title: Intravenous administration of recombinant human macrophage colony-stimulating factor to patients with metastatic cancer: a phase I study.
abstract: OBJECTIVE
  Recombinant human macrophage colony-stimulating factor (M-CSF) has been shown to stimulate specifically macrophage lineage differentiation in vitro and to induce cells capable of antitumor activity alone or in combination with an antibody. The administration of M-CSF to mice has demonstrated antitumor therapeutic effects in vivo. Therefore, a phase I trial of M-CSF administration to patients with metastatic cancer was undertaken.
  
  
  METHODS
  M-CSF was given by intermittent intravenous bolus infusion every 8 hours for 7 days; the treatment cycle was repeated once after a week of rest. Cohorts of three patients underwent dose escalation from 10 to 100,000 micrograms/m2/d; 23 patients received 27 courses of M-CSF administration. All patients had metastatic solid tumors refractory to conventional therapy, including renal cell carcinoma (RCC) (nine), melanoma (seven), and colorectal carcinoma (seven).
  
  
  RESULTS
  Treatment-related toxicity was minimal; five patients developed transient signs of ocular or periorbital inflammation, with iridocyclitis as the most severe manifestation. At the highest doses, platelet counts decreased with therapy (but remained > 100,000/mm3) and the absolute monocyte count increased during the course of therapy. Only at 30,000 and 100,000 micrograms/m2/d was treatment limited because of toxicity (iritis and malaise). Pharmacokinetic studies demonstrated up to a 1,000-fold increase in circulating serum M-CSF after bolus infusion; half-life varied from 1 to 6 hours. Complete regression of mediastinal adenopathy and multiple pulmonary metastases were observed in one patient with RCC.
  
  
  CONCLUSIONS
  Recombinant M-CSF can be administered safely to patients with metastatic cancer at doses that demonstrate biologic activity.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: M G
authors.initials: MG
authors.lastname: Sanda
authors.forename: J C
authors.initials: JC
authors.lastname: Yang
authors.forename: S L
authors.initials: SL
authors.lastname: Topalian
authors.forename: E S
authors.initials: ES
authors.lastname: Groves
authors.forename: A
authors.initials: A
authors.lastname: Childs
authors.forename: R
authors.initials: R
authors.lastname: Belfort
authors.forename: M D
authors.initials: MD
authors.lastname: de Smet
authors.forename: D J
authors.initials: DJ
authors.lastname: Schwartzentruber
authors.forename: D E
authors.initials: DE
authors.lastname: White
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor