definition of febrile neutropenia

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 × 109/l.

incidence of FN, complication rates and mortality

Despite relatively high rates of low neutrophil count during standard-dose chemotherapy regimens for malignancies other than acute leukaemias, rates of FN, other complication rates and mortality rates are relatively low for most standard chemotherapies (Table 1).

Table 1.

Incidence of FN

Leukopenia WHO grade 4 2%–28% 
Febrile neutropenia up to 10%–57% 
Infection WHO grade 3 or 4 up to 16% 
Death in FN 0%–7% 
Leukopenia WHO grade 4 2%–28% 
Febrile neutropenia up to 10%–57% 
Infection WHO grade 3 or 4 up to 16% 
Death in FN 0%–7% 

WHO, World Health Organization.

These rates do not justify the systematic use of haematopoietic 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].

indication for primary prophylaxis of FN by hGFs

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%.

Table 2.

Indications for primary prophylaxis of FN by hGFs

Reasonable only if Parameter 
Probability of FN of ∼20% based on chemotherapy and/or special situations (see Table 4) or Affected: ANC recovery [I], fever [I], infection rate [I], use of i.v. antibiotics [II], hospital discharge [I] 
Dose reduction deemed detrimental to outcome [A] Controversial: infectious mortality [I], early mortality 
 Not affected: survival [I] 
Reasonable only if Parameter 
Probability of FN of ∼20% based on chemotherapy and/or special situations (see Table 4) or Affected: ANC recovery [I], fever [I], infection rate [I], use of i.v. antibiotics [II], hospital discharge [I] 
Dose reduction deemed detrimental to outcome [A] Controversial: infectious mortality [I], early mortality 
 Not affected: survival [I] 

i.v., intravenous.

Table 3.

Examples of regimens with a risk of FN of ∼20%

Bladder cancer MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) 
 TC (paclitaxel, cisplatin) 
Breast cancer TAC (docetaxel, doxorubicin, cyclophosphamide) 
 Dose-dense AC/T (doxorubicin, cyclophosphamide, paclitaxel) 
Cancer of the cervix TC (paclitaxel, cisplatin) 
Gastric cancer DCF (docetaxel, cisplatin, fluorouracil) 
Head and neck cancer Paclitaxel, ifosfamide, mesna, cisplatin 
Non-Hodgkin lymphoma CHOP-14 
 ICE 
 RICE 
 DHAP (dexamethasone, cisplatin, cytarabine) 
Non-small-cell lung cancer DP (docetaxel, carboplatin) 
Ovarian Topotecan 
Sarcoma MAID (mesna, doxorubicin, ifosfamide, etoposide) 
 Doxorubicin, ifosfamide 
Small-cell lung cancer CAE (cyclophosphamide, doxorubicin, etoposide) 
 Topotecan 
Testicular cancer VIP (vinblastine, ifosfamide, cisplatin) 
Bladder cancer MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) 
 TC (paclitaxel, cisplatin) 
Breast cancer TAC (docetaxel, doxorubicin, cyclophosphamide) 
 Dose-dense AC/T (doxorubicin, cyclophosphamide, paclitaxel) 
Cancer of the cervix TC (paclitaxel, cisplatin) 
Gastric cancer DCF (docetaxel, cisplatin, fluorouracil) 
Head and neck cancer Paclitaxel, ifosfamide, mesna, cisplatin 
Non-Hodgkin lymphoma CHOP-14 
 ICE 
 RICE 
 DHAP (dexamethasone, cisplatin, cytarabine) 
Non-small-cell lung cancer DP (docetaxel, carboplatin) 
Ovarian Topotecan 
Sarcoma MAID (mesna, doxorubicin, ifosfamide, etoposide) 
 Doxorubicin, ifosfamide 
Small-cell lung cancer CAE (cyclophosphamide, doxorubicin, etoposide) 
 Topotecan 
Testicular cancer VIP (vinblastine, ifosfamide, cisplatin) 

special situations for use of hGFs for standard therapy

Table 4 describes special situations for the use of hGFs for standard therapy.

Table 4.

Special situations for the use of hGFs for standard therapy

Indication Special situation Use of hGF 
Primary prophylaxis Reduced marrow reserve (e.g. ANC <1.5 × 109/l) due to radiotherapy of >20% marrow Yes [III, C] 
 Human immunodeficiency virus Yes [II, B] 
 Patients aged ≥65 years treated with curative regimens (CHOP or more intensive regimens for patients with aggressive NHL) Yes 
Secondary prophylaxis Further infections in the next treatment cycle considered life threatening Yes 
 Dose reduction below threshold Yes 
 Delay of chemotherapy Yes 
 Lack of protocol adherence if compromising cure rate, overall or disease-free survival Yes 
Therapy of afebrile neutropenia – No [II, D] 
Therapy of FN General No [C] 
Therapy of high-risk FN Protracted FN (>7 days), hypotension, sepsis, pneumonia or fungal infection Yes 
Indication Special situation Use of hGF 
Primary prophylaxis Reduced marrow reserve (e.g. ANC <1.5 × 109/l) due to radiotherapy of >20% marrow Yes [III, C] 
 Human immunodeficiency virus Yes [II, B] 
 Patients aged ≥65 years treated with curative regimens (CHOP or more intensive regimens for patients with aggressive NHL) Yes 
Secondary prophylaxis Further infections in the next treatment cycle considered life threatening Yes 
 Dose reduction below threshold Yes 
 Delay of chemotherapy Yes 
 Lack of protocol adherence if compromising cure rate, overall or disease-free survival Yes 
Therapy of afebrile neutropenia – No [II, D] 
Therapy of FN General No [C] 
Therapy of high-risk FN Protracted FN (>7 days), hypotension, sepsis, pneumonia or fungal infection Yes 

NHL, non-Hodgkin's lymphoma.

dose schedule, route of application of G-CSF and pegfilgrastim

Use 5 μg/kg/day of G-CSF subcutaneoulsy (s.c.) 24–72 h after the last day of chemotherapy until sufficient/stable post-nadir ANC recovery (achieving a target ANC of >10 × 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].

note

Primary prophylaxis with G-CSF is not indicated during chemoradiotherapy to the chest due to the 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 leukaemia (AML) or myelodysplastic 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 leukaemic 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.

use of G-CSF and pegfilgrastim in high-risk situations

Therapy of acute leukaemias, 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 leukaemia (ALL) induction chemotherapy.

Mortality: 0%–10% in autologous TPL, highly variable in allogeneic TPL, 80% during graft failure, 20%–26% during the first 2 months in AML and 2%–10% during induction of ALL.

indications for granulopoietic CSFs in high-risk situations

Table 5 describes the indications for granulopoietic CSFs in high-risk situations.

Table 5.

Indications for G-CSFs in high-risk situations

Indication Use of hGFs Parameter 
Autologous marrow transplant Yes ANC [I], fever [I, C], infection [I, C], i.v. antibiotics [I, C] 
  Not affected: infectious mortality [I, A], overall survival [I, A] 
Autologous hGF PBSC TPL after reinfusion Controversial ANC [I] Not consistently affected: fever, use of i.v. antibiotics 
  Not affected: infectious mortality [I, A], overall survival [I, A] 
Allogeneic marrow transplant Yes ANC [I, A] 
  Other parameters inconsistent 
Graft failure Yes Mortality [III–IV, B] 
AML No (trials) ANC [I, A] 
  Not affected: infectious mortality [I, C], overall survival [I, C] 
MDS No Mortality may be increased [II, B], despite the absence of an increased transformation to AML 
ALL Controversial ANC [I, A] 
  Not consistently affected: severe infections, infectious mortality, hospitalization, survival. Increased rates of secondary leukaemia have been reported in childhood ALL treated with G-CSF 6 radiotherapy [III, C] 
Indication Use of hGFs Parameter 
Autologous marrow transplant Yes ANC [I], fever [I, C], infection [I, C], i.v. antibiotics [I, C] 
  Not affected: infectious mortality [I, A], overall survival [I, A] 
Autologous hGF PBSC TPL after reinfusion Controversial ANC [I] Not consistently affected: fever, use of i.v. antibiotics 
  Not affected: infectious mortality [I, A], overall survival [I, A] 
Allogeneic marrow transplant Yes ANC [I, A] 
  Other parameters inconsistent 
Graft failure Yes Mortality [III–IV, B] 
AML No (trials) ANC [I, A] 
  Not affected: infectious mortality [I, C], overall survival [I, C] 
MDS No Mortality may be increased [II, B], despite the absence of an increased transformation to AML 
ALL Controversial ANC [I, A] 
  Not consistently affected: severe infections, infectious mortality, hospitalization, survival. Increased rates of secondary leukaemia have been reported in childhood ALL treated with G-CSF 6 radiotherapy [III, C] 

G-CSF after autologous stem-cell TPL

  • Marrow TPL: start of hGF. Application may safely be postponed until days 5–7 [I]. The 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.

G-CSF after allogeneic TPL

Reasonable after marrow TPL. Clinical benefit restricted to recovery of ANC. Start 5–7 days after TPL is sufficient [I, A]. Insufficient data for TPL with allo-PBSC.

mobilization of PBSCs

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 to 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.

special comments on CSFs as a treatment for radiation injury

The use of CSFs as treatment for radiation injury is shown in Table 6.

Table 6.

Lethal doses of total body radiotherapy (accidental or intentional)

Indication Clinical outcome Use of CSFs 
Doses of 3–10 Gy Probable or certain death from bone marrow failure Yes 
Doses <3 Gy Survival with excellent nursing care No 
Doses >10 Gy Death due to injury to other organs such as gastrointestinal tract No 
Indication Clinical outcome Use of CSFs 
Doses of 3–10 Gy Probable or certain death from bone marrow failure Yes 
Doses <3 Gy Survival with excellent nursing care No 
Doses >10 Gy Death due to injury to other organs such as gastrointestinal tract No 

note

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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Author notes

Approved by the ESMO Guidelines Working Group: February 2002, last update February 2010. This publication supercedes the previously published version—Ann Oncol 2009; 20 (Suppl 4): iv162–iv165.
Conflict of interest: Dr Crawford has reported that he is conducting research sponsored by Agennix, Amgen and Morphotek through his University. He has spoken at CME events sponsored by Amgen, Lilly and Genentech. He has been on advisory boards for Amgen and Genentech. Dr Caserta and Dr Roila have reported no conflicts of interest