This study investigated the predictive value of the contrast enhancing pattern on pre-treatment MRI for stratifying patients with IDH-wild type recurrent glioblastoma according to treatment response on anti-angiogenic treatment. In the CEL dominant group, bevacizumab showed a clear benefit (longer PFS) compared with temozolomide, but in the NEL dominant group, bevacizumab showed no benefit, but rather harm (shorter PFS) compared with temozolomide. These results suggest that patients with the CEL dominant type might have a better treatment response to anti-angiogenic treatment, and that the contrast enhancing pattern seems to be a promising predictive imaging biomarker for pre-treatment stratification of patients according to predicted treatment response on anti-angiogenic treatment.
Contrast enhancing tumor represents the angiogenic component of glioblastoma,, which tends to be driven by VEGF . Overexpression of VEGF in contrast enhancing tumor promotes angiogenesis, forming immature tumor vessels with excessive leakiness, which can contribute to disruption of the blood–brain barrier (BBB) [23, 24]. Furthermore, contrast enhancing tumor is thought to be the site of increased proteolysis, with the presence of matrix metalloproteinases, destruction of the basement membrane, and increased vascular density and permeability . Therefore, the combination of increased VEGF level and efficient drug delivery with increased vascular permeability and microvascular density in CEL dominant type glioblastoma might result in favorable treatment outcomes with anti-angiogenic treatment targeting VEGF signaling. Pope et al.  revealed that anti-VEGF therapy suppresses contrast enhancing tumor more effectively than non-enhancing tumor in the same patient. Liu et al.  described a subgroup of patients with elevated perfusion features (angiogenic subgroup) that were associated with poor overall survival, but significantly better survival when treated with anti-angiogenic treatment than not treated.
There are several potential imaging biomarkers for antiangiogenic treatment, with a low pre- or post-treatment rCBV, low change in rCBV during treatment, low pre-treatment Ktrans, low pre-treatment ADC values for the lower peak of bimodal histogram anlalysis, and small ADC volume changes during treatment all indicating a good prognosis [6–9, 27]. However, these observations are limited because the imaging studies describing them did not include a temozolomide treatment group as a comparison, and they can only be considered as prognostic markers, rather than predictive markers of treatment. Furthermore, their predictions were based on advanced MRI techniques (including perfusion-weighted imaging and diffusion-weighted imaging) or differences in MRI features between pre- and post-treatment examinations. Here, we describe a potential predictive imaging biomarker using the contrast enhancing pattern on conventional MRI for the pre-treatment stratification of patients according to the predicted treatment effect of anti-angiogenic therapy in comparison with temozolomide.
Non-enhancing tumor that appears as T2 FLAIR hyperintensity represents the invasive or migratory component of glioblastoma, from which viable and proliferating tumor cells invade adjacent highly vascularized normal tissue . Tumor cells in such areas can co-opt the pre-existent normal vasculature to acquire their blood supply and metabolic support . These co-opted vessels are refractory to anti-angiogenic treatment and offer an efficient escape mechanism against anti-angiogenic therapy . Disruption of the BBB is an important factor in transendothelial diffusion of anticancer agents, because large molecules have difficulty passing the BBB if it is not fully disrupted [30, 31]. Non-enhancing tumor tends to have a relatively intact BBB, and this might explain the low treatment efficacy of bevacizumab (molecular weight = 149 kDa) in comparison with temozolomide (molecular weight = 194 Da) in patients with NEL dominant type glioblastoma. Although the importance of non-enhancing tumor in glioblastoma has been emphasized in recent studies [32, 33], the prognostic and predictive values of non-enhancing tumor in recurrent glioblastoma are poorly understood. Molecular imaging techniques such as amide proton transfer imaging  may produce helpful imaging biomarkers for NEL after antiangiogenic therapy, but further study is required to investigate their use as predictive imaging biomarkers for stratifying patients with NEL dominant type glioblastoma according to treatment response.
In this study, we performed quantitative volumetric analysis using deep learning segmentation, which segmented the enhancing tumor region, necrotic tumor region, and T2 FLAIR high signal intensity region on CE-T1WI and FLAIR images. This quantitative analysis matched with the qualitative determination (index biomarker) of the contrast enhancing pattern, which showed substantial agreement between two readers. This result suggests that the contrast enhancing pattern is a reliable and reproducible imaging biomarker that can be generally accepted in multicenter clinical practice.
Radiographic progression patterns have been categorized using standard-of-care imaging into local enhancing, diffuse non-enhancing, and distant progression types [11, 20]. Our study found the frequencies of these progression patterns varied depending on the secondary treatment. A substantial proportion of patients treated with bevacizumab showed diffuse non-enhancing progression, whereas a substantial proportion of patients treated with temozolomide showed local enhancing progression. Diffuse non-enhancing progression is promoted by prolonged blockade of vascular proliferation and tumor escape through vascular co-option, whereas local enhancing progression indicates failure of local disease control . Several previous studies have shown that anti-VEGF therapy facilitates co-option of the normal vasculature and tumor invasion, consequently promoting non-enhancing diffuse tumor infiltration [35, 36]. Our findings are consistent with a previous meta-analysis, in that high-grade glioma patients tend to show non-local or non-enhancing radiologic patterns of recurrence after bevacizumab , which may suggest that bevacizumab effectively controls local tumor growth, but either fails to control or actually promotes distant and diffuse recurrences.
This study has several limitations in addition to those due to its retrospective nature. First, histological confirmation was not possible at the time of radiographic progression because of the invasiveness of the required procedures. Second, the number of patients treated with temozolomide was relatively small because bevacizumab is the major standard treatment for recurrent glioblastoma in our institution. Third, we did not incorporate the results of advanced MRI, including DWI and perfusion-weighted imaging, which increase the diagnostic accuracy of progression and help to assess treatment response. However, the lack of standardization in advanced imaging protocols has prevented their use as reproducible imaging biomarkers in multicenter practices.
In conclusion, we found that patients with CEL dominant type recurrent glioblastoma had a better treatment response to bevacizumab than those with the NEL dominant type. The contrast enhancing pattern on pre-treatment MRI can be used as a reliable and reproducible imaging biomarker to stratify patients according to treatment response on anti-angiogenic treatment, and to personalize treatment planning in patients with IDH wild-type recurrent glioblastoma.