title: Dynamic treatment effect (DTE) curves reveal the mode of action for standard and experimental cancer therapies.
abstract: We present a method for estimating the empirical dynamic treatment effect (DTE) curves from tumor growth delay (TGD) studies. This improves on current common methods of TGD analysis, such as T/C ratio and doubling times, by providing a more detailed treatment effect and overcomes their lack of reproducibility. The methodology doesn't presuppose any prior form for the treatment effect dynamics and is shown to give consistent estimates with missing data. The method is illustrated by application to real data from TGD studies involving three types of therapy. Firstly, we demonstrate that radiotherapy induces a sharp peak in inhibition in a FaDu model. The height, duration and timing of the peak increase linearly with radiation dose. Second, we demonstrate that a combination of temozolomide and an experimental therapy in a glioma PDX model yields an effect, similar to an additive version of the DTE curves for the mono-therapies, except that there is a 30 day delay in peak inhibition. In the third study, we consider the DTE of anti-angiogenic therapy in glioma. We show that resulting DTE curves are flat. We discuss how features of the DTE curves should be interpreted and potentially used to improve therapy.
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, NC, USA.
authors.forename: Kingshuk Roy
authors.initials: KR
authors.lastname: Choudhury
authors.affiliation: Preston Robert Tisch Brain Tumor Research Center, Duke University Medical Center, NC, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, NC, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ashcraft
authors.affiliation: North Carolina State College of Veterinary Medicine, Department of Molecular Biomedical Sciences, NC, USA.
authors.forename: Mary-Keara
authors.initials: MK
authors.lastname: Boss
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, NC, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005910:Glioma / Q000628:therapy*; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D000077204:Temozolomide; D035703:Therapies, Investigational; D014018:Tissue Distribution
chemical_list: D003606:Dacarbazine; D000077204:Temozolomide
keywords: additive effects in combination therapy; inhibition rate; regrowth following radiotherapy; tumor growth delay; tumor growth modelling