[Low-dose GM-CSF and dose intensity of antineoplastic agents]

Hematopoietic growth factors are cytokines able to modulate proliferation and differentiation of bone marrow progenitors. We have reviewed the effectiveness of GM-CSF in protecting marrow from chemotherapy-induced neutropenia, mainly in the setting of cyclic polychemotherapy; in particular, studies employing low doses of GM-CSF have been considered. G-CSF or GM-CSF may be particularly useful in situations in which the likelihood of a clinically relevant neutropenia is high, both because of higher dose intensity (obtained by intensification of doses of each cycle or by shortening of intervals between cycles) or because of pretreatment patient characteristics (old age, poor performance status, previous extensive chemotherapy or radiotherapy, experience of neutropenia in the previous cycles). GM-CSF at the conventional dose of 5 micrograms/kg was utilized to increase the etoposide dose to 900 mg/m2 in a chemotherapy program including also carboplatin and ifosfamide in patients with small cell lung cancer. In a randomized study by Ardizzoni et al., the administration of GM-CSF at the dose of 10 micrograms/kg following CEF program (cyclophosphamide, epirubicin and fluorouracil) was effective in reducing from 20 to 16 days the time interval among cycles. Since there is a relationship between GM-CSF dose levels and toxicity, it is attractive to investigate whether GM-CSF at doses lower than 5 micrograms/kg retains its myeloprotective effects, with a substantial reduction in its toxic effects. Grem et al. have observed that 3 micrograms/kg GM-CSF may allow the administration of 425 mg/m2 fluorouracil for five days; Reed et al. demonstrated that 600 mg/m2 carboplatin may be safely administered if protection with 3 micrograms/kg GM-CSF is applied; Kehoe et al. achieved acceleration of cyclophosphamide-cisplatin combination by GM-CSF at the dose of 3 micrograms/kg. We conclude that low dose GM-CSF deserves further evaluation in order to determine effectiveness and potential applications in the clinical practice.