title: A randomized phase I trial of chronic oral etoposide with or without granulocyte-macrophage colony-stimulating factor in patients with advanced malignancies.
abstract: Data from an in vitro human tumor-cloning assay suggested synergistic cytotoxicity when etoposide (VP16) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined. To explore this potential, we undertook a prospectively randomized three-arm trial in a phase I setting with various schedules of VP16 and GM-CSF. Thirty-one patients were enrolled in the three-arm trial. Arm A consisted of oral VP16 daily for up to 21 days with cycles repeated every 35 days. Arm B included oral VP16 daily for up to 21 days plus concomitant GM-CSF at 5 micrograms/kg/day s.c. days 1-10. Arm C included oral VP16 daily for up to 21 days plus pretreatment with GM-CSF at the same dose for 5 days (days -6 to -2). VP16 was begun at 25 mg/m2/day on level 1 and increased to 50 mg/m2/day on level 2. Twenty-seven patients were evaluable for toxicity, nine on each arm (six patients on each arm on level 1, three patients on each arm on level 2). Neutropenia on arm B (concomitant VP16 and GM-CSF) was earlier and more profound than on arm A or C. The median absolute neutrophil count and day of nadir for arms A, B, and C were 3295, 988, and 1600/mm3 and days 23, 15, and 26, respectively. Thrombocytopenia was generally uncommon except on arm C level 2, where the median platelet count was 26,000/mm3. One partial response (arm B) in a patient with non-small cell lung cancer was seen. Dose intensity favored arm A. Neither concomitant therapy with VP16 and GM-CSF (arm B) nor pretreatment with GM-CSF (arm C) improved dose intensity over VP16 alone (arm A), and arms B and C were complicated by increased neutropenia and thrombocytopenia.
authors.affiliation: Brooke Army Medical Center, Fort Sam Houston, Texas 78234-6200.
authors.forename: D W
authors.initials: DW
authors.lastname: Shaffer
authors.forename: L S
authors.initials: LS
authors.lastname: Smith
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: G M
authors.initials: GM
authors.lastname: Clark
authors.forename: J R
authors.initials: JR
authors.lastname: Eckardt
authors.forename: S M
authors.initials: SM
authors.lastname: Fields
authors.forename: G R
authors.initials: GR
authors.lastname: Weiss
authors.forename: D A
authors.initials: DA
authors.lastname: Rinaldi
authors.forename: K J
authors.initials: KJ
authors.lastname: Bowen
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D011446:Prospective Studies; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor