First and Subsequent Cycle Use of Pegfilgrastim Prevents Febrile Neutropenia in Patients With Breast Cancer: A Multicenter, Double-Blind, Pl
http://www.100md.com
《临床肿瘤学》
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
Hospital General de Occidente, Zapopan, Jalisco, Mexico
ABSTRACT
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
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
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.
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
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.
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).
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).
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
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
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
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
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
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
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
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
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
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
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
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
13. Welte K, Gabrilove J, Bronchud MH, et al: Filgrastim (r-metHuG-CSF): The first 10 years. Blood 88:1907-1929, 1996
14. Hochberg Y: A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75:800-802, 1988
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
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
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)(Charles L. Vogel, Marek Z)
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
Hospital General de Occidente, Zapopan, Jalisco, Mexico
ABSTRACT
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
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
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.
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
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.
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).
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).
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
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
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
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
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
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
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
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
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
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
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