Prophylactic Granulocyte-colony Stimulating Factor for Chemotherapy-induced Febrile Neutropenia


colony-stimulating factor (GM-CSF) in a wide range of settings showed little to no mortality benefit with CSFs compared with placebo or no treatment.60


Similar results were reported in a Cochrane database review of 13 trials in patients with lymphoma.40


This disparity may be


attributed to the heterogeneity of the studies analysed. Furthermore, the two meta-analyses showing no effect on mortality endpoints included studies of GM-CSF, which is thought to be less effective than G-CSF at reducing FN.61


Comparisons Between Different Formulations of Granulocyte-colony Stimulating Factor Filgrastim and Lenograstim


Evidence from a meta-analysis suggests that filgrastim and lenograstim have comparable efficacy with regards to FN and FN-related endpoints.39


Eight studies of prophylactic G-CSF


A recent systematic review further confirms the comparability of lenograstim and filgrastim.62


Comparability of Biosimilars XM02 (Tevagrastim® Ratiograstim®


and Biograstim® and Filgrastim Hexal® ) with Originator Product


In order for biosimilars to be approved, they must undergo numerous trials that prove their similarity to the originator product in terms of efficacy and safety. A meta-analysis of three clinical studies involving a total of 608 breast cancer, lung cancer and NHL patients investigated the comparability of the G-CSF biosimilar XM02 with its originator filgrastim.63


Patients were treated with


prophylactic G-CSF during the first cycle of chemotherapy and the incidence of FN was determined. The collective results indicated the non-inferiority of XM02 relative to filgrastim with respect to the incidence of FN and this was seen regardless of the myelotoxicity of the chemotherapy regimen.


Similarly, the biosimilar EP2006 was evaluated in Phase I and III studies in healthy volunteers and neutropenic patients.64


The studies


in healthy volunteers confirmed the biosimilarity of EP2006 with its reference product filgrastim with regards to pharmacodynamics and pharmacokinetics. The open Phase III study included 170 breast cancer patients undergoing four cycles of doxorubicin and docetaxel chemotherapy. Primary prophylaxis of severe neutropenia using EP2006 demonstrated its efficacy and safety. It was therefore concluded that this biosimilar had sufficient comparability with its originator filgrastim.64


Hospira Filgrastim (NivestimTM )


A further biosimilar molecule developed by Hospira based on the originator filgrastim was approved in June 2010. A study was designed to evaluate the similarities of this Hospira filgrastim with the reference filgrastim from Amgen.65


characterisation study that assessed and compared the physiochemical properties of the two products. Both drugs were evaluated using state-of-the-art analytical methods and no significant


EUROPEAN ONCOLOGY & HAEMATOLOGY , ) and EP2006 (Zarzio®


administered prior to the onset of FN in patients with solid tumours or malignant lymphomas receiving systemic chemotherapy were included in this analysis: five trials of filgrastim and three of lenograstim. Findings demonstrated that both these products were effective in reducing the risk of FN as well as infections associated with chemotherapy regimens. Bone pain was the only adverse effect reported, where the mean frequency of complaints among patients receiving growth factor was 21 % compared with 6 % in control subjects.39


However, in terms of stability, Hospira filgrastim has an out of refrigerator stability of up to seven days allowing it to be used in an ambulatory setting, whereas Amgen filgrastim can only be left at room temperature for a maximum of 24 hours before it must be discarded. This suggests an improvement in the quality of product available in later generation formulations while retaining the fundamental biological aspects.


differences were found regarding their physiochemical properties, molecular characteristics, purity and biological activity. Furthermore, when subjected to stress conditions (storage at 40º C), product-related impurities were similar between the two drugs for up to 12 weeks.65


Additional Phase I and III studies further support the equivalence of the Hospira filgrastim and Amgen filgrastim in healthy volunteers and 282 patients with breast cancer.66–68


These randomised trials


demonstrated that Hospira filgrastim was comparable in pharmacokinetic properties, pharmacodynamic profile, efficacy and safety to filgrastim.


Pegfilgrastim


With its approval in 2002, pegfilgrastim had overtaken filgrastim as the standard of care for cancer patients undergoing chemotherapy owing to its convenient dosing schedule. As its name suggests, pegfilgrastim is pegylated and therefore has a longer half-life than filgrastim within the body. As a result, only a single dose of pegfilgrastim is required per cycle of chemotherapy versus daily filgrastim injections. A meta-analysis of five studies with a total of 617 patients receiving myelosuppressive therapy was conducted to investigate the relative efficacies of pegfilgrastim and filgrastim.69


The pooled findings of the


trials suggest that one dose of pegfilgrastim is significantly more effective at reducing the rate of FN in patients than a median of 10–14 days of filgrastim (pooled relative risk of 0.64; 95 % CI, 0.43–0.97). Similarly, the rate of grade 4 neutropenia was also significantly reduced using pegfilgrastim compared with filgrastim. While these findings may reflect the sustained activity of pegfilgrastim, trial heterogeneity was an acknowledged limitation of this meta-analysis and may have influenced the results. The trials included varied in the type of cancer, chemotherapy regimen and trial design.69


At present,


biosimilars of pegfilgrastim are in development and will soon be entering the market.


Current Use of Prophylactic Granulocyte-colony Stimulating Factor for Chemotherapy-induced Febrile Neutropenia


With the number of G-CSF products available, it is important to develop comprehensive guidelines to ensure consistency in their application across different institutions and that all appropriate patients are considered for these drugs. Prior to 2006, primary G-CSF prophylaxis was only recommended for cancer patients receiving chemotherapy regimens associated with a 40 % risk of FN or higher.70


This was an extensive


However, later evidence suggested a clinical benefit at much lower levels of risk. Data showed that G-CSF prophylaxis confers positive results to patients with a FN risk of 20 % or higher.9,71 The European Organisation for Research and Treatment of Cancer guidelines have since been updated to reflect this change stating that primary prophylaxis with any of the available G-CSF formulations should be given to adult cancer patients receiving cytotoxic chemotherapy when the overall FN risk is ≥20 % to prevent FN and FN-related complications.1,72


Further to risks associated with chemotherapy regimens, individual patient factors need to be taken 17


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