This retrospective study had been approved by the institutional review board at our institution and informed consent was obtained from all individual participants included in the study.
Patients And Meningiomas
Included into the retrospective study were 70 patients between 27 and 81 (mean 56) years of age, who had been diagnosed as carriers of an intracranial low-grade meningioma and had been treated by SRS at our Gamma Knife center. Pre-operated cases with a histologic diagnosis of a higher grade than grade 1 were excluded as well as cases with multifocal lesions. Further inclusion criteria were a pre-treatment MRI measured during the last two months before SRS, an “early” follow-up (FU) MRI approximately 6 months after SRS to examine changes of diffusion parameters, and a late FU MRI after a period of 18 months or more to assess for tumor response after SRS. MRI images with obvious movement or susceptibility artifacts were excluded. MR acquisition included pre- and post-treatment DWI and DTI sequences, to allow for subtractions to access for radiation-induced changes of the parameter values.
We were able to retrieve histology results from 9 of 33 cases in which a preceding operation was documented. All operated cases followed subtotal resection; no recurrent meningioma was included to this study. Six of the tumors were characterized as meningothelial and psammomatous meningioma, three as a fibroblastic subtype, all without atypical features. Cases without known histology were assigned as WHO grade I, based on criteria such as homogeneously enhancing, dural tails, no extension through cranial foramina, no substantial peritumoral edema, no significant lobulations47. 58 meningiomas (83%) were localized at the cranial base, 9 meningiomas were localized at the convexity, and 3 meningiomas were localized at the tentorium.
MRI had been performed within 2 months before their GKRS, and follow-up data from at least one early FU MR scan (range 2.4–15.2 months, mean 7.2 months) and one late FU MR scan (range 17.0–108.1 months, mean 52.7 months) were available (Table 1).
Table 1
Patients and treatment characteristics
Patient and treatment characteristics | Value | Range |
Number of patients | 70 | - |
Age in years (mean, range) | 55.8 | (26.6 / 81.3) |
Pre-SRS tumor volume in cm3 (mean, range) | 9.58 | (0.62 / 33.09) |
Previous RT, SRS | 0 | - |
Previous surgery | 33 | - |
KPS before SRS | 90.6 | (60 / 100) |
Single fraction SRS treatments | 63 | - |
Hypofractionated SRS treatments | 7 | - |
Number of Fractions (mean, range) | 1.29 | (1 / 4) |
Coverage index (mean, range) | 96.6% | (87.0% / 99.0%) |
Selectivity index (mean, range) | 66.0% | (17.0% / 91.0%) |
Paddick conformity index (mean, range) | 63.8% | (16.8% / 88.3%) |
Margin physical Dose in Gy (mean, range) | 14.4 | (11 / 20) |
Maximum physical Dose in Gy (mean, range) | 28.8 | (22 / 40) |
Margin BED in Gy (mean, range) | 63.1 | (43.2 / 104.2) |
Margin SFED in Gy (mean, range) | 13.5 | (11.0 / 18.0) |
Abbreviations: SRS, stereotactic radiosurgery; RT, radiotherapy, GK, gamma knife; BED, biologically effective dose; SFED, single fraction equivalent dose; |
Gamma Knife Treatment
All treatment were performed using a Gamma Knife model 4C (Elekta AB, Stockholm, Sweden). Details of the GKRS treatment technique were previously described,23 with the exception that at our center, MRI images were acquired up to 2 months before treatment. On treatment day, after placement of a stereotactic G frame (Elekta AB), MRI sequences were coregistered to the stereotactic contrast-enhanced 3D CT image set.
Depending on tumor size and localization, the margin dose varied from 11 to 20 Gy (Table 1). Sixty-three meningiomas were treated in a single session, with margin doses between 11 and 18 Gy (mean 13.8 Gy). According to our institutional protocol, meningioma abutting organs at risk, particularly the anterior optic pathway, were treated using hypofractionated radiosurgery (HFSRS). This was the case for seven meningiomas that were treated with an application of 6 Gy for 3 days or of 5 Gy for 4 days. Biologically effective dose (BED) is routinely used to compare doses of different dose-fraction regimens, based on the widely accepted linear quadratic (LQ) model, although with its limitations for high doses still in debate.24 HFSRS doses can be converted to single fraction equivalent doses (SFED),25 to intuitively compare radiation effects to conventional physical doses of single fraction radiosurgery. Margin SFED of the seven HFSRS treatments was on average 11.5 Gy, applying an α/β ratio of 3.76 Gy.26 Treatments were planned on a Leksell GammaPlan 10.1 workstation (Elekta AB, Stockholm, Sweden), by optimizing tumor coverage (mean 96.6%), while restricting doses to sensitive structures, such as the optic apparatus, the cochlea, or the brainstem.
Magnetic Resonance Imaging
MRI was performed on a 3-Tesla scanner (Achieva; Philips, Eindhoven, Netherlands). The following sequences were applied:
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3D T1 magnetization-prepared rapid acquisition (MPRAGE) sequence: gradient echo, TR/TE/TI 6.8/3.2/900 ms, flip angle 8⁰, measured voxel size 0.6*0.6*1.0 mm, before and after intravenous injection of contrast medium.
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T2-weighted sequence: TR/TE 3693.8/80 milliseconds, 150 transversal slices, thickness 1 mm, matrix 512 x 512.
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Fluid-attenuated inversion recovery (FLAIR) sequence: TR/TE/TI 11,000/120/2800 milliseconds, 90 transversal slices, thickness 2 mm, matrix 512 x 512.
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DWI spin echo-based fat sat 2D sequence: TR/TE 2445/70ms, flip angle 90°, b-factor 0 and 1000 s/mm2, 3 gradient directions, measured voxel size 0.9x0.9x5 mm, 25 slices covering whole head, SENSE factor 2, scanning time 29.3 s.
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DTI spin echo-based fat-sat 2D sequence: TR/TE = 6542/60ms, flip angle 90°, 32 gradient directions, b = 0 and 800 mm²/s, measured voxel size 2x2x2mm, 60 slices covering the whole head, SENSE factor 2, scanning time 4.5 min
DTI and DWI sequences differ with respect to slice thickness and voxel size. Therefore, the DWI sequence is more prone to partial volume averaging than the DTI dataset. Special care was taken to exclude bones, CSF spaces, and vascular structures in a similar way in both sequences.
Postprocessing
Tumor volumes were outlined manually and measured from 3D T1-weighted contrast-enhanced images on the Leksell GammaPlan workstation. The volumetric outcome was classified according to RANO criteria for meningiomas, which divides response into five types based on T1-weighted images after injection of contrast media29 (Table 2). In case of DWI images, the “MRIcro” program (people.cas.sc.edu/rorden/mricro) was used for tumor delineation, and special care was taken to exclude CSF/containing and bone containing spaces outside the meningioma as well as big vessels passing the tumor as in parasellar growths. Thus, average ADC values could be measured directly from d-maps and were recorded voxel-wise. DTI data were transferred into the “ExploreDTI” program (http://exploredti.com). Images were corrected for motion artifacts and maps of Fractional Anisotropy (FA), Mean Diffusivity (MD), Longitudinal Diffusivity (LD) and Radial Diffusivity (RD) as well as b0-images were calculated and exported. Using MRIcro, meningiomas were outlined in b0-images. These regions of interest (ROIs) were placed on the parameter maps and DTI parameter values were calculated as described above (Fig. 1).
Table 2
Treatment results | Value | Range |
Delay to first MRI FU in months (mean, range) | 7.2 | (2.4 / 15.2) |
Delay to last MRI FU in months (mean, range) | 52.7 | (17.0 / 108.1) |
Complete response | 0 [0%] | - |
Partial response | 17 [24.3%] | - |
Minor response | 29 [41.4%] | - |
Stable disease | 23 [32.9%] | - |
Progressive disease | 1 [1.4%] | - |
Control Rate | 98.6% | |
Absolute volume change in cm3 (mean, range) | -3.17 | (-16.91 / 5.75) |
Relative volume change (mean, range) | -34.94% | (-91.4% / 73.1%) |
Volume change per month (mean, range) | -0.77% | (-3.16% / 0.68%) |
Volume change per ln(month) (mean, range) | -0.209 | (-0.626 / 0.360) |
Abbreviations: FU, follow up |
Parameters were correlated to a tumor volume change per natural logarithm of time, to account for the near-exponential decrease of tumor volume over time. During an initial phase of 6 months after SRS, early imaging estimations of the tumor volume may not correlate with the final tumor response.27 After this 6-months period, most meningiomas volumes follow an exponential trend, according to our data. To compare volume changes at different points in time, tumor volume change per natural logarithm of time is more accurate than volume change per time, particularly for long FU periods (FUP). Relative volume change per time was defined as the difference between tumor volume before SRS and at last FU, related to initial tumor volume and the natural logarithm of the time interval between the date of SRS and last FU. The following formula was applied:
Statistical analysis
While meningioma volume was measured before SRS and compared to volume at last FU, ADC and DTI parameters were measured before SRS (“parameter 1”) and at first follow-up (“parameter 2”). Differences between parameters 1 and 2 were calculated (“diff”). To compensate for the variation of first FU times (average 7.2 months, range 2.4 to 15.2 months), we related the difference between parameters 1 and 2 to time. To evaluate partial correlation, individual linear regression analyses were performed using relative volume change per ln(month) as the dependent variable and ADC and the following DTI parameters as independent variables: FA, MD, LD, and RD, each of them measured before SRS, at first FU and as difference, related to its initial value and the time interval between SRS and first FU.
Further, all analyses were corrected for age, gender, tumor volume before SRS, and the Paddick conformity index (PCI) as independent variables. These covariates were included in the regression models to adjust the results to reduce bias, as they could pose potential confounding factors based on their biological plausibility.
All multiple linear regression statistical requirements were met in each analysis. There was linearity, as assessed by partial regression plots and a plot of studentized residuals against the predicted values; independence of residuals, as assessed by Durbin-Watson statistic tests; homoscedasticity, as assessed by visual inspection of a plot of studentized residuals versus unstandardized predicted values; no evidence of multicollinearity, as assessed by tolerance values greater than 0.1 and univariate Pearson correlations no greater than 0.4 for independent variables. There were no significant outliers assessed by no studentized deleted residuals greater than ± 3 standard deviations, no leverage values greater than 0.25, no values for Cook's distance above 1, and no multivariate outliers based on Mahalanobis distance analyses. The assumption of normality was met, as assessed by a Q-Q Plot and histogram visual inspection of standardized residuals.
A p-value ≤ 0.05 was considered as a nominal statistical significance. All analyses were performed using SPSS v.26.0.28