Leon E Cosler(1,2)
Gary H Lyman(2)
MD MPH FRCP(Edin)
1Department of Humanities and Social Sciences
Albany College of Pharmacy
2James P Wilmot Cancer Centre
3Department of Community and Preventive Medicine
University of Rochester School of Medicine and Dentistry
Neutropenia is the most common dose-limiting toxicity of cancer chemotherapy. Fever in the setting of neutropenia (FN) is considered a medical emergency, commonly requiring hospitalisation and the prompt administration of empirical broad-spectrum antibiotics.(1) The risk of FN and infectious complications, including mortality, increases with the severity and duration of the neutropenia. However, the epidemiology and cost of FN, as well as the factors associated with the risk of FN, have received limited study.(2) Similarly, the influence of neutropenic complications on treatment delays and dose reductions potentially compromising long-term clinical outcomes have only recently gained attention.(3)
Recombinant granulocyte colony-stimulating factor (G-CSF; eg, filgrastim) has been shown to reduce the severity and duration of neutropenia, the incidence of FN and documented infection in patients receiving myelosuppressive chemotherapy.(4) In addition, recent studies have also demonstrated the ability of G-CSFs to sustain chemotherapy dose intensity and enable the delivery of dose-dense chemotherapy regimens. The cost of G-CSFs and their widespread clinical use have also led to economic analyses and clinical practice guidelines for their use.
The risk of FN has been shown to increase as a direct consequence of the duration and severity of neutropenia.(5) The risk of FN appears to be greatest in the first cycle of chemotherapy, with a gradual accumulation of cumulative risk throughout the remaining treatment course.(6) The risk of FN depends on the specific chemotherapy regimen and dose intensity, patient characteristics (such as age, previous treatment, comorbidities and baseline blood counts) and the use of other treatments, such as G-CSFs.
Discharge data from 115 academic medical centres on 55,276 episodes of FN in adult non-transplant patients over a six-year period have been analysed. The distribution of length of stay for FN is highly skewed, related to a small portion of patients with greatly prolonged hospitalisations (see Figure 1). One-third of patients hospitalised for more than 10 days account for 74% of the hospital days and 78% of the cost. While the average length of stay decreased by 10% over the six years, the cost per day increased by 28%, raising the total cost per FN episode by 13%.(2)
Dose reductions and delays remain the most commonly employed strategy for reducing the risk of neutropenia and its complications in chemotherapy. However, this strategy may compromise long-term disease-free and overall survival. A recent US survey of 1,243 community oncology practices with data extracted from 20,799 early-stage breast cancer patients determined that 55% of the patients studied received less than 85% of the relative dose intensity (RDI) of their intended chemotherapy. Predictors of reduced RDI include older and obese patients, the regimen being utilised, 28-day treatment cycles and no primary G-CSF prophylaxis. (3)
Clinical trials conducted in both Europe and the USA have demonstrated that G-CSFs reduce the risk of FN when administered prophylactically before the onset of fever.(4) In eight prospective randomised controlled trials, the overall odds ratio for FN as an estimate of relative risk with filgrastim compared with control was 0.38 (95% CLs, 0.29–0.50) (see Figure 2).(4) The associated relative risk reduction for FN with filgrastim in these trials was 49% (95% CLs, 36–59%).(4)
Clinical decision models have been useful for studying the tradeoff between the added cost of growth factor use and the reduction in risk of FN in chemotherapy patients.(7,8) The initial economic models of prophylactic G-CSF administration were based on the results of early randomised clinical trials along with crude estimates of direct medical costs. Under these original assumptions, a threshold risk of FN, where the added cost of G-CSF was offset by the reduction in costs associated with hospitalisation for FN, was estimated at 40%. Incorporation of more recent and inclusive cost estimates yields threshold risk estimates for G-CSF prophylaxis closer to 20%.(8,9)
A recent study of time lost from work as well as out-of- pocket expenses for patients experiencing neutropenia and their caregivers estimated the indirect and patient out-of- pocket costs per episode of severe neutropenia.(10) Incorporation of such costs into the previous economic models generated an FN risk threshold favouring the prophylactic use of G-CSF of approximately 18%.
The relatively short half-life of filgrastim, requiring daily injections, has recently led to the development of a long- acting molecule, pegfilgrastim. Pegfilgrastim given once per chemotherapy cycle has been shown to be at least as safe and effective as filgrastim.(11,12) Pegfilgrastim appears to have several additional advantages related to patient convenience, improved compliance and potentially greater potency.(13)
Febrile neutropenia still represents a major source of patient morbidity and mortality in patients receiving systemic cancer chemotherapy, thus potentially limiting the delivery of effective and lifesaving treatments in patients with responsive and potentially curable malignancies.
Prophylactic G-CSF has been shown to reduce the risk of FN, the risk of documented infections and the need for dose reductions and treatment delays. In addition to the potential for reducing costs associated with FN, G-CSFs may aid in optimising long-term outcomes by enabling the delivery of greater chemotherapy dose intensity.
The recent introduction of a longer-acting G-CSF, pegfilgrastim, may further improve the effectiveness and cost savings associated with these agents in support of patients receiving systemic cancer chemotherapy. Additional studies are needed to identify patients at increased risk for FN and its complications to enable the targeted, more effective and cost-effective use of these agents in a broad range of common malignancies.
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