While magnetic resonance imaging (MRI) for target delineation in brain tumors was introduced many decades ago [16, 38–40], the significance of pretreatment MR imaging for treatment outcomes is recently becoming recognized more widely [41–46]. In 2015, Seymour et al. were the first to demonstrate the prognostic significance of the time interval between planning MRI and SRS for subsequent local control. While they observed a local control rate of 95% at 6 months post-SRS, if the planning MRI had been performed less than 14 days before SRS, control dropped to a mere 56% if the interval was greater. [13] Since then the high relevance of up-to-date MR imaging for treatment planning has been confirmed by numerous studies [17, 18, 20, 27] with Salkeld et al. even reporting considerable anatomical changes within imaging intervals of less than 8 days. [14]
Gradient nonlinearity-related distortions are the most relevant type of image distortions in MRI. [9] In MRI, spatial encoding is achieved by linearly varying gradients of magnetic field strength in the X, Y and Z-direction that are generated by dedicated gradient coils. [16–19, 48, 49] However, because of gradient coil design, gradient nonlinearities are present especially at the periphery of the scanner. [18, 20] These nonlinearities lead to distortions in reconstructed images that increase with radial distance from the isocenter and may reach several millimeters at the periphery of the brain. [20, 27, 48, 50, 51] As gradient nonlinearities are specific to each MR scanner type, the resulting distortions vary profoundly [16, 17, 20, 27, 48, 52]. While severe cases may lead to a characteristic barrel aberration of acquired images [16], more subtle distortions on the order of few millimeters are nearly impossible to identify, even when coregistering to a planning CT.
Fortunately, as gradient nonlinearity-related distortions are a constant property of the gradient coil set known to the manufacturer [18, 20], they can be corrected using vendor-specific distortion correction. Vendor-specific distortion correction is typically applied as a post-processing step using an image wrapping technique, similar to deformable registration, which necessitates resampling and incorporates intensity correction. [20, 26, 27]
A large amount of important studies has been performed in various types of non-anthropomorphic phantoms to characterize distortions in MRI and to evaluate methods for correction. [16–18, 20, 26, 27] However, results of these studies are frequently difficult to transfer into the clinical setting. Therefore, the actual clinical relevance of distortion correction for brain stereotactic radiotherapy has largely remained elusive to this date. This circumstance may also have contributed to an overall low awareness of MR image distortions in the general radio-oncology community. We identified one simulation study that addressed the clinical significance of MRI distortions in brain stereotactic radiotherapy. In this study, Seibert et al. compared 3D corrected with uncorrected MR images. They found a median metastasis displacement of 1.2 mm and a maximum displacement of 3.9 mm in uncorrected images. Following the results of this simulation study, geographic miss would have occurred in 8 out of 28 evaluated lesions if uncorrected MR images had been used. [21]
In a retrospective simulation study, Ohira et al. recently showed the dosimetric implications of MR distortion on brain stereotactic radiotherapy. 3D correction reduced the underdosage of the GTV significantly as a function of the distance from the isocenter. A 5% relative dose difference at the 98%-isodose was observed at 48 mm from the MR isocenter for non-corrected images compared with 70 mm for 3D-corrected images. [53]
While expert consensus and recent guidelines define vendor-specific 3D distortion correction as a minimum requirement for brain stereotactic radiotherapy to minimize gradient nonlinearity-induced distortions and to reduce total distortions to below 1 mm, corresponding clinical data are scarce. [9, 47] To further elucidate the significance of distortion correction on clinical outcomes, we reviewed a historic cohort of brain metastases patients treated with stereotactic radiotherapy comparing real clinical results achieved with 2D distortion-corrected and uncorrected MRI datasets. Using competing risk analysis, we found local failure to be significantly and substantially reduced in the subset of metastases treated based on 2D distortion-corrected MRI. The two cohorts were reasonably well balanced across major prognostic factors for local control (Table 1). While slight differences in the distribution of primary histology have to be noted, the frequency of radioresistant histologies was not significantly different between the two subsets. To further exclude confounding by the primary tumor histology, we performed a subgroup analysis for the largest subset of melanoma brain metastases (n = 178, Fig. 3). While the subgroup analysis indicates a reduction of local failures for melanoma brain metastases (12-months 14.3% vs. 21.2%), the case number in the melanoma subgroup and therefore the statistical power is only sufficient to show a trend towards significance (p = 0.120). To further account for known prognostic factors of local control in brain metastases, we performed a multivariate competing risk analysis, in which distortion correction remained significantly associated with improved local control. To account for potential confounding changes in imaging or treatment delivery over the 12-year study period, the year of the planning MRI was included in univariate and multivariate analyses. The year of the planning MRI was not found to be a significant prognostic factor in univariate or multivariate analysis (HR 0.97, p = 0.326 and HR 0.99, p = 0.981 respectively), while distortion correction remained the most important multivariate prognostic factor (HR 0.55, p = 0.020). This study therefore is the first to provide evidence that distortion-correction does improve local control in brain stereotactic radiotherapy. This adds to the growing body of literature indicating that optimal pretreatment MR imaging substantially influences actual clinical outcomes in radio-oncology.
However, no significant impact of 2D correction on overall survival was observed between the corrected and uncorrected subgroup (12 months OS, 52.3% vs 57.5%, p = 0.782) in the present cohort. This finding aligns with existing literature indicating that enhanced local control of brain metastases does not necessarily translate into improved overall survival for the general population. [54] Furthermore, there are methodological limitations regarding the assessment of overall survival in this cohort. For instance, important prognostic parameters such as systemic tumor burden and extracerebral tumor control were not captured. Additionally, the long observation period of over 12 years hinders interpretation of survival outcomes and the statistical power was not sufficient to detect significant differences in overall survival.
Consistent with previous studies, we found that increasing time intervals between MRI and stereotactic radiotherapy were associated with reduced local control (HR 1.02 per day in multivariate analysis). However, this parameter did not reach significance in the present analysis (p = 0.170 in multivariate analysis), which can be explained by the fact that the median interval between stereotactic radiotherapy and planning MRI was only 9 days. The number of lesions with very high interval consecutively might have been too low to achieve statistical significance.
It has to be noted that distortion correction could have achieved improved local control not only by a more accurate depiction of real tumor boundaries that avoided marginal miss as in the study by Seibert et al., but also by improvements in MRI-to-CT coregistration, that may have been impaired by distortions near the brain and skull surface as well as accompanying shifts in signal intensity in uncorrected images. We are currently comprehensively investigating these mechanistic questions that were out of the scope of the present work.
While we were only able to evaluate the effects of 2D distortion correction in this historic series, it has to be stressed that vendor-specific 3D distortion correction is currently considered a minimum requirement for radiotherapy treatment planning. [9] While 2D distortion correction only repairs gradient nonlinearity-induced distortions in-plane, 3D distortion-correction also rectifies through-plane distortions. [20] Enabling vendor-specific 3D distortion correction at the MR scanner unfortunately is not an all-in-one solution to comprehensively address all distortions in MR images, however. Even after vendor-specific 3D correction, residual gradient nonlinearity-related distortions may remain that could require additional correction. Current expert consensus therefore recommends to characterize these residual distortions via phantom measurements and to apply additional corrections if necessary. [9]
Moreover, additional types of MRI distortions that are not addressed by distortion correction are relevant for brain stereotactic radiotherapy. Inhomogeneities in the main magnetic field, which arise because of residual magnet imperfections but also because of magnetic field perturbations individually induced by the patient anatomy itself cause distortions [9, 55, 56] Instead of applying distortion correction as a post-processing step these distortions need to be addressed by patient-specific active shimming and by setting an RT-optimized pixel-bandwidth during sequence acquisition, among others. [9, 15]
Limitations:
Due to the retrospective nature of this study, the presence of confounding effects cannot be fully excluded. Slight imbalances between the 2D corrected and uncorrected subset could have influenced results. Also hidden confounders are possible in retrospective series. However, no other study design would have been ethically acceptable.