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ASCO convened an Update Committee composed of the original Expert Panel and select ad hoc members to present the 2006 evidence-based clinical practice guideline update (J Clin Oncol 24:3187-3205, 2006) for the use of hematopoietic colony-stimulating factors (CSF).
Clinical trial data support the use of CSF when the risk of febrile neutropenia (FN) is in the range of 20% or higher. This recommendation represents a departure from the 2000 update, which recommended the use of CSF when the risk of FN was 40% or higher. Most commonly used regimens have an FN risk of less than 20%. Oncologists should consider the optimal chemotherapy regimen, individual patient risk factors and treatment intention when deciding whether to use prophylactic CSF. The use of regimens that do not require CSF because of equal efficacy and lower risk of FN remains standard medical practice.
Secondary prophylaxis with CSF is recommended for a select group of patients. Oncologists should be mindful of previous neutropenic complications, prior CSF administration, and appropriateness of dose reduction. No definitive conclusions can be drawn regarding the benefits of secondary prophylaxis on survival, quality of life, or cost.
Therapeutic intervention with CSF can help reduce the incidence of infectious episodes and infection-related morbidity and mortality. However, therapeutic CSF use should be reserved for patients with fever and neutropenia and those at high risk for infection-associated complications or poor clinical outcomes. This intervention should not be routinely used in afebrile patients or FN patients receiving antibiotic therapy. Clinical prediction models have been developed to help prospectively identify patients with cancer who are at higher risk of complications as a result of fever and neutropenia; a risk model for mortality in hospitalized patients has also been reported recently (Table 2).
Data on using CSF to increase dose-intensity or -density chemotherapy regimens are limited. Evidence has shown that the use of CSF allows for a moderate increase in dose-dense (but not dose-intense) regimens in certain settings (e.g., node-positive breast cancer; and possibly non-Hodgkin's lymphoma pending confirmation of results of individual trials). This treatment approach should only be used within the constructs of a clinical trial or if supported by appropriate evidence.
Major complications of high-dose chemotherapy supported by autologous bone marrow transplantation or peripheral-blood progenitor cell (PBPC) transplantation include disease recurrence, infection, delayed or incomplete engraftment, and organ damage from the ablative regimen. The use of CSF to mobilize PBPC and to shorten the period of neutropenia after cytoreduction and PBPC transplantation is well established.
Considerations and available evidence vary for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphocytic leukemia (ALL), and acute leukemia in relapse. Several studies have shown that CSF administration can produce modest decreases in the duration of neutropenia when begun shortly after completion of the initial induction chemotherapy for patients with AML. Studies on CSF priming of leukemia cells in patients with AML produced results showing no effect on complete response rates or overall survival. Additional studies on AML patients (those in remission) showed a seemingly profound shortened duration of neutropenia after consolidation chemotherapy. These studies produced no effect on complete response duration or overall patient survival. Though CSF use can increase the absolute neutrophil count in neutropenic patients with MDS, data supporting the routine, long-term, continuous use of CSF for this population are lacking. Using CSF for patients with ALL (after initial chemotherapy induction or postremission course) may shorten the duration of neutropenia by 1 week. However, CSF use in patients with relapsed or refractory acute leukemia may provide only a few days of shortened neutropenia.
Though concurrent chemotherapy with radiation therapy is important in certain treatment settings, oncologists should avoid CSF administration for these patients. However, in the absence of chemotherapy, and if prolonged delays secondary to neutropenia are expected, patients receiving radiation therapy alone may benefit from the therapeutic use of CSF.
Aging is one of the conditions for which prophylactic use of growth factors may be indicated irrespective of the threshold risk of neutropenia. However, aside from data available in patients with lymphoma, there is insufficient evidence to support the use of prophylactic CSF in patients, based solely on age. Oncologists should consider additional patient risk factors when deciding whether to administer CSF to elderly patients.
The use of CSF in pediatric patients will almost always be guided by clinical protocols. Several multicenter randomized clinical trials have evaluated prophylactic CSF in children, particularly those with acute leukemia. Based on this research, oncologists should consider cautiously the use of CSF in children with ALL. When determining whether CSF administration would prophylactically or therapeutically benefit a pediatric patient, the oncologist should consider the patient's likelihood of developing FN and incidence of other risk factors.
Filgrastim (G-CSF), pegfilgrastim (pegylated G-CSF), and sargramostim (GM-CSF) are the growth factors currently in use. The administration protocol for each agent varies according to setting (Table 3).
No guideline recommendation can be made regarding the equivalency of the two colony-stimulating agents. As in 2000, further trials are recommended to study the comparative clinical activity, toxicity, and cost-effectiveness of G-CSF and GM-CSF.
Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.
Growth factors should be used when indicated for clinical reasons, not economic ones. When available, alternative regimens offering equivalent efficacy but not requiring CSF support should be utilized. Further research into CSF cost implications and impact on quality of life is warranted.
The 2006 Update Committee was guided by the 1996 ASCO outcomes criteria that justify the use of a drug or technology based on improvements in survival, quality of life, toxicity reduction, and cost-effectiveness. The Committee agreed unanimously that reduction in FN was an important clinical outcome that justified use of CSF, regardless of impact on other factors, when the risk of FN was about 20% and no other equally effective regimen that did not require CSF was available.
The 2006 Update Committee performed a complete literature review and analysis of data published from 1999 through September 2005. Whenever possible, the Committee focused on randomized controlled trials and systematic reviews and meta-analyses of published trials.
The 2006 Update is available in the July 1, 2006, print edition of JCO and also at www.jco.org (J Clin Oncol 24:3187-3205, 2006). In addition to the full text of the guideline recommendations, available online at http://www.asco.org/guidelines/wbcgf, further resources from ASCO include a patient guide and PowerPoint slide set. A CSF flow sheet and orders form is available online at www.jopasco.org.
The ASCO 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors was developed and written by Thomas J. Smith (Chair), James Khatcheressian, Gary H. Lyman, Howard Ozer, James O. Armitage, Lodovico Balducci, Charles L. Bennett, Scott B. Cantor, Jeffrey Crawford, Scott J. Cross, George Demetri, Christopher E. Desch, Philip A. Pizzo, Charles A. Schiffer, Lee Schwartzberg, Mark R. Somerfield, George Somlo, James C. Wade, James L. Wade, Rodger J. Winn, Antoinette J. Wozniak, and Antonio C. Wolff.
It is important to realize that many management questions have not been comprehensively addressed in randomized trials and guidelines cannot always account for individual variation among patients. A guideline is not intended to supplant physician judgment with respect to particular patients or special clinical situations and cannot be considered inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same results.
Accordingly, ASCO considers adherence to this guideline to be voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. In addition, the guideline describes administration of therapies in clinical practice; it cannot be assumed to apply to interventions performed in the context of clinical trials, given that clinical studies are designed to test innovative and novel therapies in a disease and setting for which better therapy is needed. Because guideline development involves a review and synthesis of the latest literature, a practice guideline also serves to identify important questions for further research and those settings in which investigational therapy should be considered.