Prophylaxis of chemotherapy-induced febrile neutropenia with granulocyte colony-stimulating factors: where are we now?

Abstract

Updated international guidelines published in 2006 have broadened the scope for the use of granulocyte colony-stimulating factor (G-CSF) in supporting delivery of myelosuppressive chemotherapy. G-CSF prophylaxis is now recommended when the overall risk of febrile neutropenia (FN) due to regimen and individual patient factors is >or=20%, for supporting dose-dense and dose-intense chemotherapy and to help maintain dose density where dose reductions have been shown to compromise outcomes. Indeed, there is now a large body of evidence for the efficacy of G-CSFs in supporting dose-dense chemotherapy. Predictive tools that can help target those patients who are most at risk of FN are now becoming available. Recent analyses have shown that, by reducing the risk of FN and chemotherapy dose delays and reductions, G-CSF prophylaxis can potentially enhance survival benefits in patients receiving chemotherapy in curative settings. Accumulating data from 'real-world' clinical practice settings indicate that patients often receive abbreviated courses of daily G-CSF and consequently obtain a reduced level of FN protection. A single dose of PEGylated G-CSF (pegfilgrastim) may provide a more effective, as well as a more convenient, alternative to daily G-CSF. Prospective studies are needed to validate the importance of delivering the full dose intensity of standard chemotherapy regimens, with G-CSF support where appropriate, across a range of settings. These studies should also incorporate prospective evaluation of risk stratification for neutropenia and its complications.

Fig. 1

Algorithm for determining whether granulocyte colony-stimulating factor (G-CSF) prophylaxis is indicated in patients undergoing chemotherapy (represents a combined interpretation of the 2006 G-CSF guidelines of the European Organisation for Research and Treatment of Cancer and the American Society of Clinical Oncology [16, 17]). FN febrile neutropenia. Adapted from (a) Aapro et al. [16], with permission from Elsevier. Incorporating data from (b) Smith TJ et al. [17]

Fig. 2

Efficacy of primary prophylactic granulocyte colony-stimulating factor (G-CSF; pegfilgrastim, filgrastim or lenograstim) versus placebo or no treatment in preventing febrile neutropenia (FN), infection-related mortality (INF mortality) and early mortality (all-cause, during chemotherapy) in 3,493 patients treated with chemotherapy for solid tumours or lymphoma. Results of a meta-analysis of 17 studies [69]

Fig. 3

Efficacy of different granulocyte colony-stimulating factors in preventing infection-related mortality, early mortality and febrile neutropenia in 3,493 patients treated with chemotherapy for solid tumours or lymphoma. Forest plot of data from a meta-analysis of 17 randomised controlled studies comparing G-CSF primary prophylaxis with placebo or no treatment [69]

Fig. 4

Comparison of febrile neutropenia and grade 4 neutropenia incidence per patient and per cycle in patients receiving TAC chemotherapy for early breast cancer, supported by different primary prophylactic regimens: ciprofloxacin 500 mg orally twice daily on days 5–14 (n = 253 patients), daily granulocyte colony-stimulating factor (G-CSF; filgrastim 5 µg/kg per day or lenograstim 150 µg/m² per day) on days 5–10 (n = 374), pegfilgrastim (PEG) 6 mg on day 2 (n = 303) or pegfilgrastim plus ciprofloxacin (PEG + CIP; n = 314) [33]. *p < 0.01, **p < 0.001 versus CIP; †p < 0.01, ††p < 0.001 versus daily G-CSF. Reprinted from von Minckwitz et al. [33]. By permission of Oxford Journals/European Society for Medical Oncology