© 2007 European Society for Medical Oncology
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Granulocyte colony-stimulating factor-associated complications and increase in leukocyte number
In their manuscript, Dagia et al. [1] assert that ‘granulocyte colony-stimulating factor (G-CSF) may preferentially mobilize subsets if myeloid cells that express high-affinity E-selectin ligands’, suggesting that strategies which interfere with E-selectin receptor-ligand axis may prevent G-CSF associated complications. The same Authors report that G-CSF-associated events occur in parallel to increases in leukocyte numbers [2, 3].In order to evaluate the comparative efficacy of varying intensity schedules of recombinant human G-CSF (Filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose Epirubicin plus Cyclophosphamide (EC), we randomly assigned 506 stage I-II breast cancer women to receive, in a factorial 2x2 design, EC on day 1 every 21 days for 4 cycles ± Lonidamine ± G-CSF [4]. Five consecutive G-CSF schedules were tested every 100 randomized patients: (i) 480 µg/die s.c. days 8-14; (ii) 480 µg/die days 8, 10, 12, 14; (iii) 300 µg/die days 8-14; (iv) 300 µg/die days 8, 10, 12, 14; (v) 300 µg/die days 8, 12.
Groups 1–4 experienced a marked response to G-CSF, with the mean peak of absolute neutrophil count (ANC) on day 14 exceeding even about five times the upper normal limit. In group 5 (300 µg on day 8 and 12) the mean ANC on day 14 was within the normal range, with a trend to increase after the G-CSF suspension. In particular, G-CSF administered as schedule 5 was better tolerated. A statistically significant difference in G1–G3 bone pain (53% vs 29%, P = 0.01) and G1–G2 fever (24% vs 8%, P = 0.04) was observed between the daily schedules (1 + 3) and the schedule 5. However, no difference in bone pain (40% vs 29%, P = 0.28) and fever (13% vs 8%, P = 0.055) was observed between the every-other-day schedules (2 + 4) and the schedule 5 [4]. Moreover, serum levels of lactate dehydrogenase (LDH) and alkaline phosphatase (AP) were significantly higher in G-CSF group than in control (P = 0.0001). Serum AP and LDH concentrations closely resembled peripheral blood leukocytes count and increased with increasing leucocytosis, throughout the five treatments. G-CSF induced LDH and AP rises in a dose-dependent manner, and the minimal amount was seen for the lowest Filgrastim dosage (300 mcg/day, on days 8 and 12) [5–7].
The goal of G-CSF intensity should be to keep leukocyte values within the normal range without inducing leukocytosis. In our study, the short, as opposed to the prolonged schedules, was able to maintain an absolute neutrophil count on day 14 (the nadir time) within the normal range, suggesting that the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (8th and 12th day) without altering outcome [4].
Based on our clinical experience, we agree with Dagia et al. [1] that providing mechanistic insight into the pathobiology of G-CSF complications is of fundamental importance, particularly for healthy donors for hematopoietic stem cell transplantation, though it remains crucial to select those more susceptible to G-CSG-induced vascular and inflammatory complications.
Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy
* Email: gia.fer{at}flashnet.it
References
1. Dagia NM, Gadhoum SZ, Knoblauch CA, et al. G-CSF induces E-selectin ligand expression on human myeloid cells. Nat Med (2006) 12:1185–1190.[CrossRef][Web of Science][Medline]
2. Dereure O, Hillaire-Buys D, Guilhou JJ. Neutrophil-dependent cutaneous side-effects of leucocyte colony-stimulating factors: manifestations of a neutrophil recovery syndrome? Br J Dermatol (2004) 150:1228–1230.[CrossRef][Web of Science][Medline]
3. Adler BK, Salzman DE, Carabasi MH, et al. Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. Blood (2001) 97:3313–3314.
4. Papaldo P, Lopez M, Marolla P, et al. Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubicin and cyclophosphamide. J Clin Oncol (2005) 23:6908–6918.
5. Papaldo P, Di Cosimo S, Ferretti G, et al. Effect of filgrastim on serum lactate dehydrogenase and alkaline phosphatase values in early breast cancer patients. Cancer Invest (2004) 22:650–653.[CrossRef][Web of Science][Medline]
6. Menekay S, Ozsan GH, Demirkan F, et al. Effect of granulocyte-colony-stimulating factor on serum lactate dehydrogenase levels and isoenzymes in a rabbit model. Acta Haematol (2002) 107:18–22.[CrossRef][Web of Science][Medline]
7. Watanabe T, Suzuya H, Onishi T, et al. Effect of granulocyte colony-stimulating factor on bone metabolism during peripheral blood stem cell mobilization. Int J Hematol (2003) 77:75–81.[Web of Science][Medline]
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