A Dutch team is recommending the continued use of primary granulocyte colony-stimulating factor (G-CSF) prophylaxis throughout all chemotherapy cycles in women with early breast cancer who are at high risk of febrile neutropenia (FN).
Maureen J. Aarts, MD
A Dutch team is recommending the continued use of primary granulocyte colony-stimulating factor (G-CSF) prophylaxis throughout all chemotherapy cycles in women with early breast cancer who are at high risk of febrile neutropenia (FN). At present, the approach is standard practice in this population.
The researchers had theorized that it might be possible to omit G-CSF prophylaxis during later chemotherapy cycles as a cost-effectiveness measure given that the risk of FN is highest during the first two chemotherapy cycles, after which the risk rapidly declines and the benefit of G-CSF largely disappears.
In a phase III study with a noninferiority design, Maureen J. Aarts, MD, with Maastricht University Medical Center, and colleagues elsewhere randomized patients to primary G-CSF prophylaxis throughout all chemotherapy cycles or primary G-CSF prophylaxis only in the first two cycles. Pegfilgrastim at a 6-mg fixed dose was administered 24 to 30 hours after chemotherapy administration.
Women with breast cancer were considered eligible for enrollment provided they were fit enough to receive chemotherapy every 3 weeks in the adjuvant, neoadjuvant, or advanced setting, and also had a >20% risk for FN.
The noninferiority hypothesis of the study was that the incidence of FN with primary G-CSF prophylaxis during the first two chemotherapy cycles only would not be inferior to primary G-CSF prophylaxis throughout all chemotherapy cycles, using a noninferiority margin of 7.5% difference.
The study authors, who are with the Dutch Breast Cancer Clinical Trialists’ Group, noted that they believe that their study is the first to use such a design.
The standard and experimental treatment arms were similar with regard to demographic and clinical characteristics. Most subjects were <65 years of age and had an ECOG performance score of 0 to 1.
After 167 eligible patients were enrolled, the independent data monitoring committee recommended that the study be halted prematurely because of an unanticipated high FN rate in the experimental treatment group. Of 83 women assigned to G-CSF during the first two cycles, only 30 (36%) had an FN episode (95% CI, 0.13-0.54). Notably, 24% of episodes occurred in the third cycle. The incidence of FN rapidly decreased thereafter to 7%, 5%, and 2% in cycles four, five, and six, respectively .
FN Incidence (%)
aG-CSF administered during chemotherapy cycles 1-6.
bG-CSF administered during chemotherapy cycles 1-2.
FN indicates febrile neutropenia; G-CSF, granulocyte
Aarts et al pointed out that secondary G-CSF prophylaxis was used in 14 of 20 patients in the experimental arm who developed FN in the third chemotherapy cycle, which was the first cycle without G-CSF prophylaxis. The use of secondary G-CSF prophylaxis may have contributed to the decreasing incidence of FN in later cycles, they said.
In the 84 women who received G-CSF throughout all treatment cycles, eight (10%) experienced an FN episode.
The authors noted that the high FN rate that occurred when primary pegfilgrastim prophylaxis was limited to the first two chemotherapy cycles is as high as that reported in prior studies of docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (TAC) chemotherapy without primary G-CSF prophylaxis.
Finally, they reported that the introduction of the combined use of anthracyclines and taxanes in the neoadjuvant or adjuvant breast cancer setting has, in part, fueled a marked increase in the number of patients who are eligible for prophylactic G-CSF use. In turn, treatment costs have dramatically increased in The Netherlands by at least 10 to 20 million euros per year.
Aarts MJ, Peters FP, Mandigers CM, et al. Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia [published online ahead of print April 26, 2013]. J Clin Oncol. doi:10.1200/JCO.2012.44.6229.