Neutropenia is the primary dose-limiting toxicity in patients with cancer treated with systemic chemotherapy. The risk of febrile neutropenia (FN) has been estimated on the basis of the chemotherapy regimen, but studies are now finding a number of patient-related and disease-related risk factors for FN and other complications, such as hospitalization, chemotherapy dose reductions and delays, and mortality. These patient-related risk factors have been incorporated into clinical guidelines for managing neutropenia. The newly released guidelines on the use of myeloid growth factors with cancer chemotherapy of the National Comprehensive Cancer Network use disease- and patient-related factors along with the chemotherapy regimen risk. These guidelines also differ from previous guidelines in that they recommend the routine use of colony-stimulating factors (CSFs) in patients in whom the risk of neutropenia is > 20% (the previous threshold was ≥ 40%); this recommendation is based on recent data that show the clinical benefits of filgrastim (Neupogen) and pegfilgrastim (Neulasta) in studies in which the overall populations had FN risks of between 20% and 40%. The use of guidelines such as these in clinical practice will make it possible to target CSFs to appropriate patients in the first cycle of chemotherapy, when the risk of neutropenia is highest.
Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in patients with cancer treated with chemotherapy, with potentially severe clinical consequences such as febrile neutropenia (FN), infection, sepsis, and death. In addition, chemotherapy alterations such as dose reductions and delays that are triggered by CIN may also compromise long-term treatment outcomes. The use of colony-stimulating factors (CSFs) such as filgrastim (Neupogen) and pegfilgrastim (Neulasta) reduces the rates of FN and of FN-associated hospitalization and the use of intravenous anti-infectives and also helps maintain the chemotherapy at full dose and on schedule. The use of CSFs in all patients treated with myelosuppressive chemotherapy is not considered cost-effective, however, and a more appropriate strategy may be to target them to patients who are at increased risk for neutropenia and its complications.
Most efforts to define the risk of neutropenia have focused on the prescribed chemotherapy regimen. It is difficult, however, to determine the actual risk for neutropenia and its complications with common chemotherapy regimens, for many reasons. As discussed in a report of the findings in a survey of the literature on randomized clinical trials of chemotherapy in patients with early-stage breast cancer and non-Hodgkin's lymphoma, the rates of neutropenia with the same and similar regimens varied greatly. Some of this variation may be due to underreporting of the rates of myelosuppression and the relative dose intensity (RDI) of the chemotherapy. In addition, the differences in the rates of neutropenia may also reflect differences in patient characteristics. It is therefore likely that estimating the risk of neutropenia and targeting CSF therapy to appropriate patients can be improved by assessing not only the planned chemotherapy regimen but also patients’ individual risk factors.
This article reviews patient-related risk factors for neutropenia and its complications, as well as the recently published guidelines of the National Comprehensive Cancer Network (NCCN), which make recommendations for appropriate use of CSFs in patients with cancer.
Risk Factors for Chemotherapy-Induced Neutropenia and Febrile Neutropenia
A number of studies have found risk factors that predict the development of FN or FN-related complications in patients treated with chemotherapy. The most reliable models have been conditional models that use the absolute neutrophil count in the first cycle of chemotherapy to predict the risk of neutropenia in later cycles. Conditional models, however, cannot be used in the first cycle, when the risk of CIN, FN, and infection-related death is highest.[3,6] The preferred approach is to use an unconditional model that assesses the risk for neutropenia before the chemotherapy is initiated, so that CSFs can be given to patients at increased risk beginning in the first cycle, when the risk is highest.
A number of pretreatment factors have been found that predict the risk of FN, FN mortality, chemotherapy dose alterations, and related events. These risk factors fall into three major categories: disease-related, patient-related, and treatment-related (Table 1).[1,3]
Disease-related risk factors indicate the degree to which the underlying disease may render a patient susceptible to chemotherapy-induced myelosuppression. For example, FN-related hospitalizations are longer and inpatient mortality higher in patients with leukemia than in those with solid tumors. In addition, the risk is also higher in patients with bone marrow involvement of the disease, advanced cancer, and cancer that is not controlled by antineoplastic therapy.
Patient-related risk factors pertain to the patient's general health. The most widely used patient risk factor is advanced age, generally defined as 65 years or older.[6,9-12] A number of comorbidities have also been found to be risk factors, including lung disease, renal disease, liver disease, cerebrovascular disease, cardiovascular disease, and diabetes mellitus.[3,6,10] Other patient risk factors are poor performance status, existing immunodeficiency or neutropenia, female sex, active tissue infections, open wounds, and low pretreatment hemoglobin level.
Treatment-related risk factors involve the inherent risk of the regimen, as well as the patient's treatment history. Frequently cited risk factors are the planned intensity of the chemotherapy regimen and the absence of CSF.[11,12] Some cytotoxic agents have also been found to have a high risk, such as etoposide, cyclophosphamide (Cytoxan, Neosar), and anthracyclines. The primary risk factors in the patient's treatment history are extensive previous chemotherapy and previous radiotherapy (specifically, radiation to marrow-containing anatomic structures).
The risk factors mentioned here provide an opportunity to assess the risk of FN and other complications of neutropenia before the first cycle of chemotherapy, making it possible to target CSFs to those patients who are at increased risk at the time of greatest potential danger.
Dr. Crawford has received research funding from and has served on advisory boards for Amgen.
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