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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1178-1184
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.09.102
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First and Subsequent Cycle Use of Pegfilgrastim Prevents Febrile Neutropenia in Patients With Breast Cancer: A Multicenter, Double-Blind, Placebo-Controlled Phase III Study

Charles L. Vogel, Marek Z. Wojtukiewicz, Robert R. Carroll, Sergei A. Tjulandin, Luis Javier Barajas-Figueroa, Brian L. Wiens, Theresa A. Neumann, Lee S. Schwartzberg

From the Cancer Research Networks, Inc, Plantation; Gainesville, FL; Amgen Inc, Thousand Oaks, CA; The W Clinic, Memphis, TN; Regional Oncology Centre and Department of Oncology, Medical University, Bialystok, Poland; Russian Cancer Research Center, Moscow, Russia; and Hospital General de Occidente, Zapopan, Jalisco, Mexico

Address reprint requests to Charles L. Vogel, MD, 150 NW 84th Ave, Ste 300, Plantation, FL 33324; e-mail: drcvogel{at}aol.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: We evaluated the efficacy of pegfilgrastim to reduce the incidence of febrile neutropenia associated with docetaxel in breast cancer patients.

PATIENTS AND METHODS: Patients were randomly assigned to either placebo or pegfilgrastim 6 mg subcutaneously on day 2 of each 21-day chemotherapy cycle of 100 mg/m2 docetaxel. The primary end point was the percentage of patients developing febrile neutropenia (defined as body temperature ≥ 38.2°C and neutrophil count < 0.5 x 109/L on the same day of the fever or the day after). Secondary end points were incidence of hospitalizations associated with a diagnosis of febrile neutropenia, intravenous (IV) anti-infectives required for febrile neutropenia, and the ability to maintain planned chemotherapy dose on time. Patients with febrile neutropenia were converted to open-label pegfilgrastim in subsequent cycles.

RESULTS: Nine hundred twenty-eight patients received placebo (n = 465) or pegfilgrastim (n = 463). Patients receiving pegfilgrastim, compared with patients receiving placebo, had a lower incidence of febrile neutropenia (1% v 17%, respectively; P < .001), febrile neutropenia–related hospitalization (1% v 14%, respectively; P < .001), and use of IV anti-infectives (2% v 10%, respectively; P < .001). The percentage of patients receiving the planned dose on time was similar between patients receiving pegfilgrastim and patients who initially received placebo (80% and 78%, respectively), as would be expected of the study design. Pegfilgrastim was generally well tolerated and safe, and the adverse events reported were typical of this patient population.

CONCLUSION: First and subsequent cycle use of pegfilgrastim with a moderately myelosuppressive chemotherapy regimen markedly reduced febrile neutropenia, febrile neutropenia–related hospitalizations, and IV anti-infective use.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Febrile neutropenia is a dose-limiting event for many myelosuppressive chemotherapy regimens. The risk of developing febrile neutropenia is driven by both the chemotherapy dose and schedule and patient-related factors. In general, febrile neutropenia has been treated with immediate hospitalization and the administration of intravenous (IV) antibiotics.1 Guidelines on the use of colony-stimulating growth factors, such as pegfilgrastim, recommend that they be used in the first cycle of chemotherapy only with highly myelosuppressive chemotherapy that is associated with an incidence of febrile neutropenia of approximately 40%.2 Patients who received placebo in the pivotal phase III trial for filgrastim were reported to have a 77% incidence rate of febrile neutropenia compared with a febrile neutropenia incidence rate of 40% in patients who received filgrastim.3 In a similar placebo-controlled study using filgrastim from the first cycle, the rate of febrile neutropenia in the placebo group was 53% compared with 26% in the filgrastim group.4 In the pivotal pegfilgrastim studies, the rate of febrile neutropenia in the filgrastim groups was 15% to 18% compared with 9% to 10% in the pegfilgrastim groups.5,6 The expected rate of febrile neutropenia using the same chemotherapy regimen was approximately 40% without growth factor support.7

The current study was designed to determine whether first and subsequent cycle use of pegfilgrastim in a myelosuppressive regimen associated with a risk of developing febrile neutropenia in the range of 10% to 20% provides a clinically meaningful reduction in the incidence of febrile neutropenia and associated hospitalizations and IV anti-infective use. Recombinant myeloid colony-stimulating growth factors have been shown to reduce the severity and duration of neutropenia and facilitate the delivery of full dose-intensity of chemotherapy on schedule.8 Early studies in economic modeling suggested that the cost of filgrastim can be offset when the risk of febrile neutropenia is more than 40%.9,10 More recent economic modeling studies suggest that the cost of filgrastim can be offset when the risk of febrile neutropenia is 20% to 25%.8 This model does not consider any direct or indirect costs to the patient or family, which may further reduce this risk threshold. Single-agent docetaxel at a dose of 100 mg/m2 every 3 weeks is associated with a 10% to 20% incidence of febrile neutropenia in the absence of growth factor.11,12

Pegfilgrastim is a recombinant human granulocyte colony-stimulating factor that acts in the same manner as the endogenous protein to stimulate the production of neutrophil precursors and the differentiation and release of mature neutrophils.13 Clinical studies have shown that pegfilgrastim can reduce the incidence of febrile neutropenia associated with myelosuppressive chemotherapy.5,6 On the basis of these results, we investigated the ability of pegfilgrastim to reduce the incidence of febrile neutropenia with chemotherapy associated with a rate of febrile neutropenia of 10% to 20%.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patients
The institutional review boards of participating medical centers approved the protocol, and all patients gave written informed consent before any study-related procedures were performed. Patients were eligible if they were at least 18 years of age, were a candidate for docetaxel chemotherapy (100 mg/m2 every 3 weeks) for the treatment of breast cancer, and had an absolute neutrophil count ≥ 1.5 x 109/L and a platelet count ≥ 100 x 109/L. Patients were required to have adequate renal function (ie, creatinine ≤ 1.5 x the upper limit of normal) and hepatic function (ie, bilirubin ≤ the upper limit of normal institutional standard and AST, ALT, or both < 1.5 x the upper limit of normal concomitant with alkaline phosphatase < 2.5 x the upper limit of normal). Patients were excluded if they had previous single-agent docetaxel treatment, had a recent infection, or received prophylactic antibiotics, pegfilgrastim, filgrastim, or other colony-stimulating factor treatment within the preceding 6 weeks.

Study Drug
Pegfilgrastim (Neulasta; Amgen Inc, Thousand Oaks, CA) in a 6-mg fixed dose and placebo were presented as identical prefilled syringes. All study drug administration was administered by subcutaneous injection given by a health care provider.

Study Design
This study was a phase III, multicenter, multinational, double-blind, placebo-controlled study that evaluated the use of pegfilgrastim starting in the first cycle of chemotherapy to reduce the incidence of febrile neutropenia. Eligible patients were randomly assigned to receive a subcutaneous injection of either 6 mg pegfilgrastim or placebo once per cycle on the day after administration of docetaxel. Patients were randomly assigned to receive pegfilgrastim or placebo after they received the first dose of chemotherapy. The study was amended after the first 88 patients were enrolled to stratify the randomization process for metastatic disease. Patients could receive up to four cycles of docetaxel administered every 3 weeks.

Patients who experienced febrile neutropenia, either clinical or protocol defined, were removed from double-blind treatment but remained on study as long as they were able to continue to receive chemotherapy with docetaxel. These patients were treated with open-label pegfilgrastim (Fig 1). If a patient had a clinical diagnosis of febrile neutropenia that required administration of IV anti-infectives and hospitalization but that did not meet the primary end point definition of febrile neutropenia, the patient was removed from the double-blind portion of the study and treated with open-label pegfilgrastim. Primary prophylactic anti-infectives were not allowed, but if a patient developed febrile neutropenia, the patient could receive antibiotics in subsequent cycles. Body temperature was recorded twice a day by the patient, and absolute neutrophil counts were measured weekly if the patient was febrile. CBCs were collected once a week throughout each chemotherapy cycle.



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  		Fig 1. Patient disposition in the study. (a) In the placebo group, 89 patients were converted per protocol at cycle 2 or a subsequent cycle to receive open-label pegfilgrastim after experiencing a primary end point–defined or clinically diagnosed event of febrile neutropenia.

 
End Points
The primary measure of efficacy was the percentage of patients who developed febrile neutropenia (defined as body temperature ≥ 38.2°C and neutrophil count < 0.5 x 109/L on the same day of the fever or the day after). Secondary efficacy end points were the incidence of hospitalizations associated with a clinical diagnosis of febrile neutropenia, the incidence of need for IV anti-infectives as a result of febrile neutropenia, and the ability to maintain planned chemotherapy dose on time for cycles 2, 3, and 4 (defined as receiving at least 80% of the planned dose and no dose > 3 days late). Safety was measured by reports of adverse events and changes in laboratory values.

Statistical Analysis
The statistical analysis was prospectively defined. All patients who were randomly assigned were included in the analysis of efficacy. The primary end point was tested with the Cochran-Mantel-Haenszel test with a two-sided significance level ({alpha}) of .05. The secondary end points of hospitalization for febrile neutropenia and use of IV anti-infectives for febrile neutropenia were tested using the Cochran-Mantel-Haenszel test only if the primary end point was significant. For the secondary end points, if the larger of the two P values from the secondary end points was less than .05, then both of these secondary end points were concluded to be significant. If the larger of the two P values from the secondary end points was more than .05 but the smaller P value was less than .025, then only the secondary end point associated with the smaller P value was concluded to be significant.14 This controlled the type I error rate at 5% for the primary and secondary end points. The other secondary end point of planned dose on time was summarized with two-sided 95% CIs because no tests were planned. The percentage of patients who received their planned dose on time was planned to be descriptive, with no testing or P values to be provided. All patients who receive study drug were included in the summaries of safety. Adverse events were classified by preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA) and were graded by severity according to the WHO toxicity criteria. Changes from baseline in laboratory variables were summarized using descriptive statistics. Patients who were crossed-over to open-label pegfilgrastim were analyzed as randomized (ie, in either the placebo or the pegfilgrastim group).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patients
A total of 928 patients at 88 sites in Europe and North America were randomly assigned, and all patients received at least one dose of blinded study drug (placebo, n = 465; pegfilgrastim, n = 463; Fig 2). The groups were well matched in characteristics of demography, disease history, disease severity, and proportions of metastatic versus nonmetastatic disease at baseline (Table 1). The patient population in this study was predominantly women (99%) and white (66%), and the mean age was 52 years. More patients who received pegfilgrastim compared with placebo completed the four planned cycles of chemotherapy (placebo, 89%; pegfilgrastim, 92%) and fewer withdrew early from study (placebo, 8%; pegfilgrastim, 6%). Thirty-five patients (8%) in the initial placebo group and 27 patients (6%) in the pegfilgrastim group withdrew from the study.



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  		Fig 2. Study design. Chemotherapy (100 mg/m2 intravenously) was administered on day 1 in 21-day cycles for up to four cycles. Pegfilgrastim or placebo was administered on day 2 at least 24 hours after chemotherapy as a subcutaneous injection. FN, febrile neutropenia.

 

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  		Table 1. Demographic and Clinical Characteristics of Patients at Baseline

 
Efficacy
The incidence of febrile neutropenia for all cycles was lower among patients who initially received pegfilgrastim compared with patients who initially received placebo (1% v 17%, respectively; P < .001; Table 2). By cycle, the incidence of febrile neutropenia was lower in the pegfilgrastim group compared with the initial placebo group (< 1% v 11%, < 1% v 2%, < 1% v 2%, and < 1% v 1% for cycles 1, 2, 3, and 4, respectively). Two-thirds of all febrile neutropenia events (67%) in the initial placebo group occurred in the first cycle of chemotherapy.


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  		Table 2. Incidence of Febrile Neutropenia Reported on Study for All Cycles

 
The incidence of hospitalization associated with a clinical diagnosis of febrile neutropenia was lower among patients who received pegfilgrastim compared with patients who initially received placebo (1% v 14%, respectively; P < .001; Table 3). In each cycle, the incidence of hospitalization as a result of febrile neutropenia was lower in the pegfilgrastim group compared with the initial placebo group (1% v 9%, 0% v 2%, 0% v 3%, and < 1% v < 1% for cycles 1, 2, 3, and 4, respectively).


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  		Table 3. Incidence of Hospitalizations Associated With a Clinical Diagnosis of Febrile Neutropenia for All Cycles

 
The incidence of IV anti-infective use for the treatment of febrile neutropenia was lower in patients who received pegfilgrastim compared with patients who initially received placebo (2% v 10%, respectively; P < .001; Table 4). In each cycle, the incidence of the use of IV anti-infectives was lower in the pegfilgrastim group compared with the initial placebo group (1% v 6%, < 1% v 2%, 1% v 2%, and < 1% v 1% for cycles 1, 2, 3, and 4, respectively).


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  		Table 4. Incidence of Intravenous Anti-Infective Use Associated With a Clinical Diagnosis of Febrile Neutropenia for All Cycles

 
The percentage of patients who received their planned dose on time was similar between patients who received pegfilgrastim and patients who initially received placebo (80% and 78%, respectively). These results were to be expected because of the study design (ie, patients in either group who experienced the primary end point or clinically diagnosed febrile neutropenia in the double-blind phase of the study were converted to open-label pegfilgrastim treatment for subsequent cycles of chemotherapy). Ten patients in the pegfilgrastim group and 89 patients in the initial placebo group were converted to open-label pegfilgrastim treatment, which may have contributed to this result.

Safety
Pegfilgrastim was well tolerated in this patient population; the adverse events reported were typical of those in a patient population with breast cancer who were receiving docetaxel chemotherapy (ie, alopecia, diarrhea, fever, and nausea and vomiting) and occurred in similar percentages of patients in each group during the study. Most events were of mild or moderate intensity. During the study, 40 patients withdrew because of adverse events (placebo, n = 19, 4%; pegfilgrastim, n = 21, 5%). The primary reason for withdrawal was disease progression (placebo, n = 14, 3%; pegfilgrastim, n = 9, 3%). Fourteen patients (3%) in the initial placebo group and five patients (1%) in the pegfilgrastim group experienced fatal adverse events. Generally, the deaths were attributed to disease progression or infection-related events and not to study drug. Two patients in the initial placebo group died of infections, whereas no patients in the pegfilgrastim group died of infections.

Bone pain is a known side effect for pegfilgrastim. Bone pain occurred in 126 patients (27%) in the initial placebo group and 146 patients (31%) who received pegfilgrastim. Most reports of bone pain were mild or moderate in severity, but six patients (1%) and 11 patients (2%) in the initial placebo and pegfilgrastim groups, respectively, reported severe bone pain. Most patients reporting bone pain were managed adequately by treatment with non-narcotic analgesics, but 28 patients (6%) who initially received placebo and 30 patients (6%) who initially receiving pegfilgrastim required opioids, which would be expected in this patient population. No substantial changes from baseline were noted in serum chemistry analyses, including alkaline phosphatase, ALT, AST, lactic dehydrogenase, or uric acid (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
Pegfilgrastim is approved to decrease the incidence of infections in patients who are receiving myelosuppressive chemotherapy that is associated with a clinically significant incidence of febrile neutropenia. In this study, we evaluated the utility of using pegfilgrastim in a setting with a risk of developing febrile neutropenia in the range of 10% to 20%. Pegfilgrastim administered 24 hours after chemotherapy profoundly reduced the rate of febrile neutropenia from 17% to 1%. The high frequency of first-cycle febrile neutropenia in this study emphasizes the need to initiate pegfilgrastim from the first cycle of chemotherapy to significantly reduce the risk of febrile neutropenia. This finding of first-cycle neutropenia is consistent with data derived from a retrospective analysis of trials in non-Hodgkin's lymphoma that showed that hospitalization for febrile neutropenia occurs early with chemotherapy.15,16 The use of pegfilgrastim from the first cycle also significantly reduced the need for hospitalization and IV anti-infectives, which parallels earlier reports of pegfilgrastim used to support more myelosuppressive chemotherapy5,6 (Fig 3). The detected rate of febrile neutropenia observed in the initial placebo group is consistent with earlier reports of single-agent docetaxel without growth factor support.11,12



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  		Fig 3. Pegfilgrastim reduces the incidence of febrile neutropenia and the need for hospitalization and intravenous anti-infectives as a result of febrile neutropenia. (solid bars) Pegfilgrastim, n = 463; (open bars) placebo, n = 465. (*) P < .001.

 
Chemotherapy regimens that are less myelosuppressive (ie, rate of febrile neutropenia < 20%) are generally not administered with concomitant growth factor support. This practice is consistent with current guidelines from the American Society of Clinical Oncology2 that call for the use of a colony-stimulating factor in the first cycle of a cytotoxic chemotherapy regimen associated with a febrile neutropenia incidence of 40% or greater. However, our study shows that because the intensity of myelosuppression is reduced, as reflected in the incidence of 20%, febrile neutropenia can be markedly reduced by more than 94% with first-cycle use of pegfilgrastim. Similarly encouraging reports have appeared using the myelosuppressive regimen of docetaxel, doxorubicin, and cyclophosphamide.17,18 In that trial, filgrastim greatly reduced the incidence of febrile neutropenia from this myelotoxic adjuvant breast cancer regimen.

Planned dose on time was not significantly different between the two groups. However, because most febrile neutropenia occurred in the first cycle, patients who developed febrile neutropenia were allowed to receive pegfilgrastim in subsequent cycles, which, in essence, prevented the determination of a difference between pegfilgrastim compared with placebo.

Early intervention with pegfilgrastim prevents febrile neutropenia by 94% and further prevents hospitalizations and use of IV anti-infectives by 80%. The use of pegfilgrastim with chemotherapy regimens with a moderate rate of febrile neutropenia, such as standard-dose docetaxel and combination docetaxel, doxorubicin, and cyclophosphamide chemotherapy, is warranted.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The following authors or their immediate family members have 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. Employment: Brian L. Weins, Amgen; Theresa A. Neumann, Amgen. Consultant/Advisory Role: Lee S. Schwartzberg, Amgen. Stock Ownership: Brian L. Weins, Amgen; Theresa A. Neumann, Amgen. Honoraria: Charles L. Vogel, Amgen, Aventis; Robert R. Carroll, Amgen; Sergei A. Tjulandin, Aventis, Eli Lilly, Hoffman-La Roche; Lee S. Schwartzberg, Amgen. Research Funding: Charles L. Vogel, Amgen, Aventis; Robert R. Carroll, Amgen; Sergei A. Tjulandin, Amgen, Janssen-Cilag, Hoffman-La Roche; Luis Javier Barajas-Figueroa, Kendle. For a detailed description of these 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 of Information for Contributors found in the front of every issue.


   Acknowledgment
 
MaryAnn Foote, PhD, assisted in writing the article. Phillippa Barker, Martine Brassard, PhD, and Sumana Jana assisted with the study conduct; and Aurelia Chang, MA, assisted with statistics and programming.


   NOTES
 
Supported by Amgen Inc, Thousand Oaks, CA.

Presented at the Multinational Association of Supportive Care in Cancer Meeting, June 2004, Miami Beach, FL; and submitted at the European Society for Medical Oncology Meeting, October 2004, Vienna, Austria; and the San Antonio Breast Cancer Symposium, December 2004, San Antonio, TX.

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
 
1. Infectious Diseases Society of America: 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730-751, 2002[CrossRef][Medline]

2. Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines—American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18:3558-3585, 2000[Free Full Text]

3. 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]

4. Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 29A:319-324, 1993

5. Holmes FA, O'Shaughnessy JA, Vukelja S, et al: 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. J Clin Oncol 20:727-731, 2002[Abstract/Free Full Text]

6. Green MD, Koelbl H, Baselga J, et al: A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 14:29-35, 2003[Abstract/Free Full Text]

7. Misset JL, Dieras V, Gruia G, et al: Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 10:553-560, 1999[Abstract/Free Full Text]

8. Lyman GH, Kuderer N, Green J, et al: The economics of febrile neutropenia: Implications for the use of colony-stimulating factors. Eur J Cancer 34:1857-1864, 1998

9. Glaspy JA, Bleecker G, Crawford J, et al: The impact of therapy with filgrastim (recombinant granulocyte colony-stimulating factor) on the health care costs associated with cancer chemotherapy. Eur J Cancer 29A:S23-S30, 1993

10. Lyman GH, Lyman CG, Sanderson RA, et al: Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst 85:488-493, 1993[Abstract/Free Full Text]

11. Chan S, Friedrichs K, Noel D, et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 17:2341-2354, 1999[Abstract/Free Full Text]

12. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165-4174, 2003[Abstract/Free Full Text]

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

14. Hochberg Y: A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75:800-802, 1988[Abstract/Free Full Text]

15. Lyman GH, Delgado DJ: Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin's lymphoma. Cancer 98:2402-2409, 2003[CrossRef][Medline]

16. Lyman GH, Morrison VA, Dale DC, et al: Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin's lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 44:2069-2076, 2003[CrossRef][Medline]

17. Martin M, Lluch A, Segul A, et al: Prophylactic growth factor (GF) support with adjuvant docetaxel, doxorubicin and cyclophosphamide (TAC) for node-negative breast cancer (BC): An interim safety analysis of the GEICAM 9805 study. Proc Am Soc Clin Oncol 23:32, 2004 (abstr 620)

18. Vogel CL, Mackey JR, Martin M: The role of growth factor support following neutropenic events in early stage breast cancer (BC) patients treated with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC): A sub-analysis of BCIRG 001. Proc Am Soc Clin Oncol 23:46, 2004 (abstr 877)

Submitted October 5, 2004; accepted November 22, 2004.


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