al: Double blind, placebo controlled randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94:1211-1220, 2002[Abstract/Free Full Text]

16. Chang J, Couture F, Young S, et al: Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 23:2597-2605, 2005[Abstract/Free Full Text]

17. Cleeland CS, Demetri GD, Glaspy J, et al: Identifying hemoglobin level for optimal quality of life: Results of an incremental analysis. Proc Am Soc Clin Oncol 18:547a, 1999 (abstr 2215)

18. Crawford J, Cella D, Cleeland CS, et al: Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetinalfa therapy. Cancer 95:888-895, 2002[CrossRef][Medline]

19. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology: Cancer and Treatment-Related Anemia—National Comprehensive Cancer Network, Version 1.2005. http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf. Accessed May 26, 2005

Submitted May 26, 2005; accepted August 9, 2005.

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