For years, chemotherapy-associated myelosuppression has represented a major limitation to a patient’s tolerance of anticancer therapy. In addition, the clinical consequences of chemotherapy-induced myelosuppression (such as febrile neutropenia, dose reductions, or lengthy dose delays) may have had significant negative effects on quality of life or even response to treatment.
Before the widespread availability of agents to stimulate host hematopoiesis, administration of antibiotics, transfusion of blood products, and reductions or delays in chemotherapy dose have been the major means of combating the myelotoxicity of chemotherapy. It is now possible to stimulate clinically relevant production of several formed elements of the blood: neutrophils, erythrocytes, and platelets.
This chapter summarizes data supporting the clinical activity of several hematopoietic growth factors. A thorough knowledge of these data will help clinicians to make judicious, informed decisions about how to use these agents most responsibly.
Hematopoietic growth factors
Over the past several years, a great deal of progress has been made in understanding the process of hematopoiesis by which mature cellular elements of blood are formed. Hematopoietic growth factors are a family of regulatory molecules that play important roles in the growth, survival, and differentiation of blood progenitor cells, as well as in the functional activation of mature cells.
Table 1 lists the recombinant human hematopoietic growth factors (also known as hematopoietic cytokines) that have been approved by the US Food and Drug Administration (FDA) for clinical use: granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]); pegfilgrastim [Neulasta]; yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine, Prokine]); recombinant human erythropoietin (epoetin alfa, EPO [Epogen, Procrit]); darbepoetin alfa (Aranesp); and interleukin-11 (IL-11, oprelvekin [Neumega]). In addition, several other hematopoietic cytokines are under clinical development.
The commercial availability of these recombinant human hematopoietic growth factors has led to their wide clinical application in oncology practice. However, the substantial costs of colony-stimulating factor utilization as supportive care for patients receiving myelosuppressive chemotherapy make it imperative to identify the optimal settings in which their use can make a significant difference in patient outcomes.
This chapter discusses the appropriate uses of only the FDA-approved hematopoietic growth factors/cytokines: G-CSF, GM-CSF, EPO, darbepoetin alfa, and IL-11. For a more detailed review of recommendations for the use of myeloid CSFs, readers are referred to the evidence-based, clinical practice guidelines developed in 1994 (last updated in 2007) by the American Society of Clinical Oncology (ASCO). The ASCO guidelines were formulated to encour-age reasonable use of CSFs when their efficacy has been well documented but to discourage excess use when marginal benefit is anticipated. These clinical practice guidelines have been published and are most easily accessed at the official web site of ASCO (www.asco.org). In addition, the National Comprehensive Cancer Network (NCCN; www.nccn.org) has published guidelines on the use of colony-stimulating factors, which are updated annually.
Myeloid growth factors
Three myeloid growth factors are currently licensed for clinical use in the United States: G-CSF, pegfilgrastim, and GM-CSF.
G-CSF (filgrastim) is lineage-specific for the production of functionally active neutrophils. G-CSF has been extensively evaluated in several clinical scenarios. G-CSF was first approved in 1991 for clinical use to reduce the incidence of febrile neutropenia in cancer patients receiving myelosuppressive chemotherapy.
This broad initial indication has since been expanded even further to include many other areas of oncologic practice, such as stimulation of neutrophil recovery following high-dose chemotherapy with stem-cell support. In addition, G-CSF is indicated to increase neutrophil production in endogenous myeloid disorders, such as congenital neutropenic states.
Pegylated G-CSF (pegfilgrastim) When polyethylene glycol was attached to the protein backbone of filgrastim, a new molecule (pegfilgrastim) with a longer half-life than the standard human G-CSF was created. Pegfilgrastim was approved in 2002 to reduce febrile neutropenia. It has been studied and shown to be equally efficacious as filgrastim, with the advantage of once-per-cycle dosing and self-regulating features of clearance of the drug during neutrophil recovery. Findings have suggested that pegfilgrastim is more effective than G-CSF in preventing febrile neutropenia, but further study is required. The use of pegfilgrastim in cycles < 3 weeks has not been approved; however, it has been studied in 2-week regimens and appears to be safe and effective. In addition, pegfilgrastim is not currently approved in bone marrow transplantation (BMT) or in pediatrics, but studies are under way.
GM-CSF (sargramostim), primarily a myeloid lineage-specific growth factor, stimulates the production of neutrophils, monocytes, and eosinophils. It has been extensively evaluated and received a more narrow FDA approval in 1991 for clinical use in patients with nonmyeloid malignancies undergoing autologous BMT. Since that initial indication, GM-CSF has also been approved for an expanded range of conditions, such as mitigation of myelotoxicity in patients with leukemia who are undergoing induction chemotherapy.
To date, no large-scale randomized trials have directly compared the efficacy of sargramostim with that of either filgrastim or pegfilgrastim in the same clinical setting. Future comparative trials may help to determine the optimal clinical utility of these CSFs in different clinical situations.
Uses to support chemotherapy
CSFs have been used to support both conventional and intensified doses of chemotherapy. The use of CSFs in this setting can be defined as prophylactic or therapeutic.
Prophylactic use is defined as the administration of a growth factor to prevent febrile neutropenia. “Primary prophylaxis” denotes the use of CSFs following the first cycle of multicourse chemotherapy prior to any occurrence of febrile neutropenia. The term “secondary prophylaxis” is reserved for the use of CSFs to prevent a subsequent episode of febrile neutropenia in a patient who has already experienced infectious complications in a previous chemotherapy cycle.
Primary prophylaxis G-CSF has been evaluated in at least three major randomized clinical trials in cancer patients receiving chemotherapy. The use of G-CSF as primary prophylaxis reduced the incidence of febrile neutropenia by approximately 50% in these trials, in which the incidence of febrile neutropenia in the control group was high (≥ 40%). More recently studies have evaluated the value of CSFs in patients receiving less myelosuppressive (~20%) regimens.
Vogel and colleagues evaluated a single dose of pegfilgrastim versus placebo 24 hours after chemotherapy in 950 patients with breast cancer receiving docetaxel (Taxotere; 100 mg/m2). This regimen was specifically chosen to try to assess the potential benefit of growth factor in a setting associated with approximately a 20% risk of febrile neutropenia. The placebo group experienced a 17% incidence of febrile neutropenia, compared with a 1% incidence in the pegfilgrastim group. The results from this study and other abstracts presented over the past several years suggest a benefit to pegfilgrastim at least as great or greater than that seen in the previous clinical trials that evaluated filgrastim in treatment settings where the risk of febrile neutropenia was higher. The results of this study were pivotal in the new labeling of pegfilgrastim and recommendations for prophylactic use with regimens associated with a 17% risk of febrile neutropenia. Furthermore, pharmacoeconomic sensitivity analyses have suggested that CSF use may be cost-effective if the anticipated risk of febrile neutropenia is > 20%.
A recent update of the ASCO guidelines established the threshold for use of prophylactic growth factor at 20%. In addition, the NCCN guidelines have recommended CSFs be used in regimens with a 20% risk of neutropenic fever (Table 2). In addition, certain patient risk factors for neutropenia have been identified and should be considered in conjunction with the chemotherapy regimen (Table 3).
Secondary prophylaxis Available data indicate that the use of CSFs as secondary prophylaxis in patients who have had a prior episode of febrile neutropenia can decrease the likelihood of febrile neutropenia in subsequent cycles of chemotherapy. It is important to recognize that this conclusion has never been specifically proven in any randomized clinical trial. Rather, it has been derived from analyses of subsets of patients who crossed over from the placebo arms of the initial randomized clinical trials, as well as large clinical experience.
Thus, in clinical settings where maintenance of chemotherapy dose appears to be important, secondary prophylaxis with CSFs to prevent new episodes of neutropenic fever is appropriate. CSF support can also be considered to maintain standard-dose delivery of chemotherapy when the maintenance of dose may impact outcome.
Therapeutic use is defined as the administration of a growth factor at the time when neutropenia or neutropenic fever is documented in a patient who had not been receiving CSFs previously.
Clinical trials do not support the routine use of CSFs as an adjunct to antibiotics in the treatment of all patients with uncomplicated febrile neutropenia. However, in certain high-risk patients who have features predictive of poor outcome (eg, sepsis syndrome, pneumonia, fungal infection), use of a CSF with antibiotics may be justified. To conduct appropriate clinical trials to test the hypothesis that CSF support may improve the outcomes of subsets of patients, selection of patients based on risk-stratification criteria that have been validated to predict poor outcomes or delayed recovery from neutropenia will be critical. Certain trials performed with more selective entry criteria (such as absolute neutrophil count [ANC] < 100 cells/µL) have, in fact, shown statistically significant benefits from the use of CSFs as an adjunct to antibiotics in these high-risk patients with febrile neutropenia. Continued analyses of these data and the performance of larger scale, confirmatory studies are needed to further assess the therapeutic use of CSFs.
There are no indications for CSF use to treat uncomplicated neutropenia without fever. A large-scale randomized clinical trial noted no difference in patients who had CSF support in whom afebrile neutropenia was detected versus those patients whose hematologic status was allowed to recover spontaneously without CSF support. Thus, low neutrophil counts alone do not represent a reason to prescribe CSF support. One effective way to use CSFs is prophylactically, 24 hours after chemotherapy is completed.
Use to increase dose intensity of chemotherapy
The available evidence indicates that CSF use can permit chemotherapy dose maintenance or allow modest increases in dose intensity in clinical scenarios where the main toxicity is neutropenia. Recently, delivery of dose-dense chemotherapy every 2 weeks with G-CSF support has improved survival compared with standard every-3-week dosing in women with breast cancer receiving adjuvant cyclophosphamide and doxorubicin, followed by paclitaxel. This promising dose-dense approach warrants study in other settings. Outside this setting of dose-dense adjuvant chemotherapy, the study of dose density/intensity should be limited to clinical trials.
Meanwhile, in patients with potentially curable disease for which chemotherapy dose delivery may be critical, the use of CSF support to maintain dose intensity may be appropriate. In settings where dose is not a critical determinant of outcomes, modification of chemotherapy dose and implementation of reasonable supportive care measures remain sound alternatives.