Volumetric measurements are preferred in the evaluation of mutant IDH inhibition in non-enhancing diffuse gliomas: Evidence from a phase I trial of ivosidenib

Abstract

Background: Since IDH-mutant (mIDH) low-grade gliomas (LGGs) progress slowly and have a relatively long survival, there is a significant need for earlier measurements of clinical benefit. Guidance using the LGG RANO criteria recommends serial bidirectional (2D) measurements on a single slice; however, questions remain as to whether volumetric (3D) measurements are better, since they would allow for more accurate measurements in irregular shaped lesions and allow readers to better assess areas of subtle change.

Methods: Twenty-one (out of 24) non-enhancing, recurrent mIDH1 LGGs were enrolled in a phase I, multicenter, open-label study of oral ivosidenib (NCT02073994), and with imaging pre- and post-treatment as part of this exploratory ad hoc analysis. 2D and 3D measurements on T2-weighted FLAIR images were centrally evaluated at an imaging contract research organization using a paired read and forced adjudication paradigm. The effects of 2D vs 3D measurements on progression-free survival (PFS), growth rate measurement variability, and reader concordance and adjudication rates were quantified.

Results: 3D volumetric measurements showed significantly longer estimated PFS (P = .0181), more stable (P = .0063) and considerably slower measures of tumor growth rate (P = .0037), the highest inter-reader agreement (weighted kappa = 0.7057), and significantly lower reader discordance rates (P = .0002) with 2D LGG RANO.

Conclusion: 3D volumetric measurements are better for determining response assessment in LGGs due to more stable measures of tumor growth rates (ie, less "yo-yo-ing" of measurements over time), highest inter-reader agreement, and lowest reader discordance rates. Continued evaluation in future studies is warranted to determine whether these measurements reflect clinical benefit.

Keywords: IDH-mutant gliomas; LGG RANO; ivosidenib; low-grade gliomas.

Fig. 1

Example of a IDH-mutant LGG patient measured by both 2D bidimensional (green and blue lines) and 3D volumetric measurements (red outline) at 2 different time points, a baseline time point (A) and the subsequent time point (B) 60 days (eg, cycle 3 day 1, first response assessment per protocol) later. While 2D measurements show a 33% reduction in bidimensional product, volumetric measurements only showed a 4% reduction in total volume. Abbreviation: LGG, low-grade gliomas.

Fig. 2

Waterfall plots showing (A) “best response” using 2D bidirectional measurements and (B) 3D volumetric measurements after implementing a retrospective, consensus review where all readers agree on the measurements. (C) Concordance in “best response” for individual patients and (D) concordance in all time-point responses using 2D and 3D measurements after retrospective, consensus review by all radiologists.

Fig. 3

(A) Spider plot showing percentage change in tumor size using 2D bidirectional measurements and (B) 3D volumetric measurements with respect to baseline or nadir for all patients. Arrows show examples of potential “yo-yo-ing” from erroneous 2D measurements. (C) Measurement variation estimates using the distribution of residuals (errors) after model fitting to 2D and 3D growth rate estimates. (D) Kaplan-Meier curves comparing progression-free survival (PFS) between 2D and 3D measurements.