Introduction
Glioblastoma (GBM) is one of the most common malignant brain tumors and has a poor prognosis. The current standard treatment for newly diagnosed GBM (nd-GBM) is maximal safe removal with concurrent temozolomide and radiation (TMZ-RT), followed by maintenance TMZ with, if possible, tumor-treating fields [
1]. Despite such multimodal treatment, the median overall survival (OS) remains less than 2 years.
In addition to these treatments, the FDA approved bevacizumab (BEV), an anti-VEGF antibody molecular-targeted drug that produces an indirect antitumor activity via inhibition of tumor angiogenesis [
2], as treatment for recurrent GBM in 2009. Thereafter, two randomized trials, AVAglio and RTOG0825, were conducted to verify the efficacy of BEV for the treatment of nd-GBM, resulting in only progression-free survival (PFS) prolongation, but failed to impact OS [
3,
4]. Accordingly, there is no robust evidence supporting the efficacy of BEV treatment for nd-GBM; however, BEV has been approved in Japan as an insurance-covered first-line drug for GBM concurrently with its second-line application, considering the benefit of maintaining patient performance status [
5]. Thereafter, Japanese institutes, including ours, have launched several real-world studies, which indicate the clinical benefits of optional first-line BEV for patients with severe clinical conditions [
1,
6‐
10]. Practically, we selected first-line BEV for patients with unresectable GBM and accumulated the clinical data [
11]. These case series revealed that the radiographic course following first-line BEV for unresectable tumors varied among patients, and its outcome was considered an unresolved issue that needs to be addressed.
In the response judgment of GBM, gadolinium-enhanced T1-weighted image (GdT1WI) measurement based on the Macdonald criteria has generally been applied [
12]. However, in BEV treatment for GBM, apparent tumor reduction on GdT1WI, the so-called pseudo-response, can be observed at an earlier time. Therefore, the evaluation of response using GdT1WI alone may overestimate the therapeutic effect of BEV. This type of complicated radiographic response during BEV treatment was taken into consideration, and the Response Assessment in Neuro-Oncology (RANO) criteria added the evaluation of non-enhanced lesions using T2/FLAIR [
13]. Consequently, integrated evaluation based on multiple magnetic resonance imaging (MRI) sequences became essential for the assessment of treatment response; however, the association between complicated radiographic response and clinical outcome remains a controversial issue.
Only a limited number of studies have explored the relationship between radiographic response and clinical outcome following BEV treatment for nd-GBM [
14,
15]. In this study, we retrospectively examined the detailed radiographic response using MRI scans during TMZ-RT combined with BEV for unresectable nd-GBM, and aimed to elucidate the relationship between early radiographic response and clinical outcome.
Discussion
We analyzed the impact of radiographic changes during BEV-containing chemoradiotherapy for unresectable nd-GBM. As a result, while changes in DWI and FLAIR images did not have a significant impact, only GdT1WI improvement was associated with significant OS prolongation. The Macdonald criteria applied to GdT1WI have been the standard for determining the treatment response of GBM. The RANO criteria added FLAIR image progression to predict pseudo-response [
12,
13]. In previous reports, the relationship between the radiographic response assessed by the RANO criteria and survival outcome following BEV treatment was analyzed in patients with recurrent GBM. Ellingson et al. reported that the changes in FLAIR and GdT1WI were not related to both PFS and OS, and the pre-treatment ratio of FLAIR to contrast-enhancing volume was a predictive marker of both PFS and OS [
27]. Boxerman et al. reported that early progression of GdT1WI was a poor prognostic factor for OS and that changes in FLAIR images showed no significant impact on OS [
28]. Both studies investigated recurrent GBM, and the therapeutic situations were different from those for nd-GBM. These two studies indicated that quantitative FLAIR improvement showed no significant correlation with OS because BEV treatment improved FLAIR hyperintensity with an anti-permeability effect and supported our results that an early response on FLAIR images is not likely to reflect the survival outcome after BEV treatment. It is speculated that FLAIR progression is useful for differentiating the pseudo response and that FLAIR improvement does not indicate an antitumor effect. An exploratory analysis of AVAglio classified the type of radiologic progression of nd-GBM treated with TMZ-RT and BEV, revealing that CR in the GdT1WI group showed longer OS than that in the PR group [
12]. Our results indicated that even PR on GDT1WI could have a survival impact in real-world clinics. The discrepancy between AVAglio and our results might be due to differences in the background characteristics. Our case series consisted of patients with severe clinical conditions that were more likely to be excluded from clinical trials due to their strict inclusion criteria. In addition, the extent of resection should be taken into consideration because CR on GdT1WI is likely to occur after treatment of patients with near completely resected tumors, while there were very few such cases included in our cohort. The impact of GdT1WI improvement in clinical practice is currently an unsolved issue to be elucidated by the accumulation of clinical reports from Japanese institutes where BEV is approved for treatment of nd-GBM.
Other MRI sequences were analyzed for their impact on outcome. DWI has been recognized as a promising sequence for the prediction of the response to BEV treatment because the apparent diffusion coefficient level can reflect the cellularity of tumor tissues [
29]. Yamasaki et al. reported that DWI can distinguish the pseudo-response from true response after BEV treatment for recurrent GBM, and the evaluation based on the RANO criteria predicted OS more precisely when combined with DWI change, suggesting that DWI can clearly demonstrate the true extent of the tumor area at an early point [
12]. In this study, DWI evaluation was performed according to the method of Yamasaki et al.; however, there was no correlation between the OS and DWI responses. It is noteworthy that the impact of radiotherapy should be considered when discussing these issues because the treatment situation is different between nd- and recurrent GBM. Regarding nd-GBM, relative cerebral blood volume (rCBV) is attracting attention for its association with the response to BEV treatment. An exploratory analysis of RTOG0825 revealed OS prolongation with BEV treatment in the high pretreatment rCBV group compared to the placebo group [
30]. However, rCBV changes during BEV treatment did not show an impact on OS in both nd- and recurrent GBMs [
30,
31]. Another recent study focused on the contrast between DWI and perfusion images to generate an automated threshold by measuring the hypercellular tumor volume and hyperperfused tumor volume and showed that the ratio changes of these two values during chemoradiotherapy had an impact on OS [
32]. On the other hand, they reported that significant GdT1WI volume reduction during chemoradiotherapy was also observed; however, the GdT1WI volume change was not correlated with OS. Nonetheless, the treatment situation in this study was also different from that in ours, in which chemoradiation included BEV administration. Further studies including multiple MRI sequences are warranted to confirm the relationship between early radiographic response and outcome in clinical situations where first-line BEV is approved.
Our study revealed that Gd-improvement evaluated not only by the RANO criteria but also by neuroradiologist’s impression can predict the outcome of unresectable GBM treated with BEV-combined regimen. In addition, the extent of GD-SPPD improvement correlated with significant outcome impact ranging from 20 to 50%, similar to the GD-IP and GD-SPPD thresholds. In other words, OS prolongation can be predicted even in cases when GD-improvement is insufficient to determine PR according to the RANO criteria. These results indicated that, for outcome prediction, evaluation by a neuroradiologist hinted at a clinically appropriate response judgment of BEV-combined treatment for nd-GBM. The criteria of radiographic response by measuring contrast-enhancement lesions have been consistently used from the Macdonald criteria to the RANO criteria [
12,
13]. McDonald's standard was created based on the WHO oncology response criteria, which is a general diagnostic imaging standard for solid tumors [
33]; therefore, the measurement protocol for contrast-enhancement lesions has not been changed for more than 20 years. Our results propose the possibility that some patients evaluated as SD by the RANO criteria may have a good prognosis and suggest an alternative threshold value for identifying the group with a good prognosis [
26].
Our study has several limitations. First, this was a single-center, non-randomized, retrospective study that included a small number of patients. Hence, our results should be verified in a larger cohort. As first-line BEV for GBM has not been approved outside of Japan, a multi-institutional clinical study involving several Japanese facilities is desirable. Second, subsequent treatments were inconsistent among the enrolled patients, which might have affected the outcome. Third, the analyzed image sequences were limited to only DWI, Gd, and FLAIR, and other sequences such as rCBV may be more significant predictors. Fourth, while there existed a correlation between the extent of GD-improvement and outcome, how the background bioactivity attributed to such a relationship was unclear. In the present study, univariate analysis for molecular markers revealed an unmethylated
MGMT status, and
CDKN2A homozygous deletion showed a trend toward poor prognosis. Our recent study also reported that MGMT and CDKN2A status could stratify Japanese GBM patients into three race-specific groups with different prognoses [
26]. Further accumulation of studies including molecular-genetic signatures and evidence beyond real-clinic data are warranted to evaluate the significance of image changes during BEV-included regimens for unresectable GBM.
Conclusions
We examined the radiographic response in multiple MRI sequences (FLAIR, Gd-SPPD, and DWI) in patients with unresectable nd-GBM treated with BEV-including chemoradiotherapy and proved that the Gd-SPPD improvement group showed a significant prolongation of OS. Furthermore, the OS impact was significant even with less strict judgment of radiographic response compared with that of the RANO criteria. This raised the possibility that some patients evaluated as SD by the RANO criteria may have a good prognosis, and the interpretation of neuroradiologists likely hinted at an alternative evaluation for outcome prediction.
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