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.