Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer.

Abstract

BACKGROUND: Recent dose-intensity studies of small-cell lung cancer (SCLC) have yielded conflicting results. We carried out a phase III randomized trial in patients with better-prognosis SCLC (i.e., prognostic score of 0-1) to investigate whether doubling the dose density of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with filgrastim and blood-progenitor-cell support improves survival, compared with standard ICE chemotherapy. METHODS: We studied 318 patients with pathologically proven SCLC who were randomly assigned to receive six cycles of ICE chemotherapy with a 4-week (standard arm) or 2-week (dose-dense arm) interval between cycles. Patients in the dose-dense arm received filgrastim subcutaneously daily on days 4 through 14 and had autologous blood collected before cycles 2 through 6, which was returned 24 hours after treatment. Toxicities, including hematologic toxicity and incidence of neutropenic sepsis, were monitored. Survival was calculated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: The delivered median dose intensity was 99% (interquartile range = 96%-100%) for the standard arm and 182% (interquartile range = 163%-196%) for the dose-dense arm. After a median follow-up of 14 months, overall response to treatment was observed in 118 (80%) of the 148 evaluable patients in the standard arm and in 129 (88%) of the 147 evaluable patients in the dose-dense arm, a statistically non-significant difference. Median overall survival was 13.9 months (95% confidence interval [CI] = 12.9 to 15.8 months) in the standard arm and 14.4 months (95% CI = 12.7 to 16.0) in the dose-dense arm, and the 2-year survival was 22% (95% CI = 16% to 29%) and 19% (95% CI = 14% to 27%), respectively--neither difference being statistically significant. The median treatment free time was 286 days (95% CI = 229 to 343 days) for the standard arm and 367 days (95% CI = 321 to 413 days) for the dose-dense arm (difference = 81 days; P = .109). Statistically significantly more hematologic toxicity was reported in the dose-dense arm than in the standard arm, but the number of cycles complicated by neutropenic sepsis was statistically significantly higher in the standard arm than in the dose-dense arm (15.3% versus 11.6%, respectively; difference = 3.7%, 95% CI = -4.1% to 11.5%; P = .03). CONCLUSIONS: Dose-dense ICE chemotherapy for SCLC led to shorter treatment duration and less neutropenic sepsis than did standard ICE but did not improve overall survival.