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Journal of Clinical Oncology, Vol 20, Issue 3 (February), 2002: 727-731
© 2002 American Society for Clinical Oncology

Blinded, Randomized, Multicenter Study to Evaluate Single Administration Pegfilgrastim Once per Cycle Versus Daily Filgrastim as an Adjunct to Chemotherapy in Patients With High-Risk Stage II or Stage III/IV Breast Cancer

By F.A. Holmes, J.A. O’Shaughnessy, S. Vukelja, S.E. Jones, J. Shogan, M. Savin, J. Glaspy, M. Moore, L. Meza, I. Wiznitzer, T.A. Neumann, L.R. Hill, B.C. Liang

From Texas Oncology, PA, Dallas, TX; Oncology Hematology Association, Pittsburgh, PA; University of California-Los Angeles Medical Center, Los Angeles, and Amgen Inc, Thousand Oaks, CA; Georgia Cancer Specialists, Decatur, GA; Southwest Oncology Associates, Lafayette, LA; and Hematology/Oncology Midwest Cancer Research Group, Northfield, IL.

Address reprint requests to Frankie Ann Holmes, MD, Texas Oncology, PA, 909 Frostwood Dr, Suite 221, Houston, TX 77024; email: frankieann.holmes{at}usoncology.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: This multicenter, randomized, double-blind, active-control study was designed to determine whether a single subcutaneous injection of pegfilgrastim (SD/01, sustained-duration filgrastim; 100 µg/kg) is as safe and effective as daily filgrastim (5 µg/kg/d) for reducing neutropenia in patients who received four cycles of myelosuppressive chemotherapy.

PATIENTS AND METHODS: Sixty-two centers enrolled 310 patients who received chemotherapy with docetaxel 75 mg/m2 and doxorubicin 60 mg/m2 on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive on day 2 either a single subcutaneous injection of pegfilgrastim 100 µg/kg per chemotherapy cycle (154 patients) or daily subcutaneous injections of filgrastim 5 µg/kg/d (156 patients). Absolute neutrophil count (ANC), duration of grade 4 neutropenia, and safety parameters were monitored.

RESULTS: One dose of pegfilgrastim per chemotherapy cycle was comparable to daily subcutaneous injections of filgrastim with regard to all efficacy end points, including the duration of severe neutropenia and the depth of ANC nadir in all cycles. Febrile neutropenia across all cycles occurred less often in patients who received pegfilgrastim. The difference in the mean duration of severe neutropenia between the pegfilgrastim and filgrastim treatment groups was less than 1 day. Pegfilgrastim was safe and well tolerated, and it was similar to filgrastim. Adverse event profiles in the pegfilgrastim and filgrastim groups were similar.

CONCLUSION: A single injection of pegfilgrastim 100 µg/kg per cycle was as safe and effective as daily injections of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of doxorubicin 60 mg/m2 and docetaxel 75 mg/m2.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
NEUTROPENIA IS common in patients with cancer who receive myelosuppressive chemotherapy and contributes to morbidity associated with cancer. Moreover, neutropenia is associated with an increased risk of infections,1 which can be life-threatening and require aggressive treatment with intravenously administered antibiotics. Such antibiotic therapy necessitates hospitalization and may be associated with other complications due to the neutropenia or therapy (eg, acquisition of resistant staphylococcal infections, antibiotic-induced diarrhea).2-4 Active management of neutropenia is thus of substantial importance in patients undergoing cytotoxic chemotherapy for the treatment of neoplastic disease.

Many studies have examined recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF; filgrastim) in the treatment of the neutropenia caused by cancer therapy (for a review, see Welte et al5). Administration of filgrastim increases WBC counts and decreases the duration of neutropenia, days of hospitalization, and number of culture-confirmed infections.3,4,6,7 Such therapy has allowed the development of more dose-intense regimens8,9 and is cost-effective in predictive models of risk.10

Pegfilgrastim is produced by covalently binding a 20-kd polyethylene glycol (PEG) molecule to the N terminus of filgrastim. Pegfilgrastim stimulates the production and maturation of neutrophil precursors and enhances the functions of mature neutrophils in the same manner as filgrastim. Addition of the polyethylene glycol molecule increased terminal half-life in animal models, and data from both normal volunteer studies11 and studies in patients with cancer12 have indicated prolonged serum levels of the cytokine, with "self-regulation" of pegfilgrastim levels as a function of the neutrophil count. Such self-regulation of drug may confer a therapeutic advantage in a variety of different clinical settings by allowing less frequent dosing and maintaining stable levels of neutrophils.

The purpose of this study was to rigorously evaluate whether a single subcutaneous injection of pegfilgrastim 100 µg/kg was as safe and effective as daily subcutaneous injections of filgrastim 5 µg/kg/d in reducing chemotherapy-induced neutropenia in patients with breast cancer undergoing up to four cycles of myelosuppressive chemotherapy with doxorubicin and docetaxel. The protocol specified that the primary patient subset used for efficacy analyses was the per-protocol–treated subset with a modified intent-to-treat subset also to be examined. For simplicity, because the results of these two analyses lead to identical conclusions, only the results of the modified intent-to-treat analysis have been reported.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
The study protocol was reviewed and approved by the institutional review board at each participating center, and all patients gave written informed consent before any study-related procedure was performed. Eligible patients were men or women (> 18 years old) diagnosed with high-risk (defined as defined by the investigator) stage II or stage III/IV breast cancer. Other eligibility requirements were patients either be chemotherapy naive or have received adjuvant therapy and/or completed no more than one regimen of chemotherapy for metastatic disease; completion of previous chemotherapy more than 4 weeks before randomization; Eastern Cooperative Oncology Group performance status <= 2; absolute neutrophil count (ANC) >= 1.5 x 109/L, platelet count >= 100 x 109/L; and adequate hepatic and cardiac function.

Patients were excluded if they had been enrolled onto or had not yet completed other investigational drug trials within 30 days before randomization into this study; were still receiving other investigational agents; had previous exposure to pegfilgrastim; were pregnant or breast-feeding; had received systemic antibiotics within 72 hours of chemotherapy; or had undergone prior radiation therapy within 4 weeks of randomization into this study (with the exception of spot radiation for bone metastases), prior bone marrow or stem-cell transplantation, or prior total cumulative lifetime exposure to doxorubicin more than 240 mg/m2 or epirubicin more than 600 mg/m2.

Study Design
This was a multicenter, randomized, double-blind, noninferiority study to evaluate the safety and efficacy of a single injection of pegfilgrastim compared with daily injections of filgrastim. Patients at each center were randomized separately and were assigned in a 1:1 ratio to pegfilgrastim 100 µg/kg or filgrastim 5 µg/kg/d treatment groups by using a stratified permuted-block randomization schedule with center and previous chemotherapy as the stratification variables.

Study Drugs
Patients randomized to pegfilgrastim received a single subcutaneous injection of pegfilgrastim 100 µg/kg per chemotherapy cycle, based on actual body weight, on day 2 of each cycle, approximately 24 hours after completion of chemotherapy. Daily subcutaneous injections of placebo were administered until a documented ANC >= 10 x 109/L after the expected nadir or for up to 14 days, whichever occurred first.

Patients randomized to filgrastim received daily subcutaneous injections of filgrastim 5 µg/kg/d, based on actual body weight, beginning on day 2 of each cycle, approximately 24 hours after chemotherapy, and continuing until a documented ANC >= 10 x 109/L after the expected nadir or for up to 14 days, whichever occurred first.

Chemotherapy Treatment
On day 1 of each chemotherapy cycle, patients received an intravenous bolus infusion of doxorubicin (60 mg/m2), followed approximately 1 hour later by a 1-hour intravenous infusion of docetaxel (75 mg/m2). Chemotherapy was repeated every 3 weeks for up to four cycles unless a dose delay was necessary. To begin full-dose chemotherapy on day 1 of the next cycle (day 22 of the previous cycle), a patient must have recovered to ANC more than 1 x 109/L and platelet count more than 100 x 109/L.

Efficacy Measurements
The primary efficacy end point was the duration of grade 4 neutropenia (defined as ANC < 0.5 x 109/L) in chemotherapy cycle 1. Other efficacy end points were the duration of grade 4 neutropenia in chemotherapy cycles 2 to 4, the depth of ANC nadir in each of the cycles (1 to 4), rates of febrile neutropenia, and the time to ANC recovery in chemotherapy cycles 1 to 4.

Safety End Points
The safety end points of this study were incidence of adverse events, changes in clinical laboratory values, and the presence of antibodies. Serum was collected for detection of antibodies before the start of study and at various time points during the study.

Statistical Methods
Treatment differences in duration of severe neutropenia were assessed by confidence intervals (calculated via bootstrap resampling). An upper 97.5% one-sided confidence interval (95% two-sided) was evaluated with respect to a noninferiority margin of 1 day. Treatment differences in depth of ANC nadir, time to ANC recovery during each of cycles 1 to 4, and febrile neutropenia during the study and between the pegfilgrastim and filgrastim groups for each cycle were assessed by an upper 97.5% one-sided confidence interval (95% two-sided) via normal-based methods. No adjustments for multiplicity were made (eg, analyses of multiple cycles).

Adverse events were tabulated by body system, severity, relationship to study drug, and treatment group. Changes in laboratory variables were depicted by use of shift tables and through the tabulation of summary statistics for each variable. Dose reductions and toxicity-related dose delays were tabulated by cycle and by treatment group.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Sixty-two centers enrolled 310 patients onto the study. One hundred fifty-four patients were randomized to receive a single subcutaneous injection of pegfilgrastim 100 µg/kg per chemotherapy cycle, and 156 patients were randomized to receive daily subcutaneous injections of filgrastim 5 µg/kg/d. In the modified intent-to-treat analysis, of the subjects randomized, 147 patients in the pegfilgrastim and 149 patients in the filgrastim subgroups were eligible for efficacy analysis, and 301 patients (150 pegfilgrastim and 151 filgrastim patients) were eligible for safety analysis. Patients were well matched with respect to stage of disease, previous chemotherapy, and previous radiotherapy. Most patients were younger than 65 years of age, with the mean age being similar between groups. Table 1 summarizes the baseline demographic and disease state characteristics of the enrolled patients.


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  		Table 1.  Patient Characteristics by Treatment Group
 
Efficacy
Duration of grade 4 neutropenia, cycle 1. The incidence of grade 4 neutropenia in cycle 1 is listed in Table 2. As expected, the greatest incidence of grade 4 neutropenia was in cycle 1, and was lower in the subsequent three cycles of treatment. The overall incidences between the pegfilgrastim and filgrastim groups were similar in each cycle, although the incidence tended to be lower in the pegfilgrastim group than in the filgrastim group.


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  		Table 2.  Incidence of Grade 4 Neutropenia by Cycle and Treatment Groups
 
The mean (SD) duration of grade 4 neutropenia for the pegfilgrastim group was 1.7 (1.5) days, compared with 1.8 (1.4) days in the filgrastim group. Because the means, when reported to two decimal points, were 1.73 and 1.76, the means difference between the pegfilgrastim and filgrastim groups (pegfilgrastim-filgrastim) was 0.03 days, with a two-sided 95% confidence limit of -0.36 to 0.30 days. No relationship was noted for the duration of grade 4 neutropenia and previous exposure to chemotherapy or radiotherapy, or to stage of disease.

Duration of grade 4 neutropenia, cycles 2 to 4. The mean duration of severe neutropenia for cycles 2, 3, and 4 were 0.7, 0.6, and 0.9 days for pegfilgrastim patients and 1.1, 1.2, and 1.3 days for filgrastim patients, respectively. The differences in the means (two-sided 95% confidence limits) were -0.40 (-0.64, -0.17; P = .001), -0.63 (-0.91, -0.36; P <= .001), and -0.38 (-0.71, -0.07; P = .019) for cycles, 2, 3, and 4, respectively.

As in cycle 1, the duration of grade 4 neutropenia in the patients without previous chemotherapy or radiotherapy exposure was similar to those for the entire patient population, and the results in the patients with previous chemotherapy exposure demonstrated comparability between pegfilgrastim and filgrastim. No relationship was noted with respect to stage of disease and the duration of grade 4 neutropenia in cycles 2 to 4. Table 3 summarizes the duration of grade 4 neutropenia for all cycles.


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  		Table 3.  Summary of Duration in Days of Grade 4 Neutropenia for All Cycles*
 
Depth of ANC nadir, cycles 1 to 4. The ANC profiles for the two treatment groups are similar for the first 9 days, with the values reaching a nadir at approximately cycle day 7. The depth of nadir was, as expected, greatest for cycle 1 compared with subsequent cycles. The ratio for the ANC nadirs in the two treatment groups in cycle 1 is 1.132, reflecting the slightly higher nadir in the pegfilgrastim group; the 95% confidence limits are 0.848 and 1.510. Overall, the pegfilgrastim group tended to have higher nadir counts the filgrastim group.

Figure 1 displays the ANC profile of the median ANCs for each treatment group. Both pegfilgrastim and filgrastim displayed similar ANC values through the nadir. After the expected ANC nadir, the pegfilgrastim profile reached a plateau, with limited "overshoot" of neutrophils after the nadir. In contrast, the ANC for the filgrastim group continued to increase until cycle day 13, reflecting the daily administration of the cytokine until an ANC of 10 x 109/L or for up to 14 days. Of note was that a single injection of pegfilgrastim per chemotherapy cycle resulted in a duration of grade 4 neutropenia that was clinically and statistically similar to that observed after a mean of 11 daily injections of filgrastim.



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  		Fig 1. ANC profile of the median ANC for all four cycles superimposed by treatment group.

 
Rates of Febrile Neutropenia
Table 4 lists the febrile neutropenia rates in patients who received pegfilgrastim and filgrastim. Febrile neutropenia was defined as an oral or oral-equivalent temperature of more than 38.2°C concurrent with an ANC less than 0.5 x 109/L. In cycle 1, 11 pegfilgrastim patients (7%) and 18 filgrastim patients (12%) developed febrile neutropenia. The difference between the percentages was -4.9%, with two-sided 95% confidence limits of -11.7% to 1.9%. As expected, the rate of febrile neutropenia was greater in cycle 1 compared with subsequent cycles; however, the febrile neutropenia rate for pegfilgrastim was less than or equal to the rate for filgrastim in all cycles. Over the entire study, 9% of patients treated with pegfilgrastim and 18% of patients treated with filgrastim had febrile neutropenia at some point during the study (difference in percentages, -9%; two-sided 95% confidence limits, -16.8% to -1.1%; P = .029). Thus, pegfilgrastim was associated with a lower overall rate of febrile neutropenia than filgrastim.


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  		Table 4.  Incidence of Febrile Neutropenia by Treatment and by Cycle
 
Time to ANC Recovery
Time to ANC recovery was defined as the time from chemotherapy administration until the patient’s ANC increased to 2.0 x 109/L after the expected nadir. The mean time was 9.3 days for the pegfilgrastim group and 9.7 days for the filgrastim group. The difference between group means was -0.40 days, with a two-sided 95% confidence limit of -0.88 to 0.08 days. In later cycles, a slightly shorter recovery time as noted in the pegfilgrastim group.

Safety
In general, the safety profile of pegfilgrastim was similar to that of filgrastim. On the basis of the analysis of safety data from this study, no patterns or trends indicative of pegfilgrastim toxicity were observed. Most adverse events were attributable to complications arising from myelosuppressive chemotherapy or the primary disease.

Adverse Events
The most frequently reported adverse event was skeletal pain (25% of pegfilgrastim patients and 26% of filgrastim patients). Adverse events that led to withdrawal were reported in six (4%) of 150 pegfilgrastim patients (two reports of pleural effusion and one report each of cardiac failure, dehydration, gastrointestinal disorder, hypovolemia, nausea, abdominal pain, and vomiting) and four (3%) of 151 filgrastim patients (two reports each of fever and granulocytopenia, one report each of disease progression and syncope). Serious adverse events were reported in 29 (19%) of 150 pegfilgrastim patients and 30 (20%) of 151 filgrastim patients. One patient died while receiving treatment as a result of sepsis and disease progression in cycle 1 (filgrastim group).

Laboratory Values
Transient, mild changes in lactic dehydrogenase, AST, and ALT, usually within the normal range, observed in both the pegfilgrastim and the filgrastim groups, were not associated with any reported clinical sequelae. Grade >= 3 anemia was similar between the pegfilgrastim (7%) and filgrastim (10%) groups, with grade 4 thrombocytopenia noted in less than 5% of patients over all cycles of treatment.

Antibody Formation
No neutralizing antibodies were detected. All patients who underwent treatment with either pegfilgrastim or filgrastim recovered ANC during the treatment period.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This randomized, double-blind study revealed that pegfilgrastim was at least equivalent to filgrastim in all efficacy and safety end points evaluated. These findings are of particular interest given the requirement of a single injection per cycle of chemotherapy, compared with an average 11 injections of filgrastim. Furthermore, significant differences in the duration of grade 4 neutropenia in cycles 2 to 4 and in the incidence of febrile neutropenia indicate that in some parameters, pegfilgrastim may perform even better than filgrastim in support of patients through a course of cytotoxic chemotherapy (eg, doxorubicin and docetaxel). In addition, the noted trends of higher nadir counts and lower incidence of grade 4 neutropenia with a single injection of pegfilgrastim compared with multiple daily injections of filgrastim suggest additional clinical benefits of the longer-acting form. Although the mechanism for such findings is unclear, the presumed constant stimulation of neutrophils and neutrophil precursors in bone marrow and blood may play a role in the improved efficacy noted.

The incidence and severity of adverse events in patients treated with pegfilgrastim were indistinguishable from those in patients treated with filgrastim. In particular, bone pain was not different between the pegfilgrastim and filgrastim groups in the study.

Neutropenia continues to be a challenge in the treatment of neoplastic disease and results in impairment of delivery of chemotherapy on time as well as at the prescribed dose intensity.8,9 The development of filgrastim has revolutionized the ability of oncologists to support patients who received cytotoxic chemotherapy and has allowed patients to avoid the potential complications of low neutrophil counts, particularly infection.5 Within this context, the use of filgrastim requires daily administration, which necessitates a high degree of compliance in a population of patients who can be and often times are severely ill and debilitated. A single injection per cycle of cytokine with the same properties as filgrastim would be of significant clinical value.

This trial has indicated the benefits of a single injection of pegfilgrastim for the reduction of chemotherapy-induced neutropenia similar to daily injections of filgrastim. Investigations into other settings of neutropenia (eg, congenital neutropenia) or stem-cell support (eg, mobilization of CD34+ cells) will be of interest to assess the efficacy in these contexts. The use of pegfilgrastim should provide clinical benefits to patients and caregivers as a result of the once-per-cycle administration and comparable efficacy to daily injections of filgrastim.


   ACKNOWLEDGMENTS
 
Supported in part by Amgen Inc, Thousand Oaks, CA.

We thank the research nurses and the patients who participated in this study. Martine Brassard, PhD; Bing-Bing Yang, PhD; Diane Dunford, RN; and Steve Swanson, PhD, assisted with the study. Helen Wilfehrt, PhD, and MaryAnn Foote, PhD, assisted with the writing of the article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Bodey GP, Buckley M, Sathe YS, et al: Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64: 328-340, 1966

2. Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325: 164-170, 1991[Abstract]

3. Gabrilove JL, Jakubowski A, Scher H, et al: Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 318: 1414-1422, 1988[Abstract]

4. Bronchud MH, Scarffe JH, Thatcher N, et al: Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer. Br J Cancer 56: 809-813, 1987[Medline]

5. Welte K, Gabrilove J, Bronchud MH, et al: Filgrastim (r-metHuG-CSF): The first 10 years. Blood 88: 1907-1929, 1996[Free Full Text]

6. Sheridan WP, Morstyn G, Wolf M, et al: Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 2: 891-895, 1989[CrossRef][Medline]

7. Morstyn G, Campbell L, Souza LM, et al: Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1: 667-672, 1988[CrossRef][Medline]

8. Thatcher N, Girling DJ, Hopwood P, et al: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support. J Clin Oncol 18: 395-404, 2000[Abstract/Free Full Text]

9. Sparano JA, Hu P, Rao RM, et al: Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 17: 3828-3834, 1999[Abstract/Free Full Text]

10. Silber JH, Fridman M, Shpilsky A, et al: Modeling the cost-effectiveness of granulocyte colony-stimulating factor use in early-stage breast cancer. J Clin Oncol 16: 2435-2444, 1998[Abstract]

11. Molineux G, Kinstler O, Briddell B, et al: A new form of filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans. Exp Hematol 27: 1724-1734, 1999[CrossRef][Medline]

12. Johnston E, Crawford J, Blackwell S, et al: Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 18: 2522-2528, 2000[Abstract/Free Full Text]

Submitted April 12, 2001; accepted October 3, 2001.


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V. Bhatt and A. Saleem
Drug-Induced Neutropenia - Pathophysiology, Clinical Features, and Management
Ann. Clin. Lab. Sci., April 1, 2004; 34(2): 131 - 137.
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G. A. Omura, M. F. Brady, K. Y. Look, H. E. Averette, J. E. Delmore, H. J. Long, S. Wadler, G. Spiegel, and S. G. Arbuck
Phase III Trial of Paclitaxel at Two Dose Levels, the Higher Dose Accompanied by Filgrastim at Two Dose Levels in Platinum-Pretreated Epithelial Ovarian Cancer: An Intergroup Study
J. Clin. Oncol., August 1, 2003; 21(15): 2843 - 2848.
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A. Wunderlich, M. Kloess, M. Reiser, C. Rudolph, L. Truemper, S. Bittner, H. Schmalenberg, R. Schmits, M. Pfreundschuh, and M. Loeffler
Practicability and acute haematological toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin's lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL)
Ann. Onc., June 1, 2003; 14(6): 881 - 893.
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B. L Stanford, S. D Zondor, and E. Cobos
Is pegfilgrastim appropriate for the treatment of established febrile neutropenia?
Journal of Oncology Pharmacy Practice, June 1, 2003; 9(2-3): 113 - 119.
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J.M. Vose, M. Crump, H. Lazarus, C. Emmanouilides, D. Schenkein, J. Moore, S. Frankel, I. Flinn, W. Lovelace, J. Hackett, et al.
Randomized, Multicenter, Open-Label Study of Pegfilgrastim Compared With Daily Filgrastim After Chemotherapy for Lymphoma
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Pegfilgrastim: the promise of pegylation fulfilled
Ann. Onc., January 1, 2003; 14(1): 6 - 7.
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A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy
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