Non conventional suboptimal doses of gemcitabine (G) at fixed dose rate (FDR) infusion, combined with cisplatin (C), in patients with advanced non-small cell lung cancer (NSCLC)

Abstract

7333 Background: C combined with G, at a dose ≥ 1000 mg/sqm., is widely used for advanced NSCLC. It appears that G administered at FDR of 10 mg/sqm/min could enhance its anticancer activity. In the absence of dose-finding and pharmacokinetic (PK) studies of FDR G plus C in NSCLC, we have planned a clinical and PK study to investigate the optimal dose of FDR G. Methods: The treatment consisted of G administered at a fixed dose rate of 10 mg/smq/min on days 1,8 and C (75 mg/sqm) on day 8. Cycles were repeated every 21 days for a maximum of 6 cycles. G was escalated from 600 up to 1200 mg/sqm, with a 100 mg/sqm dose escalation in absence of dose-limiting toxicity; for each cohort we enrolled at least 3 pts. PK samplings were obtained on days 1 & 8 of the first treatment course, in 3 pts per each cohort. Results: A consecutive series of 29 pts (median age 58 y, range 37–71 y) entered this study. Overall, 16 pts received a G dose < 1000 mg/smq and 13 ≥ 1000 mg/sqm. PK data showed that after stratifying by dose level, the target plasma concentration of 10μM was achieved in 8 out of the 12 evaluable pts (70%) treated with 600–900 mg/sqm, but only in 4 out of the 9 evaluable pts (44,4%) treated with 1000–1200 mg/sqm. Toxicity was manageable with 12/29 pts experiencing a grade 3–4 hematological toxicity at all dose levels. Objective responses were observed at all G dose levels: ORR was 56.5% and 46.1% among pts receiving < 1000 mg/sqm and ≥ 1000 mg/sqm respectively (see table). Conclusions: The present data may suggest that unconventional lower doses of G given at FDR could be as effective as conventional doses of G combined with C, in NSCLC. In this prospective we are completing the analysis of PK data, assessing also the correlation with intracellular accumulation of the active metabolite (dFdCTP) of G, in order to verify our data and correlate with the clinical results. No significant financial relationships to disclose.