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The use of colony-stimulating factors (CSF) allows for better management of the chemotherapy by reducing the risks of the neutropenia and its complications.
Daniel Almenar[1]
M Angeles Royo[2]
Elena Gras[3]
[1]Head of the Medical Oncology Unit
[2]Medical Resident Oncologist
[3]Clinical Resident
Pharmacist
Dr Peset University
Hospital
Valencia. Spain
Febrile neutropenia is the most feared toxicity produced by antineoplastic treatments.
Cytostatic agents cause interference in the process of cell reproduction, resulting in toxicity in the cell lines with greater capacity for multiplication such as bone marrow. Most of chemotherapy regimens produce laeucopenia, due to the interruption of the maturation of hematopoietic cell lines. The maturation time of neutrophils is about five days, so neutropenia appears approximately one week after chemotherapy administration. This chemotherapy-induced neutropenia is the most common and important dose-limiting toxicity of chemotherapy with an important impact in patient’s quality of life.[1]
Neutropenia is defined as an absolute neutrophil count (ANC) of <1.5 x 109/l, however risk of infection increases if ANC is <0.5 x 109/l the most important degree of medullar toxicity.[2] Otherwise, febrile neutropenia (FN) is defined as a rise in axillary temperature to >38.5ºC for a duration of >1 hour while having an ANC of <0.5 x 109/l.[3]
The duration and depth of neutropenia is related to drugs used, doses, duration of treatment and patient’s characteristics. The personal susceptibility has been assessed by the Multinational Association for Supportive Care in Cancer Risk Index (MASSC)[4] to identify the low-risk febrile neutropenic cancer patients and may be used to select patients for the most adequate management in each case. In addition, treatment with CSFs should be considered according to the risk of complications[5] and patient’s characteristics.
The most important consequence of neutropenia is severe infections or sepsis which are potentially life threatening and increase the need for hospitalisation and intravenous antibiotics. Fever and neutropenia in cancer patients are associated with a high medical risk, with serious medical complications reported in 21% and death in 4% to 30% of episodes in large series.[5]Otherwise, the treatment of these complications and the recovery of neutrophil count involve a delay in the administration of antineoplastic therapy.
Colony-stimulating factors (CSFs) such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are now an integral part of the prevention of potentially life-threatening FN.[6] These adjunctive agents accelerate formation of neutrophils from committed progenitors, thereby reducing the duration and severity of neutropenia with important clinical and economic consequences.[7] Uses of CSFs in oncology are prevention of FN after chemotherapy, reduction of febrile neutropenic episodes and support following bone marrow transplantation, and collection of CSF-mobilised peripheral blood progenitor cells. G-CSF is used more frequently than GM-CSF for all of these indications because of fewer associated adverse effects.[8]
The first recombinant human (rh)G-CSF, filgrastim, was approved in the USA for clinical use in chemotherapy-treated cancer patients in 1991. The potency of filgrastim has been reported to be exactly the same as that of the natural G-CSF.[9] Lenograstim is produced in Chinese hamster ovary cells, which has permitted the introduction of carbohydrate chains identical to those of the natural G-CSF molecule.[10] It does appear to confer greater stability to the G-CSF molecule. Biosimilar filgrastim is a non-glycosylated recombinant methionyl form of human granulocyte colony-stimulating factor (r-MetHuG-CSF). It has been demonstrated to be equivalent to filgrastim regarding the incidence of FN, irrespective of the myelotoxicity of the chemotherapy regimen.[11] Usual dose of G-CSF is 300-480 µgr daily (5-10 days). Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) with a long half-life and sustained duration of action. It is created with pegylation technology resulting in a larger molecule. Consequently, its renal clearance by glomerular filtration is minimised, making neutrophil-mediated clearance the predominant route of elimination, so it requires only once-per-cycle administration (6mg) for the management of chemotherapy-induced neutropenia.
The use of CSF is not exempted from complications. The most important adverse reaction is bone pain and less frequently allergic reactions like rash, urticaria or facial oedema.[12]
The most important organisations in medical oncology such as, European Organization for Research and Treatment of Cancer (EORTC), European Society of Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO), edit guidelines about the use of G-CSF. Recommendations of most recent guidelines[3,12,13,14] are summarised below.
Primary prophylaxis is recommended for prevention of FN in patients who have a high risk of FN. The risk assessment involves varied components including disease characteristics (advanced/metastasis), chemotherapy regimen (myelotoxic, high dose, dose dense, standard dose therapy), patient risk (age, comorbidities) and treatment intent. There is no consensus between guidelines for risk assessment.
Based on chemotherapy regimens and risk, G-CSF should be given as primary prophylaxis when the risk of FN with a chemotherapy regimen is >20% (like TAC, FEC100 or CHOP) or when the risk is 10-20% (intermediate risk) and the patient has other risk factors for FN. In this situation, a correct evaluation of the patient is crucial to estimate the overall risk of FN in order to individualise the CSF use based on risk-benefit ratio of the likelihood of developing a FN, the potential consequences of a neutropenic event and the implications of reduced dose of chemotherapy. Advanced age (>65 years) was the patient-related factor most consistently associated with an increase in FN incidence. Other risk factors for patient included advanced stage disease, experience of previous episode of FN, lack of G-CSF use and lack of antibiotic prophylaxis.
Routine use of CSF is not considered cost-effective for the low risk group (<10% risk).
If reductions in chemotherapy dose intensity or density are associated with poor prognosis, guidelines agree primary G-CSF should be used as a supportive treatment to maintain chemotherapy intensity planned. When the treatment intent is not crucial, use of less myelosuppressive chemotherapy or dose/schedule modification should be considered (dose reduction or cycle delay).
About secondary prophylaxis, after a FN episode, guidelines recommend to evaluate the individual’s risk before each cycle of treatment. CSFs are recommended if the delay in chemotherapy involves a lack of protocol adherence and compromises cure rate or overall or disease-free survival. If treatment intention is palliative, the use of CSFs is not recommended. Likewise, it is advisable to use them if patient had suffered serious FN-related complications in previous cycles. But, based on the available data, no definitive conclusions can be drawn regarding the benefits of secondary prophylaxis on survival, quality of life, or cost.
The use of the CSFs in patients with established febrile neutropenia caused by cancer chemotherapy reduces the amount of time spent in hospital and the neutrophil recovery period. The possible influence of the CSFs on infection-related mortality requires further investigation. In this setting CSF is indicated only in patient with high-risk FN that involves: age ≥65, comorbidities and infectious complications like hypotension, pneumonia, bacteremia, and fungal infection. CSFs are also indicated if FN starts while the patient is hospitalized and if it is expected to continue over 7 days.
About the use of CSF in bone marrow transplantation (TPL) there are two differentiate situations: G-CSF is indicated after bone marrow TPL both autologous and heterologous but its use is controverted in autologus peripheral blood stem cells transplantation (PBSC). Otherwise, G-CSF is indicated 7-10 days before apheresis in autologus PBSC TPL with superior mobilized PBSCs in terms of recovery of absolute neutrophil count over marrow stem cell plus post-infusion.
Finally, practice application of G-CSF and its consequences were analysed in the LEARN study.[15] This is the first study to compare patterns of use of pegfilgrastim and G-CSF in clinical practice in Spain. LEARN study concludes that pegfilgrastim was administrated in similar proportions of patients and in similar number of cycles to daily G-CSF as primary and secondary prophylaxis, probably because of the comfort of administration. However, pegfilgrastim is less used for the treatment of neutropenia. Importantly, the daily G-CSF prophylaxis was given for only around 5-6 days per cycle in many patients, possibly compromising protection against chemotherapy-induced neutropenia. About the incidence of NF and its complications, the study suggests that pegfilgrastim given once per cycle may be more efficacious than daily G-CSF administered according to described practice; these findings should be confirmed en further, prospective studies.
In conclusion, CSF use allows for better management of the chemotherapy by reducing the risks of the neutropenia and its complications.
References
1. Fortner BV, et al. Support Care Cancer 2005;13:522-528.
2. NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 data files. ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40.
3. Crawford J, et al. Ann Oncol 2009; 20(Suppl 4): iv162-165.
4. Klastersky J, et al. J Clin Oncol 2000;18: 3038-3051.
5. Talcott JA, et al. Oncologist 1997;2:365-373.
6. Viret F, et al. Bull Cancer 2006; 93:463-71.
7. Renwick W, et al. BioDrugs 2009; 23:175-86.
8. Dale DC. Drugs 2002;62 Suppl 1:1-15.
9. Bonig H, et al. Bone Marrow Transplant 2001;28:259-264.
10. Nissen C. Eur J Cancer 1994;30A (Suppl 3): 12-14.
11. Lubenau H, et al. BioDrugs 2009;23:43-51.
12. Crawford J, et al. NCCN 2009; V.1.
13. Aapro MS, et al. Eur J Cancer 2006; 42: 2433-53.
14. Smith TJ, et al. J Clin Oncol 2006; 24:3187-3205.
15. Almenar D, et al. European Journal of Cancer Care 2009;18:280-286.
