Open AccessPharmacometric Modeling of Liver Metastases' Diameter, Volume, and Density and Their Relation to Clinical Outcome in Imatinib‐Treated Patients With Gastrointestinal Stromal Tumors
Author(s) -
Schindler E,
Krishnan SM,
Mathijssen RHJ,
Ruggiero A,
Schiavon G,
Friberg LE
Publication year - 2017
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12195
Subject(s) - imatinib , gist , medicine , oncology , stromal tumor , proportional hazards model , hazard ratio , logistic regression , stromal cell , radiology , pathology , confidence interval , myeloid leukemia
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 (V actual ) 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 V actual . This framework may guide early clinical interventions based on three‐dimensional tumor responses to enhance benefits for patients with gastrointestinal stromal tumors (GIST).