MRI Response Assessment in Glioblastoma Patients Treated with Dendritic-Cell-Based Immunotherapy

Abstract

Introduction: In this post hoc analysis we compared various response-assessment criteria in newly diagnosed glioblastoma (GB) patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression-free survival (PFS) and overall survival (OS). Methods: 76 patients enrolled in a multicenter phase II trial receiving standard of care (SOC, n = 40) or SOC + Audencel vaccine (n = 36) were included. MRI scans were evaluated using MacDonald, RANO, Vol-RANO, mRANO, Vol-mRANO and iRANO criteria. Tumor volumes (T1 contrast-enhancing as well as T2/FLAIR volumes) were calculated by semiautomatic segmentation. The Kruskal-Wallis-test was used to detect differences in PFS among the assessment criteria; for correlation analysis the Spearman test was used. Results: There was a significant difference in median PFS between mRANO (8.6 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.0 months), RANO (4.2 months) and Vol-RANO (5.4 months). For the vaccination arm, median PFS by iRANO was 6.2 months. There was no difference in PFS between SOC and SOC + Audencel. The best correlation between PFS/OS was detected for mRANO (r = 0.65) and Vol-mRANO (r = 0.69, each p < 0.001). A total of 16/76 patients developed a pure T2/FLAIR progressing disease, and 4/36 patients treated with Audencel developed pseudoprogression. Conclusion: When comparing different response-assessment criteria in GB patients treated with dendritic cell-based immunotherapy, the best correlation between PFS and OS was observed for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel.

Keywords: glioblastoma; iRANO; immunotherapy; mRANO; radiologic response criteria; volumetric measurements.

Figure 1

Post-OP and follow-up MRI scans of patient VAX_0083 (Audencel-arm): T2- (b,d,f,h,j,l) and postgadolinium T1-weighted MRI sequences (a,c,e,g,i,k) are displayed. This figure illustrates the different time points of progression by different response assessments. At the first follow-up scan (c,d), a new contrast-enhancing lesion is seen on postgadolinium T1-weighted MRI sequences (c) and a significant increase or ≥100% increase in volume of non-enhancing abnormalities (d) compared to the post-OP scan (baseline, (b)) is seen. Progressive disease (PD) by MacDonald, RANO, Vol-RANO, while preliminary progressive disease (pPD) by mRANO, Vol-mRANO is diagnosed. Because the first follow-up MRI (c,d) is within the first six weeks of immunotherapy-treatment start, pPD by iRANO is defined. In the second follow-up MRI (e,f) this patient is diagnosed with pseudoprogression (PsP) because no further ≥25% increase in the cross-section area or ≥40% increase in total volume of the contrast-enhancing tumor mass is seen (e) compared to the first follow-up MRI (c). In the third follow-up MRI (g,h) the contrast-enhancing tumor mass does not increase in size (g) compared to the second follow-up MRI (e), hence stable disease (SD) by mRANO and Vol-mRANO is defined. In the fourth follow-up MRI (i,j), confirmed progressive disease (cPD) by iRANO is defined, as a significant increase in non-enhancing abnormalities (j) compared to the post-OP scan (baseline, (b)) is seen and this scan (i,j) is ≥3 months after the first follow-up MRI (c,d), where pPD by iRANO was diagnosed. In the fifth follow-up MRI (k,l) a ≥25% increase in the cross-section area or ≥40% increase in total volume of the contrast-enhancing tumor mass (k) compared to the second follow-up MRI (e) is seen and PD by mRANO and Vol-mRANO is diagnosed.

Figure 2

Post-OP and follow-up MRI scans of patient VAX_0066 (Audencel-arm): T2- (b,d,f,h,j,l) and postgadolinium T1-weighted MRI sequences (a,c,e,g,i,k) are displayed. This figure illustrates the progression of non-enhancing abnormalities. At the first follow-up MRI (c,d) non-enhancing abnormalities are decreased and no contrast-enhancing tumor mass is seen compared to post-OP (a,b) where no measurable disease is seen. Hence, the patient is defined as stable disease (SD) by all assessment criteria.Therefore, the first follow-up MRI (c,d) is used as baseline MRI, as it shows the best response. The second follow-up MRI (e,f) still shows SD compared to baseline (c,d). At the third follow-up MRI (g,h) an increase in non-enhancing abnormalities (corpus callosum, (h)) compared to T2-weighted sequence of the first follow-up (d) is seen. On the fourth- (i,j) and fifth follow-up scans (k,l), T2-changes are further increased (j,l). On T1-weighted MRI scans from first to fifth follow-up (c,e,g,i,k), no measurable contrast-enhancing tumor mass is seen, including the last T1-weighted follow-up MRI scan (k).