title: Phase I study of simultaneous dose escalation and schedule acceleration of cyclophosphamide-doxorubicin-etoposide using granulocyte colony-stimulating factor with or without antimicrobial prophylaxis in patients with small-cell lung cancer.
abstract: A phase I study was designed to assess whether dose intensity of an 'accelerated' cyclophosphamide-doxorubicin-etoposide (CDE) regimen plus granulocyte colony-stimulating factor (G-CSF) could be increased further, in an outpatient setting, by escalating the dose of each single drug of the regimen. Patients with previously untreated small-cell lung cancer (SCLC) received escalating doses of cyclophosphamide (C) 1100-1300 mg m-2 intravenously (i.v.) on day 1, doxorubicin (D) 50-60 mg m-2 i.v. on day 1, etoposide (E) 110-130 mg m-2 i.v. on days 1, 2, 3 and every 14 days for at least three courses. Along with chemotherapy, G-CSF (filgastrim) 5 micrograms kg-1 from day 5 to day 11 was administered subcutaneously (s.c.) to all patients. Twenty-five patients were enrolled into the study. All patients at the first dose level (C 1100, D 50, E 110 x 3) completed three or more cycles at the dose and schedule planned by the protocol and no 'dose-limiting toxicity' (DLT) was seen. At the second dose level (C 1200, D 55, E 120 x 3) three out of five patients had a DLT consisting of 'granulocytopenic fever' (GCPF). Another six patients were treated at this dose level with the addition of ciprofloxacin 500 mg twice a day and only two patients had a DLT [one episode of documented oral candidiasis and one of 'fever of unknown origin' (FUO) with generalised mucositis]. Accrual of patients proceeded to the third dose level (C 1300, D 60, E 130 x 3) with the prophylactic use of ciprofloxacin. Four out of six patients experienced a DLT consisting of GCPF or documented non-bacterial infection. Accrual of patients at the third dose level was then resumed adding to ciprofloxacin anti-fungal prophylaxis (fluconazole 100 mg daily) and anti-viral prophylaxis (acyclovir 800 mg twice a day) from day 5 to 11. Out of five patients treated three experienced a DLT consisting of severe leucopenia and fever or infection. With a simultaneous dose escalation and schedule acceleration it is indeed possible to take maximum advantage of G-CSF activity and to increase CDE dose intensity by a factor 1.65-1.80 for a maximum of 3-4 courses. The role of antimicrobial prophylaxis in this setting deserves to be investigated further.
authors.affiliation: Division of Medical Oncology I, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ardizzoni
authors.forename: M C
authors.initials: MC
authors.lastname: Pennucci
authors.forename: M
authors.initials: M
authors.lastname: Danova
authors.forename: C
authors.initials: C
authors.lastname: Viscoli
authors.forename: G L
authors.initials: GL
authors.lastname: Mariani
authors.forename: G
authors.initials: G
authors.lastname: Giorgi
authors.forename: M
authors.initials: M
authors.lastname: Venturini
authors.forename: C
authors.initials: C
authors.lastname: Mereu
authors.forename: T
authors.initials: T
authors.lastname: Scolaro
authors.forename: R
authors.initials: R
authors.lastname: Rosso
mesh_terms: D019072:Antibiotic Prophylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide