The evidence backing the use of myeloid growth factors in patients at high risk for febrile neutropenia is solid, according to Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, North Carolina.
Myeloid growth factors are the primary means of preventing chemotherapy-induced neutropenia. This often leads to febrile neutropenia, which can be fatal in 10% of patients, according to a database of more than 40,000 individuals. Concerns recently have been raised, however, that their use is associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
As chairman of the National Comprehensive Cancer Network (NCCN)’s Myeloid Growth Factors Panel, Crawford reassured clinicians that benefits substantially outweigh any risks associated with the granulocyte colony-stimulating factors (G-CSFs) filgrastim and pegfilgrastim. Including a discussion of MDS/AML associated with the use of G-CSFs was the only major change to the guidelines in 2011, he noted.
Timing of Growth Factor Use
In a 2008 study conducted by Crawford’s group, febrile neutropenia developed during the first 3 cycles in 11% of patients. Because most febrile neutropenia events occur during the first cycle of chemotherapy, clinicians should initiate growth factors from the beginning of treatment, and continue them in subsequent treatments, in any patient with a 20% or higher risk for developing febrile neutropenia.
“Our window for starting prophylaxis is not big. We should start 24 to 72 hours after chemotherapy is completed,” he noted. When administration is delayed, the duration of grade 4 neutropenia may be longer and the risk of febrile neutropenia greater, Crawford pointed out. “The data suggest that what we do in the very first cycle of treatment makes a big difference.”
Some clinicians also try to lower febrile neutropenia risk by reducing the dose of chemotherapy, but this is not advised because it diminishes the survival benefit obtained from full-dose chemotherapy, he explained.
Similarly, prophylactic antibiotics can add to the protective benefit of G-CSFs in selected settings but should not be used instead of growth factors. Widespread antibiotic prophylaxis also enhances the emergence of antibiotic resistance. “The routine application of prophylactic antibiotics should be limited to high-risk inpatients with hematologic malignancies and stem cell transplantation,” he said.
Is Pegfilgrastim Better than Filgrastim?
Is the newer, and costlier, G-CSF pegfilgrastim (Neulasta) superior to filgrastim (Neupogen)? Pegfilgrastim has a unique neutrophil-regulated clearance and, because of high sustained serum levels, is a longer-lasting drug, although clinical efficacy appears to be similar.
Although the clinical outcomes for the single dose of pegfilgrastim and the daily dose of filgrastim were comparable in a 2007 meta-analysis (Kuderer NM, et al. J Clin Oncol. 2007:3158-3167), the impact of pegfilgrastim on overall survival and disease-free survival has been apparent in all major prognostic subgroups studied to date, Crawford said.
Sargramostim is an alternative agent that is associated with more toxicity and has therefore received only a category 2B recommendation in the NCCN Clinical Practice Guidelines for Myeloid Growth Factors (V.1.2011).
MDS/AML Risk Not a Major Concern
It does appear that use of a G-CSF is associated with an increased risk of MDS/AML, Crawford acknowledged. The risk was elevated in a recent meta-analysis, regardless of tumor type or treatment regimen (Lyman GH, et al. J Clin Oncol. 2010:2914-2924); however, all-cause mortality was significantly lower among patients who received growth factor support.
“There was an increase in MDS and leukemia, but the all-cause mortality analysis showed a significant reduction in risk. Leukemia risk was 0.005%, but the survival benefit was 5%. This amounts to an almost 10-fold difference in probabilities,” he said. “There clearly is an overall net benefit of G-CSF.”
Who Should Receive Prophylaxis?
Primary G-CSF prophylaxis should be determined by the chemotherapy regimen, the NCCN guidelines state (with details), along with patient risk factors (Lyman G, et al. Cancer. 2010 Nov 29 [Epub ahead of print]), and treatment intent (curative versus palliative). Clinicians should then determine whether the patient’s risk is high (>20%), intermediate (10%-20%), or low (<10%).
High-risk patients, whose risk is elevated 5-fold over low-risk patients, should receive growth factors, regardless of treatment intent; low-risk patients should not receive them; and intermediate-risk patients should be considered for treatment based on risk factors, Crawford said.
The type of chemotherapy is only one component of risk. Type of malignancy, age, previous treatment, preexisting conditions, performance status, and other factors are also relevant.