Glioma is the most common primary brain tumor with a poor prognosis. Radiotherapy and chemotherapy are important post-treatments for glioma patients. As the treatments often produce new lesions that may mimic tumor recurrence (TR) on imaging, differentiating TR from treatment effects (TEs) remains a major clinical challenge that often leads to delay termination of ineffective therapies or premature termination of effective therapies. Hence, patients with suspected TR are frequently confirmed by stereotactic biopsy or surgery.

Tumor pseudoprogression and radiation necrosis are the major treatment-induced changes. Pseudoprogression is mainly a radiological definition, as a new or enlarging area of contrast agent enhancement, without argument of true tumor progression, which will decrease or stabilize without additional therapy (1). Pseudoprogression cases occur considerably in the first 12 weeks after the end of treatment (2), while 30% of pseudoprogression cases may occur after more than 3 months. Radiation necrosis generally occurs 3–12 months after radiotherapy, which is characterized histopathologically by fibrinoid necrosis of blood vessel walls, with adjacent perivascular parenchymal coagulative necrosis (3).

In recent years, several functional and molecular magnetic resonance (MR) imaging techniques have been applied to identify a more accurate imaging marker for tumor tissues, such as diffusion-weighted imaging (DWI), arterial spin labeling (ASL) imaging, dynamic susceptibility contrast-enhanced (DSC) imaging, MR spectroscopy (MRS), and amide proton transfer (APT) weighted imaging. Apparent diffusion coefficient (ADC) was quantified from DWI due to increased cellularity and extracellular space tortuosity. Relative cerebral blood flow (rCBF) quantified from ASL is a useful index for assessing tumor-induced neovascularization. Similar to the mechanism of rCBF, relative cerebral blood volume (rCBV) quantified from DSC seems to be a reliable technique to better identify glioma recurrence (4, 5). MRS is a molecular imaging technique that can invasively obtain information about cellular metabolism. A previous meta-analysis (6) reported that of the novel MR imaging techniques for assessing treatment response in high-grade gliomas, MRS showed the highest diagnostic accuracy; however, APT imaging was not included. APT imaging is a newly emerging molecular MR imaging technique that enables indirect measurement of endogenous mobile proteins and peptides in tissue, by detecting the magnetization transfer ratio (MTR) asymmetry at the offsets of ±3.5 ppm with respect to the water signal (7). Recent studies (8–10) have demonstrated the capability of APT imaging in assessment of post-treatment gliomas, which is a superior imaging technique to MRS (8), predominantly based on the fact that active tumors have higher protein/peptide content compared to areas of treatment-related effects due to tumor vascular endothelial damage, cytotoxicity and mutagenicity of alkylating agents, and reduced cell density (11). Positron emission tomography (PET) with the amino acid tracers is one of the most popular known to reflect protein metabolism in gliomas and has high accuracy in the diagnosis of patients with recurrent glioma (9). However, repeated radiation exposure from PET is not desirable for patients requiring long-term follow-up. Therefore, APT imaging has substantial benefit in that it uses an off-resonance radiofrequency (RF) pulse to detect endogenous mobile proteins and peptides within recurrent gliomas without ionizing radiation. Another clinical advantage of APT imaging is that it is non-invasive with no need for exogenous contrast and is a reproducible technique, which can be a potential alternative to DSC perfusion, especially in patients where contrast agent is contraindicated (12).

However, the diagnostic performance of APT imaging in assessing the response of glioma after treatment has not been systematically evaluated. Therefore, the purpose of this meta-analysis study was to evaluate the single and added value of APT imaging in differentiating TR from TE in patients with post-treatment gliomas.

This meta-analysis followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses to diagnostic test accuracy checklist (13). Two reviewers (Kai Chen and Xi-wen Jiang) performed the article search, study selection, data extraction, and quality assessment independently. Disagreements were resolved by consensus-based discussion with a third reviewer (Hua-Long She, with 13 years of neuroimaging experience).

In this meta-analysis, we evaluated the value of APT imaging in the evaluation of post-treatment response in glioma patients. Our results indicate that APT imaging is an exciting prospect in distinguishing glioma recurrence from TE, especially when combined with other multiparametric MRI parameters.

Compared to the previous mate analysis (6), we found that the diagnostic accuracy of APT imaging was similar to the nCBV derived from DSC and higher than the ADC derived from DWI, but was lower than MRS, both of which were commonly used imaging biomarkers in multiparametric MRI for the determination of treatment response after chemoradiotherapy in patients with glioblastoma (5). However, these were indirect comparisons, and only allowing all techniques to be tested in the same population would overcome the main limitation.

Mixed response in post-treatment glioma can result from a variety of nontumorous processes, including ischemia, postsurgical changes, treatment-related inflammation, subacute radiation effects, and radiation necrosis (17). rCBV and rCBF were useful indices for assessing tumor-induced neovascularization. Nevertheless, inflammation can also lead to increased value. On DWI, recurrent tumors may show reduced ADC due to increased cellularity and extra-cellular space tortuosity, but radiation necrosis may also show diffusion restriction, presumably due to intracellular edema and viscous material in the transition zone (21). Consequently, increased rCBV and rCBF does not always mean viable tumor angiogenesis, and decreased ADC values do not always mean high cellularity. Various metabolic ratios were used in the MRS studies. However, choline (Cho)/creatine (Cr) peak-area ratio was identified as the best predictor in identifying recurrent glioma after the post-treatment (6). Cho peak is one of the most important indicators in evaluating brain tumor proliferation. Cr peak maintains certain stability in the development of many diseases; thus, it is often used as a reference. In practice, MRS is more technically challenging and the voxel sizes are relatively large. Ideally, any technique that can reliably detect glioma proliferation within a larger area of TEs should cover the entire radiation volume.

APT imaging provides different regional information and increases the diagnostic value for multiparametric MRI, while the best cutoff values for the advance MRI techniques precisely distinguishing post TR from TE were arbitrary because of the heterogeneity in the biological activity of glioma and the use of different MRI systems. Of the four studies using multiparametric MRI combined with APT, one study (17) used the predefined thresholds from the literature by using the following cutoff values: APT > 1.79 (11) and rCBV > 5.6 (22), resulting in a slight increase in sensitivity, but a significant decrease in specificity. After excluding the study, the heterogeneities across the three studies in terms of pooled sensitivity and specificity were significantly reduced (Figure 4), whereas the diagnostic performance was not significantly superior to the results reported in a previous meta-analysis (5), which used multiparametric MRI but not combined with APT, with a pooled sensitivity and specificity of 0.84 (95% CI: 0.74–0.91) and 0.95 (95% CI: 0.83–0.99), respectively. However, the fact that meta-analysis only evaluated the value of multiparametric MRI for the determination of early treatment response, the studies containing mixed TE cases, such as pseudoprogression occurring after more than 3 months and radiation necrosis, were excluded. A potential source of heterogeneity among the studies using single APT imaging parameters to differentiate TR from TE might be the use of different sequences. One study used 2D SE-EPI sequence, which has low signal intensity and small differences between TR and TE groups, while relatively high estimated sensitivity and specificity were obtained in the studies using a 3D GRASE sequence. The 3D GRASE APT imaging technique has been confirmed to have reliable image quality and reasonable scan time (23).

This mate analysis used the Bayesian approach. Bayesian inference adds a small amount of informative priors that can stabilize the analysis without overwhelming data (24), as opposed to the frequentist methods that express the initial uncertainty with a prior distribution. Bayesian bivariate meta-analyses have advantages in estimating the heterogeneity among studies and pooled effect, especially when the number of studies included is small (25).

The limitations of this study include a relatively small number of studies. In addition, the mean intervals between the end of post-treatment and APT imaging were varied among studies, leading to the inclusion of several stages of treatment-related changes. However, a previous meta-analysis found no difference between early follow-up studies and studies that were conducted more than 3 months after CCRT (6). Additionally, we did not evaluate the publication bias, and another study raised a similar concern about the studies using APT in differentiating TR from TE, which consistently report positive results (26). Lastly, the repeatability of APT signal was excellent in supratentorial locations, while it was poor in infratentorial locations due to severe B0 inhomogeneity and susceptibility, which affects MTR asymmetry (27), and the locations of the glioma were not mentioned in the included studies. Nevertheless, caution is required when applying our results to daily clinical practice.

This mini-Bayesian bivariate meta-analysis disclosed that APT imaging has high diagnostic performance in evaluating treatment response in patients with post-treatment gliomas, and the addition of APT imaging to other advanced MRI techniques can improve the diagnostic accuracy for distinguishing TR from TE. However, based on the current evidence from a small number of studies, further evaluation is required.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

H-LS contributed to the study design, KC and X-WJ contributed to literature search, collection, and assembly of data. Data analysis was performed by KC and L-JD. KC wrote the first draft of the manuscript. H-LS and L-JD revised and edited the manuscript. All authors read and approved the final version.

This work was supported by the Science and Technology Planning Project of Chenzhou City, Hunan Province [zdyf 201973 and zdyf 20201811].

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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