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Published on 20 September 2010

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G-CSF in the prophylaxis and treatment of febrile neutropenia

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The use of G-CSF is well established in preventing febrile nutropenia in the supportive care management of cancer patients receiving chemotherapy

Dr Tilman Schöning
Assistant Head of Pharmacy
University Hospital of Heidelberg
Germany

Chemotherapy-induced febrile neutropenia (FN) is a serious side effect of cancer treatment. FN is defined as a single temperature greater than or equal to 38.3°C orally or 38.0°C over one hour, whereas neutropenia is defined as a neutrophil count smaller than 500/µl or smaller than 1000/µl plus a predicted decline to smaller than or equal to 500/µl over the next 48 hours.[1] The risk of developing FN or a life-threatening infection is associated with length and severity of neutropenia. Fever is caused by infection in greater than 95% of neutropenic patients, although in 50–70% of patients a pathogen is not found.[2] Hospitalisation rates in patients who develop this complication are high and often administration of intravenous broad-spectrum antibiotics becomes necessary. In addition FN compromises quality of life and can be responsible for treatment delays and dose reductions which are known to affect treatment success.[3] There are certain risk factors which predispose to a higher risk of developing FN. This includes tumour type, chemotherapy regimen and patient-related factors.[4]

Types of therapeutic G-CSF
There is clear evidence that granulocyte colony-stimulating factors (G-CSF) or granulocyte-macrophage colony-stimulating factors (GM-CSF) are able to prevent neutropenia and its associated complications as well as decrease the hospitalisation rate.[5] The first human recombinant G-CSF to be approved was filgrastim in 1991. Filgrastim is still the therapeutic G-CSF with most of the data available regarding its use in the prevention of FN. A recently published meta-analysis of 17 randomised controlled trials for the use of primary prophylactic G-CSF in 3,493 adult solid tumour and malignant lymphoma patients showed relative risk (RR) reduction of 39% in FN (p<0,001, 95% CI 0.525–0.718, number needed to treat [NNT]:6) for filgrastim.[6] It is not only indicated for the prevention of FN after antineoplastic chemotherapy but also in a variety of other treatment intentions such as the collection of CSF-mobilised peripheral blood progenitor cells and following bone marrow transplantation. Usual dosage is 5µg/kg BW once-daily (300–480µg daily) and 10µg/kg BW once-daily in patients with bone marrow or stem cell transplantation and mobilisation. Filgrastim is approved in adults as well as in children. There is a biosimilar available today which has been proved to be equally effective in the prevention of FN.[7]
Another available therapeutic G-CSF is lenograstim which can also be used in the previously mentioned indications. Its usual dosage is 150mcg/m2 or 5mcg/kg daily. Both drugs are to be applied subcutaneously or by intravenous infusion.
Pegfilgrastim is a pegylated G-CSF which is characterised by a prolonged half-life and therefore a longer duration of activity. This provides a single subcutaneous administration of a 6mg flat dose per cycle. Its elimination is directly related to the neutrophil count, which means its clearance is neutrophil-mediated. It is approved for the reduction of length of severe neutropenia in patients with antineoplastic CHT and efficacy has been proved by a randomised controlled trial in adjuvant and metastatic breast cancer patients treated with docetaxel-containing regimens which led to a RR reduction of 92% (p<0,001, 95% CI 0.034–0.175, NNT:6).[8] Reported side effects of G-CSFs are mostly back pain, joint pain and flu-like symptoms, which are generally mild under G-CSF, but reported more commonly under GM-CSF.[9] This leads to a smaller use of GM-CSF in daily practice of FN prophylaxis.

G-CSF guidelines   
Actual guidelines for the use of G-CSF are published by the European Organisation for Research and Treatment of Cancer (EORTC), the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO).[10–12]
Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics and myelotoxicity of the chemotherapy regimen. Furthermore, to provide higher dose intensity in indications which have shown better outcomes with dose-intensive regimens and to prevent treatment delays which could affect therapeutic outcomes.
It is strongly recommended to perform an individual risk assessment prior to every chemotherapy cycle based on patient risk factors. Starting with the FN risk of the chosen chemotherapy regimen defined in the literature, decision pathways are the following:

  • <10% – G-CSF use not indicated
  • 10–20% – assess factors that increase the frequency/risk of FN and redefine patients’ overall risk
  • >20% – prophylactic G-CSF is indicated.

Risk factors for the development of FN which are evidence-based are advanced age (especially ≥65 years), type of chemotherapy, advanced stage of disease, history of FN episodes in the past and lack of prophylaxis with CSF or antibiotics, whereas advanced age has been proven a factor with the best evidence. Chemotherapy regimes with an FN risk of >20% include CHOP-14, anthracycline-based regimens such as FEC100 or taxane-based regimens like TAC.
CSFs should be used as primary prophylaxis to maintain dose-intensity or dose-density if dose reductions are known to be associated with poor prognosis or as supportive care in case of survival benefits. With CSF support, 65% of high-risk patients >60 years undergoing rituximab-CHOP-14 dose-densed chemotherapy regularly kept the interval between cycles.[13] In situations where no benefit of such strategies exists, the use of less myelosuppressive regimens should be considered.
Secondary G-CSF prophylaxis can be defined as prophylaxis after a former episode of FN or an expected prolonged neutropenia after chemotherapy treatment. Individual risks to treated patients should therefore be defined before each treatment cycle. First intention should be to reduce the requirements of dose reduction and treatment delays if those are known to affect treatment success measured as overall or disease-free survival. In the case of a palliative treatment, intention dose reduction remains an important alternative.[14,15]
Therapeutic use of G-CSF in patients suffering from FN might not be generally recommended. There is still a lack of data concerning its influence on infection-related mortality rates and overall survival. It is reasonable to use G-CSF in patients with neutropenic fever if high-risk factors such as age, comorbidities and certain infection complications like hypotension, bacteraemia, pneumonia, fungal infections or bacterial infections with multiresistant strains are present, as well as in hospitalised patients with an expected prolonged neutropenic episode.

References
1. Crawford J. National Comprehensive Cancer Network 2009. Available online at: www.nccn.org
2. Link H et al. Ann Hematol 1994;69:231–43.
3. Bodey GP et al. Ann Int Med 1966;64:328–40.
4. Lyman GH et al. Oncologist 2005;10:427–37.
5. Crawford J et al. N Engl J Med 1991;325:164–70.
6. Kuderer NM et al. J Clin Oncol 2007;25:3158–67.
7. Lubenau H et al. BioDrugs 2009;23:43–51.
8. Vogel CL et al. J Clin Oncol 2005;23:1178–84.
9. Clark OA et al. J Clin Oncol 2005;23:4198–4214.
10. Aapro MS et al. Eur J Cancer 2006;42:2433–53.
11. Crawford J et al. J Natl Compr Canc Netw 2005;3:540–55.
12. Smith TJ et al. J Clin Oncol 2006;24:3187–3205.
13. Rigacci L et al. Acta Haematol 2006;115:22–27.
14. Lyman GH et al. Am J Med 2002;112:406–11.
15. Hackshaw A. Br J Cancer 2004; 90:1302–05.



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