This article appears in the following Annals of Oncology issue: ESMO Clinical Recommendations [View the issue table of contents]
ESMO clinical recommendations |
Hematopoietic growth factors: ESMO Recommendations for the applications
1 Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, USA
2 Department of Medical Oncology, S. Maria Hospital, Terni, Italy
* Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations{at}esmo.org
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definition of febrile neutropenia |
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 Top definition of febrile... incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Febrile neutropenia (FN) is defined as a rise in axillary temperature to >38.5°C for a duration of >1 h while having an absolute neutrophil count (ANC) of <0.5 x 109/l.
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incidence of FN, complication rates and mortality |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Despite relatively high rates of low neutrophil counts during standard dose chemotherapy regimens for malignancies other than acute leukemias, rates of FN, other complication rates and mortality rates are relatively low for most standard chemotherapies (Table 1).
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These rates do not justify the systematic use of hematopoietic growth factors (hGFs) such as granulocyte colony-stimulating factor (G-CSF) or its pegylated form (pegfilgrastim) in prophylaxis of chemotherapy-induced neutropenia unless the risk of FN exceeds 20%, or there are special circumstances as outlined below. Colony-stimulating growth factors should be avoided in patients who are not at high risk for FN or neutropenic complications. The use of hGFs for treatment of FN is also not recommended, except in settings with increased morbidity and mortality, including sepsis, tissue infection and prolonged neutropenia. These agents should be particularly avoided in patients with infections not related to neutropenia, such as community- or hospital-acquired pneumonia [I, A].
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indication for primary prophylaxis of FN by hGFs |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Table 2 describes the indications for primary prophylaxis of FN by hGFs and Table 3 gives examples of chemotherapy regimens with a risk of FN of
20%.
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special situations for use of hGFs for standard therapy |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Table 4 describes special situations for the use of hGFs for standard therapy.
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dose schedule, route of application of G-CSF and pegfilgrastim |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Use 5 µg/kg/day of G-CSF s.c. 24–72 h after the last day of chemotherapy until sufficient/stable post-nadir ANC recovery (achieving a target ANC of >10 x 109/l is not necessary). Pegfilgrastim, injected s.c. as a single dose of either 100 µg/kg (individualized) or of a total dose of 6 mg (general approach), is considered equally effective [I, A].
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note |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Primary prophylaxis with G-CSF is not indicated during chemoradiotherapy to the chest due to increased rate of bone marrow suppression associated with an increased risk of complications and death [I, A].
There is also a risk of worsening thrombocytopenia when hGFs are given immediately before or simultaneously with chemotherapy.
There is a possible risk of subsequent acute myeloid leukemia (AML) or myelodisplastic syndrome (MDS) in women receiving adjuvant chemotherapy for breast cancer and hGFs. However, this is confounded by the higher doses of chemotherapy received by patients receiving hGFs compared with those receiving standard dose reductions. Long-term follow-up of dose-dense adjuvant chemotherapy where total dose is the same has not demonstrated any difference in leukemic risk. If an increased risk is confirmed in some settings, the absolute risk is low (1.8% compared with 0.7% within 48 months of breast cancer diagnosis) and, therefore, the benefits of hGFs still outweigh the risk.
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use of G-CSF and pegfilgrastim in high-risk situations |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Therapy of acute leukemias, autologous and allogeneic stem cell transplantations (TPLs) lead to higher risks of FN and potentially lethal complications.
Incidence of FN in high-risk situations: regular during autologous and allogeneic peripheral blood stem-cell (PBSC) TPLs and bone marrow TPL, during graft failure, in 35–48% of AML cases at diagnosis and in 13–30% during acute lymphoblastic leukemia (ALL) induction chemotherapy.
Mortality: 0–10% in autologous TPL, highly variable in allogeneic TPL, 80% during graft failure, 20–26% during first 2 months in AML and 2–10% during induction of ALL.
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indications for granulopoietic CSFs in high-risk situations |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Table 5 describes the indications for granulopoietic CSFs in high-risk situations.
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G-CSF after autologous stem-cell TPL |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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• Marrow TPL: start of hGF. Application may safely be postponed until days 5–7 [I]. Recommended dose of G-CSF is 5 µg/kg daily.
• PBSC TPL: short acceleration of recovery of ANC [I] does not consistently translate into relevant clinical benefit. In standard-risk patients outside trials are not recommended.
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G-CSF after allogeneic TPL |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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Reasonable after marrow TPL. Clinical benefit restricted to recovery of ANC. Start 5–7 days after TPL sufficient [I, A]. Insufficient data for TPL with allo-PBSC.
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mobilization of PBSCs |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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autologous PBSC
hGFs ± chemotherapy are effective. The recommended dose of G-CSF is 10 µg/kg daily for 7–10 days before apheresis, with or without chemotherapy. hGF-mobilized PBSCs are superior in terms of recovery of ANC over marrow stem cells plus post-infusion hGFs [I, A].
allogeneic PBSC
Donor convenience, recovery of ANC hastened, no increased rate of acute graft versus host disease. Faster ANC recovery after PBSC compared with marrow stem cells. The recommended dose of G-CSF is 10 µg/kg daily for 7–10 days before apheresis, with or without chemotherapy.
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special comments on CSFs as a treatment for radiation injury |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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The use of CSFs as treatment for radiation injury is shown in Table 6.
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note |
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Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the expert authors and the ESMO faculty.
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footnotes |
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Approved by the ESMO Guidelines Working Group: February 2002, last update December 2008. This publication supercedes the previously published version—Ann Oncol 2008; 19 (Suppl 2): ii116–ii118.
Conflict of interest: Dr Crawford has reported that he has conducted research and served as a consultant/speaker for Amgen, Orto-Biotech; Dr Caserta and Dr Roila have reported no conflicts of interest.
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references |
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Topdefinition of febrile...incidence of FN, complication...indication for primary...special situations for use...dose schedule, route of...noteuse of G-CSF and...indications for granulopoietic...G-CSF after autologous stem-cell...G-CSF after allogeneic TPLmobilization of PBSCsspecial comments on CSFs...notereferences |
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