Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma

Abstract

Introduction We describe the imaging findings encountered in GBM patients receiving immune checkpoint blockade and assess the potential of quantitative MRI biomarkers to differentiate patients who derive therapeutic benefit from those who do not. Methods A retrospective analysis was performed on longitudinal MRIs obtained on recurrent GBM patients enrolled on clinical trials. Among 10 patients with analyzable data, bidirectional diameters were measured on contrast enhanced T1 (pGd-T1WI) and volumes of interest (VOI) representing measurable abnormality suggestive of tumor were selected on pGdT1WI (pGdT1 VOI), FLAIR-T2WI (FLAIR VOI), and ADC maps. Intermediate ADC (IADC) VOI represented voxels within the FLAIR VOI having ADC in the range of highly cellular tumor (0.7–1.1 × 10−3 mm2/s) (IADC VOI). Therapeutic benefit was determined by tissue pathology and survival on trial. IADC VOI, pGdT1 VOI, FLAIR VOI, and RANO assessment results were correlated with patient benefit. Results Five patients were deemed to have received therapeutic benefit and the other five patients did not. The average time on trial for the benefit group was 194 days, as compared to 81 days for the no benefit group. IADC VOI correlated well with the presence or absence of clinical benefit in 10 patients. Furthermore, pGd VOI, FLAIR VOI, and RANO assessment correlated less well with response. Conclusion MRI reveals an initial increase in volumes of abnormal tissue with contrast enhancement, edema, and intermediate ADC suggesting hypercellularity within the first 0–6 months of immunotherapy. Subsequent stabilization and improvement in IADC VOI appear to better predict ultimate therapeutic benefit from these agents than conventional imaging.

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…Of note, ICB is known to increase the risk of oedema in patients with brain tumours, sometimes resulting in death 107,108 . This observation contrasts with the vascular normalization induced by ICB in breast cancer models 105 and suggests that the vascular effects are dependent on the tumour location and/or type — a possibility that needs to be further investigated.…”

Role of medical imaging for immune checkpoint blockade therapy: From response assessment to prognosis prediction

“…This can be explained by the fact that inflammation and necrosis caused by effective treatment would lead to prominent extracellular edema and decreased cellularity. Qin et al enrolled 10 recurrent glioblastoma patients undergoing anti‐PD‐1 therapy and observed initial volumetric expansion in tumor lesion within 0‐6 months across different imaging sequences . Potential explanations for the early increase in tumor volume were continued tumor growth due to delayed responses to immunotherapy and the infiltration of inflammatory cells, which would also reduce the ADC values of the tumor lesions .…”

“…Qin et al enrolled 10 recurrent glioblastoma patients undergoing anti‐PD‐1 therapy and observed initial volumetric expansion in tumor lesion within 0‐6 months across different imaging sequences . Potential explanations for the early increase in tumor volume were continued tumor growth due to delayed responses to immunotherapy and the infiltration of inflammatory cells, which would also reduce the ADC values of the tumor lesions . They found that stable or improved intermediate ADC volumes of interest (IADC VOI) after 6 months of therapy onset can provide more useful predictive information on therapeutic benefit compared with conventional imaging, including contrast‐enhanced T1‐weighted imaging (T1WI), FLAIR‐T2–weighted imaging (T2WI) and response assessment for neuro‐oncology (RANO) criteria measures …”

MRI in Glioma Immunotherapy: Evidence, Pitfalls, and Perspectives

“…Very recently, in a retrospective analysis of 10 recurrent GBM patients [98], intermediate ADC (IADC) volumes of interest (VOI) were able to discriminate the five patients with clinical benefit (i.e., without unequivocal clinical radiologic or histopathologic evidence of glioma progression for at least five months since trial onset) from the others. IADC VOI represented voxels within the FLAIR VOI having ADC in the range of highly cellular tumors (0.7–1.1 × 10 −3  mm 2 /s).…”

“…Two are the main approaches used: (a) the histogram approach [51, 59, 65, 89, 93, 122–125] in which the evolution of the tumor during therapy is completely and quantitatively characterized estimating the statistical parameters (number of peaks, kurtosis, skewness, and other statistical moments) of the distribution of the values inside the lesion and (b) the voxel-based approach [49, 50, 75, 126], which aims to detect predictive markers of therapeutic efficacy estimating voxel by voxel the difference between the parametric maps (mainly ADC, CBV, and K trans ) of two different temporal points [75] [49]. An excellent example is that recently provided by Qin et al in 2017 [98] based on an intermediate ADC (IADC) calculation in FLAIR VOI. In fact, the technique was able to discriminate patients with clinical benefit.…”