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Filgrastim in Patients with Chemotherapy-Induced Febrile Neutropenia: A Double-Blind, Placebo-Controlled Trial

Darryl W. Maher, MMB, BS, PhD; Graham J. Lieschke, BMedSci, MB, BS; Michael Green, MB, BS; James Bishop, MD; Robin Stuart-Harris, MD; Max Wolf, MB, BS; William P. Sheridan, MB, BS; Richard F. Kefford, MB, BS, PhD; Jonathan Cebon, MB, BS, PhD; Ian Olver, MD; Joseph McKendrick, MB, BS, DM; Guy Toner, MB, BS; Kenneth Bradstock, MB, BS, PhD; Marian Lieschke, BA, RN; Scott Cruickshank, MA; Dianne K. Tomita, MPH; Eric W. Hoffman, PharmD; Richard M. Fox, MB, BS, PhD; and George Morstyn, MB, BS, PhD
[+] Article and Author Information

From the Ludwig Institute for Cancer Research, the Royal Melbourne Hospital, and the Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia; the Austin Hospital, Heidelberg, Australia; Westmead Hospital, New South Wales, Australia; Amgen, Inc., Thousand Oaks, California. Requests for Reprints: Darryl W. Maher, MB, BS, PhD, Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research, P.O. The Royal Melbourne Hospital, Victoria, Australia 3050. Acknowledgments: The authors thank A. Burgess and D. Metcalf for valuable discussions; the medical, nursing, and data management staff of the Clinical Oncology and Hematology Units of the participating hospitals, including D. Watson, G. Duggan, S. Oakes, A. Fennessy, A. Woollet, S. Treloar, J. McGrath, and L. Kelsey, for assistance with patient management; K. Alton, M. Vincent, M. Stewart, P. Lockbaum, and J. Marty for assistance and advice; P. Chambers, T. Helton, Y. Hill, L. Hughes, and V. Snelling of Amgen and the staff of Biomedicus (Boronia, Victoria, Australia) for assistance with data verification; and P. Collier and L. Blundy for secretarial assistance. Grant Support: By Amgen, Inc., and a John Maynard Hedstrom Research Fellowship of the Anti-cancer Council of Victoria.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1994;121(7):492-501. doi:10.7326/0003-4819-121-7-199410010-00004
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Objective: To determine if filgrastim (recombinant human methionyl granulocyte colony-stimulating factor) used in addition to standard inpatient antibiotic therapy accelerated recovery from infection associated with chemotherapy-induced neutropenia.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: Hematology and oncology wards of four teaching hospitals.

Patients: 218 patients with cancer who had fever (temperature >38.2 °C) and neutropenia (neutrophil count <1.0 × 109/L) after chemotherapy.

Intervention: Patients were randomly assigned to receive filgrastim (12 µg/kg of body weight per day) (n = 109) or placebo (n = 107) beginning within 12 hours of empiric therapy with tobramycin and piperacillin. Patients received treatment and remained in the study until the neutrophil count was greater than 0.5 × 109/L and until 4 days without fever (temperature <37.5 °C) had elapsed.

Measurements: Days of neutropenia and fever and days in the study (hospitalization); time to resolution of fever and febrile neutropenia; and frequency of the use of alternative antibiotics.

Results: Compared with placebo, filgrastim reduced the median number of days of neutropenia (3.0 compared with 4.0 days of a neutrophil count of <0.5 × 109/L; P = 0.005) and the time to resolution of febrile neutropenia (5.0 compared with 6.0 days; P = 0.01) but not days of fever (3.0 days for both groups). The frequency of the use of alternative antibiotics was similar in the two groups (46% compared with 41%; P = 0.48). The median number of days patients were hospitalized while on study was the same (8.0 days; P = 0.09); however, filgrastim decreased the risk for prolonged hospitalization (>11 days, 4th quartile) by half (relative risk, 2.1 [95% CI, 1.1 to 4.1]; P = 0.02). In exploratory subset analyses, filgrastim appeared to provide the greatest benefit in patients with documented infection and in patients presenting with neutrophil counts of less than 0.1 × 109/L.

Conclusions: Filgrastim treatment used with antibiotics at the onset of febrile neutropenia in patients with cancer who have received chemotherapy accelerated neutrophil recovery and shortened the duration of febrile neutropenia.

Figures

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Figure 1.
Neutrophil recovery in patients with febrile neutropenia and proportion remaining on study by number of days from study entry.A.(B)C.

Piecewise linear plot of median neutrophil counts of patients remaining on study by study days 1 to 7 and by days 1 to 28. Number of patients on study by study day.

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Figure 2.
Resolution of neutropenia, fever, and febrile neutropenia by number of days from study entry.A.9B.C.9

Probability of not achieving a neutrophil count of ≥ 1.0 × 10 /L. Probability of unresolved fever. Probability of failure to resolve febrile neutropenia. Resolution of fever was defined as the first complete day with a temperature less than 37.5 °C. Resolution of febrile neutropenia was defined as the first day of having both a temperature less than 37.5 °C and a neutrophil count greater than 1.0 × 10 /L. No further events occurred after day 17. Numbers on plots indicate the number of patients remaining at risk.

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Figure 3.
Subset analysis according to baseline neutrophil count of probability of unresolved fever by number of days from study entry.A.9B9C9

Baseline neutrophil count of less than 0.1 × 10 /L. . Baseline neutrophil count of 0.1 to less than 0.5 × 10 /L. . Baseline neutrophil count of 0.5 to less than 1.0 × 10 /L. Resolution of fever was defined as the first complete day with a temperature of less than 37.5 °C. No further events occurred after day 17. Numbers on plots indicate the number of patients remaining at risk.

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Figure 4.
Neutrophil recovery in patients with febrile neutropenia remaining on study by the number of days from study entry according to tumor type and number of days elapsed since completion of chemotherapy.A.B.C.D.

Solid tumors. Lymphomas. Less than 10 days since the completion of chemotherapy. Ten days or more since the completion of chemotherapy. The proportions of patients remaining on study at day 7 were 71% in the filgrastim group and 79% in the placebo group.

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