Interactions between pharmacokinetics of paclitaxel, physical activity and body composition in breast cancer. Search for starting points to reduce dose limiting toxicities.

For several decades, paclitaxel (PTX) has been widely used in the treatment of breast cancer with high survival rates.
However, the incidence of dose limiting toxicities (DLT) is substantial, resulting in a severe impact on the Health Related
Quality of Life (HRQoL) of many breast cancer patients, but also on prognostic and socio-economic outcomes due to relative
dose intensity (RDI) adaptations.1 Preliminary evidence is suggesting that modifiable lifestyle factors, such as body
composition and physical activity, along with other parameters, may influence DLT.2,3 Therefore, this observational pilot study
has two important goals: (1) to identify explanatory outcomes along with body composition and physical activity, for DLT of
PTX in breast cancer patients and (2) to develop a pharmacokinetic-pharmacodynamic (PK-PD) model for PTX in breast cancer
treatment. Environmental, physiological and potential other covariates for the model are carefully selected in close
cooperation with an international expert advisory board. The model will determine the effect of the studied covariates on
PTX exposure, and thus predict DLT occurrence in the individual breast cancer patient treated with PTX.
PTX is administered in a weekly schedule for 12 weeks at the UZ Brussel (UZB), while plasma levels are monitored in cycle 1
(T1), cycle 6 (T2), cycle 9 (T3) and cycle 12 (T4) with an innovative dried blood spots (DBS) method in 40 female breast cancer
patients. Blood samples, taken within 10 minutes as well as between 16 and 26 hours post-PTX infusion, are analyzed in the
specialized laboratory of UGent clustered over three points in time during the two-year project. The week following T1, T2,
T3 and T4, number and type of (DL)T, graded according to the Common Terminology Criteria for Adverse Events (CTCAE)
classification v6.0. are scored by the oncologist. Neutropenia and chemotherapy induced peripheral neuropathy are the two
main (DL)T that are monitored respectively in the blood and through patient reported outcome measures as well the week
following T2, T3 and T4 (cycle 6, 9 and 12 of PTX). Additionally, HRQoL is assessed at T0 (prior to the start of the PTX
treatment), the week following T2, T3 and T4 (cycle 6, 9 and 12 of PTX) with the European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire, the core module (C30) as well as the breast cancer specific module (BR45).
At T0, T2 and T4 (prior to infusion of cycle 1, 6 and 12), body composition will be measured by Dual X-ray Absorptiometry and
Bioelectrical Impedance Analysis to map skeletal muscle mass, fat mass and extracellular fluid in the whole body as well as in
segments of the body. All patients will carry an activity tracker for 7 days following PTX cycle 1 (T1), 6 (T2), 9 (T3) and 12 (T4)
to register the level of physical activity and sedentary behavior. These measurements will be included as covariates in the
PK-PD model and other explanatory outcomes in the correlation analyses.
In this project, a half time post doc researcher and a half time data manager/study nurse will coordinate and execute all
tasks, with supervision and expertise of a dedicated interprofessional consortium of UZB, UGent and VUB. A patient advisory
board was and will be closely consulted during the development and execution of the study to include the patients’
experiences and get input on possible challenges for the participants. Our focus in terms of feasibility is the patient’s study
burden and recruitment and dedication rates. This translational research will contribute to the missing piece in the puzzle of
personalized medicine in PTX dosing and managing DLT in breast cancer patients. It will offer necessary insights in both
feasibility of future clinical trials and data characteristics to install interventions that tackle the parameters for DLT. In the
longer term, it may also translate to other chemotherapeutics for different types of cancer and other DLT.