Combination of IVIM-DWI and 3D-ASL for Differentiating True Progression from Pseudoprogression of Glioblastoma Multiforme After Concurrent Chemoradiotherapy: Study Protocol of a Prospective Diagnostic Trial

Background: Standard therapy for Glioblastoma multiforme (GBM) involves maximal safe tumor resection followed with radiotherapy and concurrent adjuvant temozolomide. About 20 to 30% patients undergoing their first post-radiation MRI show increased contrast enhancement which eventually recovers without any new treatment. This phenomenon is referred to as pseudoprogression. Differentiating tumor progression from pseudoprogression is critical for determining tumor treatment, yet this capacity remains a challenge for conventional magnetic resonance imaging (MRI). Thus, a prospective diagnostic trial has been established that utilizes multimodal MRI techniques to detect tumor progression at its early stage. The purpose of this trial is to explore the potential role of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and three-dimensional arterial spin labeling imaging (3D-ASL) in differentiating true progression from pseudoprogression of GBM. In addition, the diagnostic performance of quantitative parameters obtained from IVIM-DWI and 3D-ASL, including apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), perfusion fraction (f), and cerebral blood flow (CBF), will be evaluated.

Methods: Patients that recently received a histopathological diagnosis of GBM at our hospital are eligible for enrollment. The patients selected will receive standard concurrent chemoradiotherapy and adjuvant temozolomide after surgery, and then will undergo conventional MRI, IVIM-DWI, 3D-ASL, and contrast-enhanced MRI. The quantitative parameters, ADC, D, D*, f, and CBF, will be estimated for newly developed enhanced lesions. Further comparisons will be made with unpaired t-tests to evaluate parameter performance in differentiating true progression from pseudoprogression, while receiver-operating characteristic (ROC) analyses will determine the optimal thresholds, as well as sensitivity and specificity. Finally, relationships between these parameters will be assessed with Pearson's correlation and partial correlation analyses.

Discussion: The results of this study may demonstrate the potential value of using multimodal MRI techniques to differentiate true progression from pseudoprogression in its early stages to help decision making in early intervention and improve the prognosis of GBM.

Trial Registration: This study has been registered at ClinicalTrials.gov ( NCT02622620 ) on November 18, 2015 and published on March 28, 2016.