Emma K. Hansson (1), Lena E. Friberg (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: Toxicity and treatment outcome varies considerably between cancer patients and new strategies for dose individualisation are needed. The aim of this project was to investigate if myelosuppression, characterized by a semi-mechanistic model, is correlated with the change in tumor size and thereby could be used as a biomarker to earlier evaluate the treatment and guide dose adjustments to increase the chance of a successful therapy.
Methods: Data on haematological toxicity and tumor size were available from 244 metastatic breast cancer patients treated with single agent docetaxel (75-100 mg/m2) [1]. The change in tumor size, i.e. the sum of longest diameters (SLD) of target lesions according to RECIST, as a function of time, was described by applying a longitudinal model for tumor growth inhibition [2]. The time-course of absolute neutrophil counts (ANC) was predicted by individual parameter estimates obtained from an earlier characterization using a semi-mechanistic myelosuppression model [3]. Docetaxel dose (in mg), individual myelosuppression model parameters [neutrophil baseline (BASE), maturation time (MTT) and drug sensitivity (SLOPE)], and the absolute [ANC(t)] and relative change in myelosuppression over time [(ANC(t)-BASE)/BASE], were evaluated separately or in combination to describe the change in tumor size. The myelosuppression descriptors were linked to changes in tumor size in the same manner as dose [2]. Model development was performed using the FOCE method with INTERACTION in NONMEM 7.
Results: The change in tumor size following treatment with docetaxel was adequately described by the tumor growth inhibition model. The relative change in ANC over time [(ANC(t)-BASE)/BASE] was the best predictor of tumor size dynamics and statistically significant better than dose (∆ OFV = -22).
Conclusion: The identified relationship between the relative change in ANC and tumor size indicates a potential use of ANC as an early predictor of tumor response and may thereby be used for dose individualisation to maximize treatment efficacy.
References:
[1] O’Shaughnessy J, et al. J Clin Oncol 2002 ;20:2812-23
[2] Claret L, et al. J Clin Oncol 2009:27, 4103-4108
[3] Hansson EK, et al Cancer Chemother Pharmacol 2010;65:839-848
Reference: PAGE 21 () Abstr 2353 [www.page-meeting.org/?abstract=2353]
Poster: Oncology