Kourlaba, G., Dimopoulos, M.A., Pectasides, D., Skarlos, D.V., Gogas, H., Pentheroudakis, G., . . . Maniadakis, N. (2015). Comparison of filgrastim and pegfilgrastim to prevent neutropenia and maintain dose intensity of adjuvant chemotherapy in patients with breast cancer. Supportive Care in Cancer, 23, 2045–2051. 

To compare effectiveness of pegfilgrastim given as a prophylactic single-fixed dose versus daily filgrastim for incidence of febrile neutropenia (FN), severe neutropenia, treatment delays, and dose reductions in high-risk breast cancer patients receiving adjuvant dose dense chemotherapy. The secondary aim was to evaluate the impact of both granulocyte–colony-stimulating factors (G-CSFs) on patients’ overall survival (OS).

All patients treated with E-T-CMF received G-CSF in each cycle of chemotherapy. Patients randomized to receive ET-CMF received G-CSF only during intensified phase of CMF treatment; patients randomized to receive E-CMF-DOC or E-CMF-PAC received G-CSF during the intensified phase of epirubicin and CMF treatment. G-CSF was arbitrarily chosen by physicians. Patients received either single fixed dose of pegfilgrastim 6 mg on the next day after chemotherapy completion or daily administration of filgrastim 5 mcg/kg per day on days 2-7 of each cycle (compliance for filgrastim was more than 90% of cycles).

• N = 1,058 (529 filgrastim; 529 pegfilgrastim)  
• MEAN AGE = 52.3 years
• AGE RANGE = 22–79 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Postoperative high-risk patients with breast cancer receiving sequential chemotherapy with epirubicin, pacitaxel, or docetaxel, and CMF supported by G-CSF.
• OTHER KEY SAMPLE CHARACTERISTICS: No difference in menopausal status, higher % of patients had positive estrogen/progesterone status, no difference in tumor size, number of positive nodes, 92% completed treatment in filgrastim arm/95.3% in pegfilgrastim arm. Eligible patients came from sample of 2,123 participants in randomized trials: ACTR N12609001036202 (HE10/00) (reported in: Fountizilas, G et al. [2008]. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: Safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Annals of Oncology, 19(5):853–860). ACTRN12610000151033 (HE 10/05) and 989 participants in an observational study (protocol HE 10/08).
• INCLUSION CRITERIA: Exposure to pegfilgrastim or nonexposure (i.e., filgrastim) during treatment with dose-dense sequential chemotherapy E-T-CMF and E-CMF-DOC or E-CMF-PAC
• EXCLUSION CRITERIA: Patients treated with ET-CMF; patients whose supportive care switched from pegfilgrastim to filgrastim and vice versa throughout the period they received chemotherapy, as well as those who received pegfilgrastim on the same day as chemotherapy

• SITE: Multisite
• SETTING TYPE: Unknown
• LOCATION: Greece

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Retrospective cohort study with matched sampling using data from prior prospective randomized phase III trials and an observational study

Data endpoints were rates of FN, severe (grade 3 or 4) neutropenia, dose reduction, and treatment delay. FN was defined as body temperature > 38.2 °C and neutrophil count < 0.5 × 10⁹/L. Severe (grade 3 or 4) neutropenia was assessed according to standard NCI criteria. Dose reduction was defined as any reduction greater than 10% of the dose planned based on the protocol assigned, and treatment delay was defined as chemotherapy administration with more than a two-day delay from the planned date.

No difference in rates of febrile neutropenia comparing filgrastim and pegfilgrastim arms existed. A significant increase in rates of severe neutropenia, treatment delays, and dose reduction in patients receiving prophylaxis with filgrastim was reported. More than half of the total episodes of febrile neutropenia occurred during the first four cycles of chemotherapy. No difference in overall survival between the two groups existed.

This retrospective study with matched sampling using data taken from a former prospective study of high-risk patients with breast cancer receiving postoperative dose dense sequential epirubicin, paclitaxel, and CMF matched samples found that those patients receiving pegfilgrastim had reduced incidence and risk for FN, dose delay, and dose reduction compared to filgrastim. No difference was found in reducing rates of neutropenia.

• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• Measurement/methods not well described
• Questionable protocol fidelity
• This study was not designed for the purpose of evaluating neutropenia as a secondary analysis with post hoc matching. 
• Unknown sampling technique and methods for patient selection were poorly described. 
• Retrospective data were from two randomized trials evaluating breast cancer treatment regimens ACTR N12609001036202 (HE 10/00) - ACTRN12610000151033 (HE 10/05) and one observational study (protocol HE 10/08). 
• Treatment dose of filgrastim two to seven days compared to pegfilgrastim could be considered unequal dosing/timing support for neutropenia prophylaxis. 
• Selection bias with G-CSF chosen arbitrarily by physician
• Several different chemotherapy regimens had no data for incidence of grades of neutropenia or FN specific to the type of regimen comparing filgrastim versus pegfilgrastim.
• No data existed for sequelae of FN events or infectious events.

Pegfilgrastim 6 mg 24 hours after chemotherapy is more effective in reducing incidence/risk of FN, dose delay, and dose reduction compared to filgrastim 5 mcg/kg/d on days two through seven in high-risk patients with breast cancer receiving postoperative adjuvant sequential chemotherapy regimens with epirubicin, paclitaxel, or docetaxel and CMF. Prospective randomized, controlled trials are needed to validate these results and to determine specific treatment regimens/population where pegfilgrastim or filgrastim dose/timing may be more effective in preventing FN.