Abstract 937: Dose-banding of docetaxel in MT-3 tumor bearing nude mice
Authors: Baasner Silke , Meyer Christoph , Mahl Marc-Alexander , Malhi Jas , Tucker Steven , Westphal Martin 
Published: August 2012

Background: Body surface area (BSA)-based dosing of chemotherapy has a number of limitations and - this coupled with a need to improve production efficiencies in hospital pharmacy compounding units - led to the development of dose-banding in a ±5% range around BSA. However, there is a paucity of data on the impact of dose-banding on clinical outcomes. In addition, it is unknown whether variations above 5% have an impact on chemotherapy-associated toxicity or anti-tumor activity. Therefore, the aim of the present study was to investigate the impact of dose-banding, with variations from the calculated dose ≤ 5%, on antitumor activity of docetaxel using a mouse xenograft model. Materials and methods: Female nude mice NMRI:nu/nu aged 6 to 8 weeks received s.c. implants of 5x106 cells (human breast cancer MT-3) on study day 0. Experiment 1: Six groups of 13-14 mice received on day 7 a single i.v. injection (200µl/20g mouse) with either vehicle (saline:polysorbate 80:EtOH at 1:0.5:0.5), the maximum tolerated dose of docetaxel (DocMTD, 25 mg/kg), or ±5% and ±7.5% MTD. Experiment 2: All animals (n=13-14/group) received i.v. injections on study days 8 and 22 with vehicle, or DocMTD, ±10%, ±15%, ±30% and ±80% MTD. Results: In the first experiment, tumor volume of the vehicle group increased ∼21-fold during the 28 days observation period, whereas treatment with DocMTD resulted in a 36% tumor volume reduction. Variations of the MTD up to ±7.5% showed no significant effect on the mean tumor volume in comparison to the DocMTD group (21-36% tumor growth reduction). Body weight decreased transiently in response to all docetaxel treatments (up to 14%, nadir 7-8 days after injection). In the second experiment, tumor growth rate of the vehicle group was comparable to the first study and administration of DocMTD resulted in 65% decreased tumor growth at day 28. At MTD +10% to +30% the tumor volume was 68% and 74% reduced vs. vehicle control group. At +80% (45 mg/kg) the tumor volumes were significantly lower after treatment (88% reduction vs. vehicle). No dose-related increase in tumor volume was observed for the -10 to -30% docetaxel-treated animals compared to the DocMTD group (mean tumor growth reduction 55% to 66% vs. vehicle). At -80% (5 mg/kg), tumor growth was comparable to vehicle-treated animals and reached a similar absolute volume at the end of the study. Conclusions: In the single-dose study, variations of up to ±7.5% from the calculated dose had no effect on tumor volume. In the repeat-dose study, doses of MTD ±30% resulted in similar efficacy on tumor volume. These data suggest that dose-banding with variations of greater than the currently accepted 5% is possible without affecting the efficacy of docetaxel. The potential impact of this finding on clinical practice may be a simplification of dose preparation in pharmacy, reduced drug wastage, as well as an improvement in the oncology service and patient experience.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 937. doi:1538-7445.AM2012-937