The purpose of this study was to evaluate the feasibility of chronic oral administration of etoposide with granulocyte-macrophage colony-stimulating factor (GM-CSF) [sargramostim (Immunex)] coadministration or premedication; to estimate and compare the frequency of toxicities accompanying etoposide administration alone, etoposide/GM-CSF coadministration and etoposide with GM-CSF premedication. Thirty-nine patients with advanced treatment-refractory malignancies were enrolled to this study. Eligible patients were randomized to one of three treatment arms: daily oral etoposide alone for 21 days (arm A); daily oral etoposide for 21 days with GM-CSF, 250 micrograms/m2, s.c. twice daily for the first 10 days of etoposide administration (arm B); or daily oral etoposide for 21 days with GM-CSF twice daily for the sixth through second days preceding etoposide administration (arm C). Courses of treatment were repeated every 28 days. Etoposide dosages for each arm were 25, 50, 75 and 100 mg/m2/day. At least three patients were treated at each dosage level until dose-limiting toxicity was observed. Patients had twice weekly blood counts and weekly clinical examinations to assess toxicity. Patients with measurable or evaluable evidence of cancer were assessed for antitumor response after every other course of therapy. Nadir neutrophil counts at each dosage level were compared between treatment arms by non-parametric Wilcoxen rank sum tests. GM-CSF coadministration (arm B) or premedication (arm C) with daily chronic oral etoposide was feasible and did not lead to excessive hematological toxicity. Pairwise comparisons of neutrophil nadirs for the first course of therapy for each treatment arm did not demonstrate any significant differences and, at most, a slight trend favoring improved neutrophil nadirs was shown for arm C compared to arm A (p = 0.07). Dose intensity as measured by mean days of etoposide administered per patient for each arm suggested only slight improvement in etoposide tolerance for treatment arms B and C. The conclusion, GM-CSF can be safely administered to patients receiving chronic daily oral etoposide. It appears that GM-CSF provides no clinically useful improvement in granulocyte tolerance of therapy.