Febrile neutropenia (FN) is a medical emergency that must be treated with antibiotics covering both Gram-positive as well as Gram-negative pathogens.1
Although the definition of neutropenia varies across institutions, most agree that an absolute neutrophil count (ANC) < 500 cells/μL, or a neutrophil count < 1,000 cells/μL with a predicted nadir < 500 cells/μL, are criteria likely to be clinically significant. The treatment of FN has improved greatly, and there has been a progressive decline in mortality rates since the prompt initiation of empiric antibiotic coverage became standard.2
Despite improvements in the management of FN, minimizing the development of FN remains the primary strategy for avoidance of morbidity and mortality. Granulocyte colony-stimulating factors (G-CSFs), such as filgrastim, sargramostim, and pegfilgrastim, when used properly, minimize the incidence of neutropenic complications. The pivotal trial leading to filgrastim approval for the prevention of FN showed a reduction in the rate of FN from 76% in placebo-treated patients to 40% in filgrastim-treated patients.3
The hospitalization rate in the first cycle decreased from 69% among placebo-treated patients to 52% among filgrastim-treated patients. Clearly, the regimens studied for initial filgrastim approval were associated with extremely high rates of neutropenic events.
Although filgrastim must be administered daily for several days after cytotoxic treatment, the development of a long-acting growth factor allows a single postchemotherapy injection. The randomized study that led to the approval of pegfilgrastim used filgrastim in the control arm.4
Both the pegfilgrastim and filgrastim arms in the pivotal trials showed FN rates in the range of 10% to 20%, with a similar incidence, depth, and duration of severe neutropenia.
CSFs are thus proven to reduce FN and associated hospitalizations. Peer-reviewed literature is abundant, describing the clinical efficacy and cost effectiveness of CSFs, when used in clinical situations deemed higher risk for FN.5–10
All nationally and internationally recognized guidelines use the likelihood of developing FN as the primary factor when determining if prophylactic CSFs should be used.11–14
It is universally recommended that prophylactic G-CSFs be used in patients receiving chemotherapy regimens with a high risk (> 20%) of FN. When using a chemotherapy regimen associated with an intermediate risk of FN (10% to 20%), guidelines recommend considering patient-related risk factors, such as age (≥ 65 years), baseline WBC count, treatment intent, and comorbid conditions. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. No national guidelines recommend the use of CSFs when the likelihood of FN is < 10%, unless there are meaningful additional clinical risks.11–14
None of the current guidelines take cost into consideration, although the 2000 American Society of Clinical Oncology (ASCO) guideline commented that the routine use of CSFs for primary prophylaxis cannot be justified on the basis of cost savings, when the FN risk is < 15%.12
Although it is also recognized that CSFs might have the ability to reduce the duration of mild neutropenia, the clinical relevance of this finding is unproven, especially in noncurative or palliative settings. We were unable to find any literature demonstrating an improvement in clinical outcome with the prophylactic use of CSFs when the risk of FN was < 10%. The lack of literature in this low-risk setting is consistent with guidelines stating that primary prophylaxis with CSFs should not be routinely used if the risk of FN is < 10%.