Evaluation of Diffusion-Weighted MRI and FDG-PET/CT to Assess Response to AdCD40L treatment in Metastatic Melanoma Patients

Abstract

The purpose was to evaluate the potential of diffusion-weighted-magnetic resonance imaging (DW-MRI) and 18F-fludeoxy-glucose-positron emission tomography integrated with CT (FDG-PET/CT) for prediction of overall survival (OS) following AdCD40L-immunotherapy in patients with metastatic malignant melanoma (MMM). Twenty-four patients with refractory MMM were treated with immunostimulatory AdCD40L gene therapy in a phase I/IIa study. Pre-therapeutic DW-MRI and FDG-PET/CT were performed and then repeated at 5 and 9 weeks post-treatment. Evaluation was conducted according to RECIST 1.1 and EORTC criteria. Apparent diffusion coefficient (ADC), true diffusion coefficient (D), maximum standardized uptake value (SUVmax) were measured in the injected lesions. Fold changes (F) in ADC (F ADC), D (F D), SUVmax (F SUVmax) were statistically assessed. F D ≥ 1 and F ADC ≥ 1 were associated with better OS in scans at week 5 and 9 respectively. F SUVmax was not correlated to OS. F ADC ≥ 1 in both post-treatment scans and F D ≥ 1 at week 5 were related to a significant decrease of size of the injected lesions. These results suggest that in patients with MMM treated with AdCD40l, functional parameters of DW-MRI are better early predictors of OS than the established metabolic and morphologic criteria for FDG-PET/CT and MRI, respectively.

Multiparametric MRI of early tumor response to immune checkpoint blockade in metastatic melanoma

“…An increase in ADC measured on DWI (equivalent to the D app measured here) has also been reported in previously treated ocular melanoma responding to immunostimulatory adenoviral CD40L gene therapy: ≥1 fold change in ADC at week 5 following treatment was a better predictor of objective survival than metabolic changes on 18 F-FDG PET and tumor size changes on MRI. 35 Interestingly, in our study, an increase in cell density (or lower D app ) was detected in the pseudoprogressive lesions at 12 weeks compared with the responding lesions, despite reduced tumor volumes measured on the 12-week MRI and standard restaging CT. No significant correlation between D app and tumor volume was detected across the imaging timepoints, which implies that the estimation of cell density based on water diffusion within the tumor microenvironment is independent of tumor volume and is therefore an important additional metric to measure. A higher degree of tumor heterogeneity, as assessed by an increase in K app , was detected in the pseudoprogressive lesions throughout the MRI imaging timepoints, compared with the responding lesions.…”

Multiparametric MRI of Early Tumor Response to Immune Checkpoint Blockade in Metastatic Melanoma

“…Further reductions in cell density within the responding lesions were detected at the 12-Weeks MRI. An increase in ADC measured on diffusion-weighted imaging (equivalent to the D app measured here) has also been reported in previously treated ocular melanoma responding to immunostimulatory adenoviral CD40L gene therapy: ≥ 1-fold change in ADC at week 5 following treatment was a better predictor of objective survival than metabolic changes on 18 F-FDG PET and tumor size changes on MRI 34 . Interestingly, in our study, an increase in cell density (or lower D app ) was detected in the pseudoprogressive lesions at 12-Weeks compared to the responding lesions despite reduced tumor volumes measured on the 12-Weeks MRI and standard restaging CT. No significant correlation between D app and tumor volume was detected across the imaging timepoints, which implies that the estimation cell density based on water diffusion within the tumor microenvironment is independent of tumor volume and is therefore an important additional metric to measure.…”

MRI techniques for immunotherapy monitoring

“…In contrast, several other researchers have reported an increase in tumor ADC following treatment with T cell-directed immunotherapy which may correspond to the later effects of cell death: a ≥1-fold increase in ADC at 5 weeks following immunostimulatory adenoviral CD40L gene therapy in previously treated ocular melanoma was shown to be a better predictor of objective survival than metabolic changes detected on [ 18 F]FDG PET and tumor size changes detected on MRI. 50 Similarly, in a recent multiparametric MRI study ( figure 1 ) on treatment-naïve patients with metastatic melanoma, a significant increase in median apparent diffusivity ( D app , equivalent to ADC ) measured on DKI was detected in both responding and pseudoprogressive lesions as early as 3 weeks following immune checkpoint blockade. 5 Treatment-induced changes in tumor cellularity detected on DKI was found to be independent of the tumor volume.…”