Journal Article

The influence of toxicity constraints in models of chemotherapeutic protocol escalation

Eleanor A. J. Boston and Eamonn A. Gaffney

in Mathematical Medicine and Biology: A Journal of the IMA

Published on behalf of Institute of Mathematics and its Applications

Volume 28, issue 4, pages 357-384
Published in print December 2011 | ISSN: 1477-8599
Published online April 2011 | e-ISSN: 1477-8602 | DOI: http://dx.doi.org/10.1093/imammb/dqr004
The influence of toxicity constraints in models of chemotherapeutic protocol escalation

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The prospect of exploiting mathematical and computational models to gain insight into the influence of scheduling on cancer chemotherapeutic effectiveness is increasingly being considered. However, the question of whether such models are robust to the inclusion of additional tumour biology is relatively unexplored. In this paper, we consider a common strategy for improving protocol scheduling that has foundations in mathematical modelling, namely the concept of dose densification, whereby rest phases between drug administrations are reduced. To maintain a manageable scope in our studies, we focus on a single cell cycle phase-specific agent with uncomplicated pharmacokinetics, as motivated by 5-Fluorouracil-based adjuvant treatments of liver micrometastases. In particular, we explore predictions of the effectiveness of dose densification and other escalations of the protocol scheduling when the influence of toxicity constraints, cell cycle phase specificity and the evolution of drug resistance are all represented within the modelling. For our specific focus, we observe that the cell cycle and toxicity should not simply be neglected in modelling studies. Our explorations also reveal the prediction that dose densification is often, but not universally, effective. Furthermore, adjustments in the duration of drug administrations are predicted to be important, especially when dose densification in isolation does not yield improvements in protocol outcomes.

Keywords: chemotherapeutic protocol modelling; age-structured modelling; Cell cycle phase specificity; toxicity constraints; drug resistance

Journal Article.  0 words. 

Subjects: Applied Mathematics ; Biomathematics and Statistics

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