Recommendations for the Use of Hematopoietic Colony-Stimulating Factors Treatment
Primary Prophylaxis
General Circumstances
Primary prophylaxis is recommended for the prevention of febrile neutropenia (FN) in patients who have a high risk of FN based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. For "dose dense" regimens, colony-stimulating factors (CSFs) are required and recommended. Clinical trial data support the use of CSF when the risk of febrile neutropenia is in the range of 20% or higher. In the absence of special circumstances, most commonly used regimens have risks of FN of <20%. In making the decision to use prophylactic CSF or not, oncologists should consider not only the optimal chemotherapy regimen but also the individual patient risk factors and the intention of treatment, that is, curative, prolongation of life, or symptom control and palliation. Examples of appropriate use in the curative setting include adjuvant treatment of early-stage breast cancer with more intensive regimens such as docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, epirubicin, and cyclophosphamide (FEC100) or the use of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) or CHOP-like regimens in older patients with aggressive non-Hodgkin's lymphoma.
Specific Circumstances
Clinicians may occasionally be faced with patients who might benefit from relatively nonmyelosuppressive chemotherapy but who have potential risk factors for febrile neutropenia or infection because of bone marrow compromise or comorbidity. It is possible that primary CSF administration may be exceptionally warranted in patients at higher risk for chemotherapy-induced infectious complications, even though the data supporting such use are not conclusive. Certain clinical factors predispose to increased complications from prolonged neutropenia, including: patient age greater than 65 years; poor performance status; previous episodes of FN; extensive prior treatment including large radiation ports; administration of combined chemoradiotherapy; bone marrow involvement by tumor producing cytopenias; poor nutritional status; the presence of open wounds or active infections; more advanced cancer, as well as other serious comorbidities. In such situations primary prophylaxis with CSF is often appropriate even with regimens with FN rates of <20%. The special circumstances have always been part of the American Society of Clinical Oncology's (ASCO's) CSF guidelines, in recognition that there are patient factors that predict for the rate and severity of febrile neutropenia. These special circumstances have been maintained from previous versions of the guideline. The rate at which the use of CSFs should be considered has changed from 40% to 20%, consistent with the new evidence that demonstrates efficacy in reducing febrile neutropenia rates when the risk is approximately 20%.
Secondary Prophylaxis
Secondary prophylaxis with CSFs is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay may be a reasonable alternative.
Patients with Neutropenia Who Are Afebrile
CSFs should not be routinely used for patients with neutropenia who are afebrile.
Therapeutic Use of CSFs
Patients with Neutropenia Who Are Febrile
CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. However, CSFs should be considered in patients with fever and neutropenia who are at high risk for infection-associated complications, or who have prognostic factors that are predictive of poor clinical outcomes. High-risk features include expected prolonged (>10 days) and profound (<0.1 x 109/L) neutropenia, age greater than 65 years, uncontrolled primary disease, pneumonia, hypotension and multi-organ dysfunction (sepsis syndrome), invasive fungal infection, or being hospitalized at the time of the development of fever.
Use of CSFs to Increase Dose Intensity or Dose Density
Use of CSFs allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens. Available data would suggest a survival benefit from the use of dose-dense (but not dose-intense) regimens with CSF support in a few specific settings (e.g., node-positive breast cancer, small cell lung cancer, and non-Hodgkin's lymphoma). However, additional data in these settings are needed and these results cannot be generalized to other disease settings and regimens absent specific trials. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data.
Use of CSFs as Adjuncts to Progenitor-Cell Transplantation
Administration of CSFs to mobilize peripheral blood progenitor cells (PBPC), often in conjunction with chemotherapy and their administration after autologous, but not allogeneic, PBPC transplant is the current standard of care.
Use of CSFs in Patients with Leukemia or Myelodysplastic Syndromes
Initial or Repeat Induction Chemotherapy (AML)
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. Beneficial effects on end points such as duration of hospitalization and incidence of severe infections have been variable and modest. CSF use following initial induction therapy is reasonable, although there has been no favorable impact on remission rate, remission duration or survival. Patients >55 years of age may be most likely to benefit from CSF use.
CSF for Priming Effects (AML)
Use of CSFs for priming effects is not recommended.
Consolidation Chemotherapy in AML
CSF use can be recommended after the completion of consolidation chemotherapy because of the potential to decrease the incidence of infection and eliminate the likelihood of hospitalization in some patients receiving intensive post remission chemotherapy. There seems to be more profound shortening of the duration of neutropenia after consolidation chemotherapy for patients with AML in remission than for patients receiving initial induction therapy. There is no effect on the duration of complete response duration or overall survival. There is, as yet, no information about the effect of longer acting, pegylated CSFs in patients with myeloid leukemias and they should not be used in such patients outside of clinical trials.
Myelodysplastic Syndrome (MDS)
No change from 2000 Update. CSFs can increase the absolute neutrophil count (ANC) in neutropenic patients with MDS. Data supporting the routine long-term continuous use of CSFs in these patients are lacking. Intermittent administration of CSFs may be considered in a subset of patients with severe neutropenia and recurrent infection.
Acute Lymphocytic Leukemia (ALL)
CSFs are recommended after the completion of the initial first few days of chemotherapy of the initial induction or first post remission course, thus shortening the duration of neutropenia of <1000/mm3 by approximately one week. There are less consistent effects on the incidence and duration of hospitalization and the acquisition of serious infections. Although there was a trend for improved complete response (CR) rates in one large study particularly in older adults, there was no prolongation of disease-free or overall survival in any of the trials. Granulocyte colony-stimulating factor (G-CSF) can be given together with the continued corticosteroid/antimetabolite therapy, which is a feature of many ALL regimens, without evidence that such concurrent therapy prolongs the myelosuppressive effects of the chemotherapy. As in AML, it is unknown from the published data whether the CSFs significantly accelerate recovery to neutrophil counts of 100-200/mm3. In most patients, regenerating counts of this level are sufficient to protect against infection so as to permit safe discharge of patients from the hospital. The use of G-CSF for children with ALL was associated with small benefits in days of antibiotics or in-hospital days, although a small amount of additional costs was incurred, after taking into consideration the costs of the CSFs. Cost estimates of CSFs for adults with ALL have not been reported.
Leukemia in Relapse
CSFs should be used judiciously, or not at all, in patients with refractory or relapsed myeloid leukemia since the expected benefit is only a few days of shortened neutropenia. Because of the relatively low response rate in AML patients with relapsed or refractory disease clinicians may be faced with the difficult dilemma of whether the persistence of leukemia after chemotherapy is a consequence of drug resistance or a stimulatory effect of the CSF. Although drug resistance is the most likely cause of treatment failure, it is sometimes necessary to stop the CSF and observe the patient for a few days to be certain. No significant change from 2000 recommendation.
Use of CSFs in Patients Receiving Radiation Therapy
CSFs should be avoided in patients receiving concomitant chemotherapy and radiation therapy, particularly involving the mediastinum. In the absence of chemotherapy, therapeutic use of CSFs may be considered in patients receiving radiation therapy alone if prolonged delays secondary to neutropenia are expected.
Use of CSFs in Older Patients
Prophylactic CSF for patients with lymphoma aged 65 and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of febrile neutropenia and infections.
Use of CSFs in the Pediatric Population
The use of G-CSF in pediatric patients will almost always be guided by clinical protocols. As in adults, the use of G-CSF is reasonable for the primary prophylaxis of pediatric patients with a likelihood of FN. Similarly, the use of G-CSF for secondary prophylaxis or for therapy should be limited to high-risk patients. However, the potential risk for secondary myeloid leukemia or MDS associated with G-CSF represents a concern in children with ALL whose prognosis is otherwise excellent. For these reasons, the specific use of G-CSF in children with ALL should be considered carefully.
CSF Initiation, Dosing, Duration and Administration
G-CSF (Filgrastim)
G-CSF should be given 24 to 72 hours after the administration of myelotoxic chemotherapy. In the setting of high-dose therapy and autologous stem cell rescue G-CSF can be given between 24 to 120 hours after administration of high-dose therapy. G-CSF should be continued until reaching an ANC of at least 2 to 3 x 109/L. For PBPC mobilization, G-CSF should be started at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis.
Pegylated G-CSF (Pegfilgrastim)
Pegfilgrastim 6 mg should be given once, 24 hours after completion of chemotherapy. Pegfilgrastim is not currently indicated for stem cell mobilization. The safety and efficacy of pegylated G-CSF has not yet been fully established in the setting of dose-dense chemotherapy.
GM-CSF (Sargramostim*)
Because GM-CSF has been licensed specifically for use after autologous or allogeneic bone marrow transplantation and for AML, the manufacturer's instructions for administration are limited to those clinical settings. GM-CSF should be initiated on the day of bone marrow infusion and not less than 24 hours from the last chemotherapy and 12 hours from the most recent radiotherapy. GM-CSF should be continued until an ANC greater than 1.5 x 109/L for 3 consecutive days is obtained. The drug should be discontinued early or the dose be reduced by 50% if the ANC increases to greater than 20 x 109/L.
Dosing
G-CSF (filgrastim) and GM-CSF (sargramostim*): In adults, the recommended CSF doses are 5 micrograms/kg/day for G-CSF and 250 micrograms/m2/day for GM-CSF for all clinical settings other than PBPC mobilization. In the setting of PBPC mobilization, if G-CSF is used, a dose of 10 micrograms/kg/day seems preferable. The preferred route of G-CSF administration is subcutaneous.
Pegylated G-CSF: Pegylated G-CSF (pegfilgrastim 6 mg) is given once in each chemotherapy cycle. The 6 mg formulation should not be used in infants, children, or small adolescents weighing <45 kg.
*Note from the National Guideline Clearinghouse (NGC): On January 24, 2008, the current liquid formulation of Leukine (sargramostim) was withdrawn from the market in the U.S. and worldwide due to an upward trend in spontaneous reports of adverse reactions, including syncope (fainting). See the U.S. Food and Drug Administration (FDA) Web site for more information.
Special Comments on Comparative Clinical Activity of G-CSF and GM-CSF
No change. 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.
Special Comments on Growth factors as a Treatment for Radiation Injury
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. Accidental or intentional (e.g., resulting from a terrorist attack or war) total body radiation leads to probable or certain death from bone marrow failure at doses of 3 to 10 Grays (Gy) without supportive care, CSFs, and/or a bone marrow transplant. Doses below that level are almost always survivable with excellent nursing care and higher doses are lethal because of injury to other organs such as the gastrointestinal tract. The chance for mortality from any radiation dose rises with combined injuries to the skin, lungs, etc. Hematopoietic growth factors can increase the survival, proliferation, amplification, and differentiation of granulocyte progenitors to produce neutrophils. Although no prospective, randomized trials have been carried out to determine the benefit of hematopoietic growth factors in humans exposed to accidental or intentional radiation injury, they have been utilized in radiation accident victims and neutrophil recovery appears to have been hastened in 25 of 28 cases (REACT/TS registry). In animal models, prompt administration of hematopoietic growth factors after otherwise lethal total body radiation exposure dramatically increases survival.
