title: Pharmacometric Modeling of Liver Metastases' Diameter, Volume, and Density and Their Relation to Clinical Outcome in Imatinib-Treated Patients With Gastrointestinal Stromal Tumors.
abstract: Three-dimensional and density-based tumor metrics have been suggested to better discriminate tumor response to treatment than unidimensional metrics, particularly for tumors exhibiting nonuniform size changes. In the developed pharmacometric modeling framework based on data from 77 imatinib-treated gastrointestinal patients, the time-courses of liver metastases' maximum transaxial diameters, software-calculated actual volumes (Vactual) and calculated ellipsoidal volumes were characterized by logistic growth models, in which imatinib induced a linear dose-dependent size reduction. An indirect response model best described the reduction in density. Substantial interindividual variability in the drug effect of all response assessments and additional interlesion variability in the drug effect on density were identified. The predictive ability of longitudinal tumor unidimensional and three-dimensional size and density on overall survival (OS) and progression-free survival (PFS) were compared using parametric time-to-event models. Death hazard increased with increasing Vactual. This framework may guide early clinical interventions based on three-dimensional tumor responses to enhance benefits for patients with gastrointestinal stromal tumors (GIST).
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Schindler
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: S M
authors.initials: SM
authors.lastname: Krishnan
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Rhj
authors.initials: R
authors.lastname: Mathijssen
authors.affiliation: Department of Radiology, Papworth Hospital NHS Foundation Trust, Cambridge University Health Partners, Cambridge, CB23 3RE, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Ruggiero
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Schiavon
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: L E
authors.initials: LE
authors.lastname: Friberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate