Neutrophil Recovery in Patients With Breast Cancer
Study Objectives: To study the impact of filgrastim 5 µg/kg given once/day through absolute neutrophil count (ANC) recovery on the duration of grade 4 neutropenia (ANC < 0.5 × 10/mm) and time to ANC recovery. Additional objectives were to study the average number of filgrastim injections/cycle required to achieve ANC recovery and differences in outcome by cycle.
Design: Combined analysis of two double-blind, randomized, multicenter trials.
Patients: Two hundred twenty-two patients treated for breast cancer.
Measurements and Main Results: All patients but one were evaluable for efficacy end points. Mean ± SD duration of grade 4 neutropenia was 1.7 ± 1.3 days in cycle 1; the duration decreased in cycles 2-4 to between 1.0 and 1.2 days. Fifty percent of patients had ANC recovery to 10 × 10/mm or greater by day 11 of the cycle, and 90% by day 13, corresponding to 10 and 12 days of filgrastim administration, respectively. Across all cycles, the mean ± SD number of filgrastim injections/cycle was 10.51 ± 1.70, with little variation among cycles.
Conclusion: When filgrastim is administered as recommended, starting 24 hours after chemotherapy and continuing through an ANC of 10 × 10/mm or greater, neutrophil recovery is rapid and predictable. Because the first cycle of chemotherapy has the highest rates of neutropenia and febrile neutropenia, it seems prudent to administer growth factor support preemptively.

Myelosuppression is a common complication of chemotherapy. Before the advent of hematopoietic growth factors, myelosuppression-most commonly neutropenia-was a profound dose-limiting toxicity. Duration of neutropenia and depth of absolute neutrophil count (ANC) nadir after a course of chemotherapy closely correlate with development of infectious complications and their attendant morbidities. The comorbidities of neutropenia can disrupt the delivery of full chemotherapy doses on time and thus potentially compromise clinical outcome. In addition, requirements for hospitalization and antibiotic administration as a result of febrile neutropenia have considerable economic implications with regard to consumption of health care resources.

Filgrastim is a hematopoietic growth factor that preferentially stimulates the growth and differentiation of neutrophil precursors and the function of mature neutrophils. In phase III trials, filgrastim, given daily starting 24 hours after delivery of cyclophosphamide, doxorubicin, and etoposide in patients with small cell lung cancer, significantly attenuated the duration of grade 4 neutropenia and severity of ANC nadir, and decreased the proportion of patients with febrile neutropenia, hospitalizations, and intravenous antibiotic therapy. The agent has been a mainstay in the adjunctive support of chemotherapy for the last decade.

The utility of neutropenia duration as an appropriate end point in chemotherapy-induced neutropenia studies is evident. In chemotherapy for acute lymphocytic and myeloid leukemias, 50% of patients with granulocyte counts below 1.0 × 10/mm for at least 7 days experienced fever and infection.1 As the duration of granulocytopenia increased, so did the risk of infection and death.

The relationship between duration of neutropenia and frequency of febrile neutropenia also was characterized in patients undergoing myelosuppressive chemotherapy for small cell lung cancer. The median duration of grade 4 neutropenia (ANC < 0.5 × 10/mm) in chemotherapy cycle 1 was 6 days for patients given placebo compared with 3 days for patients given filgrastim. Corresponding rates of febrile neutropenia were 57% and 28%, respectively (p<0.001). In a logistic regression analysis using cycle 1 data from both treatment groups, each 1-day increase in duration of grade 4 neutropenia led to a 1.7-fold increase (95% confidence interval [CI] 1.4-2.1) in the odds of developing febrile neutropenia (p<0.001; Figure 1). At 9 days' duration of neutropenia, the predicted probability of febrile neutropenia approached 90%. Similar odds were seen in subsequent cycles. These results in patients with small cell lung cancer were very similar to those in patients with acute leukemias. Other studies showed a close correlation between the frequency of febrile neutropenia and other comorbidities associated with cancer chemotherapy.



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Predicted probability of febrile neutropenia in cycle 1 of patients with small cell lung cancer receiving myelosuppressive chemotherapy. ANC = absolute neutrophil count. (Adapted from reference 2.)





Pegfilgrastim is created by the covalent attachment of a polyethylene glycol (PEG) molecule to the N terminus of filgrastim. By virtue of its longer half-life, pegfilgrastim is administered as a single injection in a cycle of chemotherapy, as opposed to an average of 11 once-daily injections through ANC recovery, as with filgrastim. In two similar phase III trials, pegfilgrastim was at least as effective as filgrastim in reducing the duration of grade 4 neutropenia, the primary end point, after myelosuppressive chemotherapy in patients with breast cancer. Cumulative percentages of patients with febrile neutropenia for pegfilgrastim and filgrastim in each trial were 9% and 18%, respectively, and 13% and 20%, respectively. Both growth factors were comparable in supporting the delivery of full chemotherapy dose on time.

These phase III studies of pegfilgrastim were conducted in patients treated with doxorubicin and docetaxel, drugs that produced clinical response rates of 74-90% and that share neutropenia as a major dose-limiting hematologic toxicity. In patients given the combination of these agents, grade 3 or 4 neutropenia is almost universal. Based on published literature using similar dosages, the expected duration of grade 4 neutropenia without hematopoietic growth factor support would be 5-7 days.

Two phase III studies compared the effects of filgrastim and pegfilgrastim in patients with breast cancer receiving myelosuppressive chemotherapy. In our analysis of these studies, emphasis was on the comparative arm, namely, filgrastim, and on the dosing duration that was required to elicit prompt neutrophil recovery in preparation for the next cycle of chemotherapy.