title: Two phase I studies of carboplatin dose escalation in chemotherapy-naive ovarian cancer patients supported with granulocyte-macrophage colony-stimulating factor.
abstract: Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) may reduce myelosuppression and, thus, allow dose escalation of certain chemotherapeutic agents. We conducted two sequential phase I trials of escalating doses of carboplatin and a fixed dose and schedule of rHuGM-CSF in ovarian cancer patients who had not previously had chemotherapy, i.e., chemotherapy-naive patients. In the first trial, patients were assigned to regimens of increasing dose levels of carboplatin (starting at 400 mg/m2) and fixed doses and schedules of cyclophosphamide (600 mg/m2) and rHuGM-CSF (10 micrograms/kg given subcutaneously once daily on days 2-11). Chemotherapy was given every 3 weeks (regimen A). In the subsequent trial, the design was the same except that cyclophosphamide was omitted (regimen B). Fifteen patients received regimen A, and seven patients received regimen B. In regimen A, all three patients treated at the first dose level tolerated five cycles at full doses. Hematologic toxicity was dose limiting at the 600-mg/m2 dose level. When 500 mg/m2 carboplatin was given, six of eight patients tolerated three or four cycles at full doses before requiring dose reductions or treatment delays. In regimen B, doses could not be escalated above the first dose level (600 mg/m2) because of severe hematological toxicity. Nonhematological toxicity was tolerable and managed with acetaminophen, antihistamines, and/or nonsteroidal, anti-inflammatory medication. Compliance was excellent. We conclude that (a) rHuGM-CSF can be given safely and reliably to chemotherapy-naive ovarian cancer patients receiving these treatment regimens, (b) early and severe thrombocytopenia was a major problem with or without cyclophosphamide with doses of carboplatin at or above 600 mg/m2, and (c) 500 mg/m2 carboplatin administered every 3 weeks is the highest dose in regimen A that can be given safely in the outpatient setting.
authors.affiliation: Ontario Cancer Treatment and Research Foundation Clinics, Hamilton, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Rusthoven
authors.forename: L
authors.initials: L
authors.lastname: Levin
authors.forename: E
authors.initials: E
authors.lastname: Eisenhauer
authors.forename: J
authors.initials: J
authors.lastname: Mazurka
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
authors.forename: G
authors.initials: G
authors.lastname: O'Connell
authors.forename: P
authors.initials: P
authors.lastname: Bryson
authors.forename: H
authors.initials: H
authors.lastname: Hirte
authors.forename: B
authors.initials: B
authors.lastname: Koski
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity*; D016190:Carboplatin / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D009367:Neoplasm Staging; D009504:Neutrophils / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D016190:Carboplatin