Abstract
Background Glioblastoma exhibits profound intratumoral heterogeneity in blood perfusion, which may cause the inconsistent response to angiogenesis inhibitor therapy in previous clinical trials. Particularly, low perfusion may create hypoxic microenvironment in tumor and induce resistant clones. Finding validated imaging approach to define these compartments for clinical management is crucial. The aim of this study was to use physiological magnetic resonance imaging (MRI) to identify the low perfusion compartments pretherapeutically and determine their contributions to survivals.
Methods and Findings A total of 112 newly-diagnosed supratentorial GBM patients were included in this study. Preoperative MRI included anatomical, dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI) and chemical shift imaging (CSI). All patients underwent maximal safe resection and diagnosis was confirmed by pathology. The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were calculated from DTI and DSC respectively. Using thresholding methods, two low perfusion compartments (ADCH-rCBVL and ADCL-rCBVL) were identified with combinations of high/low ADC and low rCBV values. Metabolic analysis using CSI revealed that the two compartments displayed higher lactate and macromolecule/lipid levels than abnormal and normal controls (p = 0.017 and p < 0.001, respectively), suggesting the hypoxic and pro-inflammatory microenvironment. The proportion of ADCL-rCBVL compartment contributed to larger tumor infiltration area visualized by FLAIR (p < 0.001, r = 0.40), while the proportion of ADCH-rCBVL contributed to smaller tumor infiltration (p = 0.001, r = −0.31). Higher lactate in the ADCL-rCBVL compartment was associated with more invasive phenotypes visualized on diffusion tensor imaging. Survival analysis showed the volume of ADCL-rCBVL compartment was associated with a better progression free survival (PFS) (Hazard ratio 0.490, p = 0.024) and the lactate level in this compartment contributed to a worse PFS (Hazard ratio 2.080, p = 0.049). In contrast, the lactate level in the ADCH-rCBVL compartment contributed to a better overall survival (Hazard ratio 0.571, p = 0.024), suggesting these two compartments had different treatment response.
Conclusions Two low perfusion compartments could be visualized by multiple advanced MRI techniques, which displayed heterogeneity in extent and intensity of hypoxia, and consequently exhibited diversity in tumor invasion and patient outcomes. Particularly, the ADCL-rCBVL compartment may represent a treatment target which may induce resistance.
Author Summary Why Was This Study Done?
Previous failure in clinical trials of angiogenesis inhibitor in glioblastoma may be caused by the inadequate understanding of angiogenesis.
Although tumor compartments with elevated perfusion have been investigated intensively, the low perfusion compartments are yet to be studied.
Conventional imaging approach is non-specific in revealing perfusion heterogeneity.
Whether multiple modalities of quantitative MRI may help to reveal the resistant treatment target remains unclear.
What Did the Researchers Do and Find?
We prospectively recruited 112 patients and performed multiple modality MRI scans on these patients. All the patients received maximal safe resection. After surgery, 82 patents received standard dose of chemoradiotherapy and were followed up.
We used thresholding to identify two low perfusion compartments from preoperative MRI images and studied their volumes, metabolic profiles, contributions to tumor infiltration and patient outcomes.
We found that two low perfusion compartments both displayed hypoxic and pro-inflammatory metabolic signatures, suggesting the selective stress in these regions. The lactate levels in these regions was associated with a larger tumor volume. However, two compartments showed different contributions to tumor infiltration and patient outcomes.
The ADCL-rCBVL compartment may contribute to a larger tumor infiltration area, and the higher lactate level in this region may contribute to more invasive DTI phenotypes. The higher proportion of this compartment in tumor was associated with a better progression free survival, but the lactate level in this region was associated with a worse survival.
The ADCH-rCBVL compartment had a significant higher volume than the ADCL-rCBVL compartment, and the higher lactate level in this region was associated with a better overall survival.
What Do These Findings Mean?
The findings of this study may change the notion that the invasiveness of GBM solely stems from the highly proliferative regions and support the approach of treating GBM as a dynamic ecosystem.
The imaging findings help to optimize the current clinical routine which is mainly based on non-specific conventional imaging. As the imaging modality used in this study has been available in clinical procedure, this approach could provide crucial information for patient personalized treatment and might be extended to other tumors.
Footnotes
Funding This study was funded by a National Institute for Health Research (NIHR) Clinician Scientist Fellowship (SJP, project reference NIHR/CS/009/011); Cambridge Trust and China Scholarship Council (CL); the Chang Gung Medical Foundation and Chang Gung Memorial Hospital, Keelung, Taiwan (JLY); CRUK & EPSRC Cancer Imaging Centre in Cambridge & Manchester (TT, grant C197/A16465); NIHR Cambridge Biomedical Research Centre (TM); the Groningen University Fund and the Marco Polo fund (BD). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
