Research Article: ACRIN 6684: Multicenter, phase II assessment of tumor hypoxia in newly diagnosed glioblastoma using magnetic resonance spectroscopy

Date Published: June 14, 2018

Publisher: Public Library of Science

Author(s): Eva-Maria Ratai, Zheng Zhang, James Fink, Mark Muzi, Lucy Hanna, Erin Greco, Todd Richards, Daniel Kim, Ovidiu C. Andronesi, Akiva Mintz, Lale Kostakoglu, Melissa Prah, Benjamin Ellingson, Kathleen Schmainda, Gregory Sorensen, Daniel Barboriak, David Mankoff, Elizabeth R. Gerstner, Daniel Monleon.


A multi-center imaging trial by the American College of Radiology Imaging Network (ACRIN) “A Multicenter, phase II assessment of tumor hypoxia in glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI (ACRIN 6684)”, was conducted to assess hypoxia in patients with glioblastoma (GBM). The aims of this study were to support the role of proton magnetic resonance spectroscopic imaging (1H MRSI) as a prognostic marker for brain tumor patients in multi-center clinical trials. Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac). Receiver operating characteristic curves for NAA/Cho, Cho/Cr, lactate/Cr, and lactate/NAA were constructed for overall survival at 1-year (OS-1) and 6-month progression free survival (PFS-6). The OS-1 for the 17 evaluable patients was 59% (10/17). Receiver operating characteristic analyses found the NAA/Cho in tumor (AUC = 0.83, 95% CI: 0.61 to 1.00) and in peritumoral regions (AUC = 0.95, 95% CI 0.85 to 1.00) were predictive for survival at 1 year. PFS-6 was 65% (11/17). Neither NAA/Cho nor Cho/Cr was effective in predicting 6-month progression free survival. Lac/Cr in tumor was a significant negative predictor of PFS-6, indicating that higher lactate/Cr levels are associated with poorer outcome. (AUC = 0.79, 95% CI: 0.54 to 1.00). In conclusion, despite the small sample size in the setting of a multi-center trial comprising different vendors, field strengths, and varying levels of expertise at data acquisition, MRS markers NAA/Cho, Lac/Cr and Lac/NAA predicted overall survival at 1 year and 6-month progression free survival. This study validates that MRSI may be useful in evaluating the prognosis in glioblastoma and should be considered for incorporating into multi-center clinical trials.

Partial Text

Glioblastoma (GBM) is the most common and, unfortunately, the most aggressive type of primary malignant brain tumor. Despite treatments with surgery, radiation, and chemotherapy, the median overall survival is less than 15 months [1]. One of the pathologic hallmarks of GBM is tumor hypoxia resulting from an inefficient blood supply [2]. Tumor hypoxia limits the efficacy of radiation and chemotherapy and may select for a more aggressive tumor phenotype. It may also be a potent stimulator of abnormal angiogenesis [3]. Thus, a multi-center imaging trial, “American College of Radiology Imaging Network (ACRIN) 6684: A Multicenter, phase II assessment of tumor hypoxia in Glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI”, was conducted to assess hypoxia in patients with GBM.

This study reports the results of the 1H-MRSI data of the ACRIN 6684 multi-center imaging trial to assess tumor hypoxia in GBM using 18F-FMISO PET and MRI. We previously showed that increased tumor hypoxia as measured by 18F-FMISO SUVpeak was significantly associated with shorter OS-1. Furthermore, increased tumor perfusion (rCBV and rCBF,) and increased vascular permeability (median ktrans) were significantly associated with shorter PFS [4]. Since MRSI is able to measure metabolites that reflect tumor burden, it may be able to provide additional information to the previously reported MRI and PET parameters.

Despite all aforementioned challenges, 1H MRSI measures were predictive of outcome in a group of patients with GBM treated using radiotherapy and temozolomide with information that appears distinct from and complementary to DCE/DSC-MRI and hypoxia PET. Therefore, standardized MRSI should be considered for incorporation into future multi-center clinical trials and may be useful in diagnosis and in risk stratifying patients.




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