A RANDOMIZED PHASE-I STUDY OF ORAL ETOPOSIDE WITH OR WITHOUT GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR FOR THE TREATMENT OF PATIENTSWITH ADVANCED CANCER

The purpose of this study was to evaluate the feasibility of chronic o ral administration of etoposide with granulocyte-macrophage colony-sti mulating factor (GM-CSF) [sargramostim (Immunex)] coadministration or premedication; to estimate and compare the frequency of toxicities acc ompanying etoposide administration alone, etoposide/GM-CSF coadministr ation and etoposide with GM CSF premedication. Thirty-nine advanced tr eatment-refractory enrolled to this study. Eligible patients were rand omized 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 mu g/m(2), s.c. twice daily for the first 10 days of etoposide administra tion (arm B); or daily oral etoposide for 21 days with GM-CSF twice da ily for the sixth through second days preceding etoposide administrati on (arm C), Courses of treatment were repeated every 28 days. Etoposid e dosages for each arm were 25, 50, 75 and 100 mg/m(2)/day. At least t hree patients were treated at each dosage level until dose-limiting to xicity 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 aft er every other course of therapy, Nadir neutrophil counts at each dosa ge level were compared between treatment arms by non-parametric Wilcox en rank sum tests, GM-CSF coadministration (arm B) or premedication (a rm C) with daily chronic oral etoposide was feasible and did not lead to excessive hematological toxicity, Pairwise comparisons of neutrophi l nadirs for the first course of therapy for each treatment arm did no t demonstrate any significant differences and, at most, a slight trend favoring improved neutrophil nadirs was shown for arm C compared to a rm A (p = 0.07), Dose intensity as measured by mean days of etoposide administered per patient for each arm suggested only slight improvemen t in etoposide tolerance for treatment arms B and C, The conclusion, G M-CSF can be safely administered to patients receiving chronic daily o ral etoposide. It appears that GM-CSF provides no clinically useful im provement in granulocyte tolerance of therapy.