A randomized phase I trial of chronic oral etoposide with or without granulocyte-macrophage colony-stimulating factor in patients with advanced malignancies

• Published in: Cancer research (Chicago, Ill.) Ill.), 1993-12, Vol.53 (24), p.5929-5933
• Main Authors: SHAFFER, D. W, SMITH, L. S, VON HOFF, D. D, BURRIS, H. A, CLARK, G. M, ECKARDT, J. R, FIELDS, S. M, WEISS, G. R, RINALDI, D. A, BOWEN, K. J, KUHN, J. G
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Etoposide - administration & dosage; Etoposide - adverse effects; Etoposide - therapeutic use; Female; Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Humans; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Neutropenia - chemically induced; Pharmacology. Drug treatments; Prospective Studies; Thrombocytopenia - chemically induced
• ISSN: 0008-5472; 1538-7445

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.