Colony-stimulating factors for the management of neutropenia in cancer patients

Abstract

Neutropenia and its subsequent infectious complications represent the most common dose-limiting toxicity of cancer chemotherapy. Febrile neutropenia (FN) occurs with common chemotherapy regimens in 25 to 40% of treatment-naive patients, and its severity depends on the dose intensity of the chemotherapy regimen, the patient's prior history of either radiation therapy or use of cytotoxic treatment, and comorbidities. The occurrence of FN often causes subsequent chemotherapy delays or dose reductions. It may also lengthen hospital stay, increase monitoring, diagnostic and treatment costs, and reduce patient quality of life. A decade after their introduction, colony-stimulating factors (CSFs) such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are now an integral part of the prevention of potentially life-threatening FN; however, only G-CSF has US Food and Drug Administration approval for use in chemotherapy-induced neutropenia. These adjunctive agents accelerate formation of neutrophils from committed progenitors, thereby reducing the duration and severity of neutropenia. Important uses of CSFs in oncology are prevention of FN after chemotherapy, treatment of febrile neutropenic episodes and support following bone marrow transplantation, and collection of CSF-mobilised peripheral blood progenitor cells. G-CSF is used more frequently than GM-CSF for all of these indications because of fewer associated adverse effects. Clinical trials to date have not demonstrated a significant effect on overall survival or disease-free survival, which is most likely to be due to small sample size and lack of power to prove effect. However, they have demonstrated clinical utility in allowing the delivery of planned chemotherapy dose on schedule, an important clinical goal especially in curative tumour settings. The high cost of these agents limits their widespread use. Current American Society of Clinical Oncology guidelines recommend primary prophylaxis, or first cycle use, with CSFs being confined to patients with > or = 40% risk of FN, which may include elderly patients and other high-risk patients. In addition to the risk of FN, primary prophylaxis should also be considered if the patient has risk factors that place them in the Special Circumstances category. These risk factors may include decreased immune function in patients who are already at an increased risk of infection and pre-existing neutropenia due to disease, extensive prior chemotherapy, or previous irradiation to the pelvis or other areas containing large amounts of bone marrow. Future studies are needed to better define the patients most likely to benefit from CSF therapy, both for prophylaxis and as an adjunct to antibiotics for treatment of FN. Other potential uses include combination therapy with stem cell factors and other cytokines to boost progenitor cell development, maintaining dose intensity of salvage therapy in metastatic cancer patients, and application in patients with pneumonia, Crohn's fistulas, diabetic foot infections and a variety of other infectious conditions.