Stereotactic radiotherapy of brain metastases: clinical impact of three-dimensional SPACE imaging for 3T-MRI-based treatment planning

Magnetic resonance imaging (MRI) is a safe and effective diagnostic examination technique for radiation treatment planning for cerebral metastases. The decision on the optimal radiotherapy for patients with cerebral oligometastases depends to a great extent on the number and location of the metastases. While whole-brain radiotherapy (WBRT) is performed for diffuse metastasis, for oligometastases, stereotactic radiosurgery (SRS) is used to protect neurocognitive function [1‐4]. In order to detect even the smallest BM, the diagnostic accuracy of the MR examination technique is thus critical.

In 2000, Hochstenbag et al. reported on the significance of the MRI examination in pretherapeutic staging of BM [5]. Through the use of MRI alone, the number of newly detected BM in SCLC patients increased by 15%. In this study on a 0.5T MRI, only T1-weighted spin echo (SE) sequences with a relatively large slice thicknesses of 10 mm were used. However, pulsation artifacts of the vessels in the posterior fossa result in poor image quality in standard SE images. Metastases in the brainstem or cerebellum can thus be missed. With the introduction of contrast-enhanced 3D GE T1-weighted MPRAGE (magnetization-prepared rapid gradient echo) images, Wenz et al. were able to detect considerably more metastases in 1.5T MRI than with SE sequences alone [6]. This was primarily due to the thinner slices. The superior spatial resolution of the 3D GE sequences is associated with a greater susceptibility for artifacts and poorer contrast compared with 2D SE sequences [7, 8]. With the introduction of new isotropic 3D fast (turbo) spin echo sequences, it is today possible to detect very small metastatic lesions (< 5 mm) in an acceptable examination time using 3.0T MRI. These sequences feature very long echo trains, lower flip angles, and ultrashort echo spacing. Mugler et al. developed a 3D fast SE sequence with variable flip angle refocusing pulses [9]. That which is termed the SPACE sequence solved the previous problems of poor 3D resolution of gradient echo sequences using sampling perfection with application-optimized contrast by using different flip angle evolutions. Due to the isotropic resolution, the voxels generated are the same size in every direction, allowing reconstruction in all three planes. Various studies have reported on the diagnostic significance of the SPACE sequence [10‐12]. By suppressing the signal in the cortical vessels, the contrast enhancement of very small cerebral metastases is much clearer in 3D SPACE than in 3D MPRAGE images. Kato et al. showed in an initial study with 16 patients with BM that 3D SPACE visualizes metastases significantly better than 3D MPRAGE due to the better contrast rate (CR) [10].

The clinical significance of this fast (turbo) spin echo technique as black blood imaging for radiotherapy has not yet been studied. This clinical study aims to investigate whether 3D SPACE can be integrated in preradiotherapy staging and radiation treatment planning. The objective of the study is to clarify how many more metastases are detected using 3D SPACE compared with 3D MPRAGE in radiation treatment planning and what effect the higher number of metastases has on the later radiation technique (SRS versus WBRT). A metastasis count of ≤ 4 BM was specified as the upper limit for SRS according to the guidelines from 2015 [13].

Several authors have reported that the lesion contrast of BM increases with delayed imaging time [14, 15]. For departments that do not have access to black blood imaging sequences such as 3D SPACE for radiation treatment planning, it should be tested whether a 3D MPRAGE late-phase contrast-enhanced image can detect the same number of metastases as 3D SPACE.

A summary of the BM characteristics is shown in Table 2. Overall, we detected 29.8% more BM on the 3D SPACE sequences and 16.9% more BM on the 3D MPRAGE late-phase sequences than on the established standard 3D MPRAGE sequences. Incidental findings were detected in 3% of the 199 patients and included one meningioma and five developmental venous anomalies (DVA). The mean numbers of BM on the 3D SPACE and 3D MPRAGE late-phase sequences were significantly higher than those found on the standard 3D MPRAGE sequences (p < 0.0001, paired-samples t-test for both comparisons). Of note, lesions of less than 2 mm in diameter on the 3D SPACE sequence were not seen in either the established standard 3D MPRAGE or the 3D MPRAGE late-phase sequence. Metastatic lesions near the cortical vessels (Fig. 1c) and periventricular metastases (Fig. 2b) were particularly well detected by the 3D SPACE sequence.

At the patient level, the 3D SPACE sequence showed 57.8% more metastatic lesions than the standard 3D MPRAGE sequence in 60 of the 199 patients (554 versus 351 metastases in 30.2% of the patients), and the 3D MPRAGE late-phase sequence detected 39.1% more lesions than the standard 3D MPRAGE sequence in 41 of the 199 patients (409 versus 294 metastases in 20.6% of the patients). The higher the number of BM detected in the standard 3D MPRAGE sequence, the higher the number of additional metastases in the 3D MPRAGE late-phase sequence (for details see Fig. 3).

Several studies have shown that black blood (BB) MRI (SPACE, VISTA) detects significantly more brain lesions < 5 mm [10, 16, 17]. This study showed for the first time that BB imaging (SPACE) can be effectively integrated into stereotactic radiation treatment planning with the CyberKnife. Among the multifactorial causes for the superior detectability of BM using SPACE are the better signal-to-noise ratio and the higher spatial resolution in the submillimeter range. The sequence is clearly superior to MPRAGE in detecting smaller short-axis diameters and thus also smaller metastases. However, false-positive findings due to insufficient suppression of cortical vessels or small contrast enhancement of an immunological inflammatory response due to antibody treatment can be misinterpreted to be a metastasis.

In the late-phase MPRAGE imaging, cerebral metastases show contrast blush as an expression of neovascularization compared with early-phase MPRAGE imaging (Fig. 1b). In addition, washout of the contrast agent was seen in the cerebral vessels in late-phase MPRAGE imaging (Fig. 1b). This facilitates better differentiation of the intracerebral vessels from metastases in late-phase MPRAGE imaging as well.

The 3D SPACE image showed more intracerebral metastases and, above all, smaller metastases in MRI-based radiation treatment planning compared with conventional 3D MPRAGE. These metastases would not have been included in radiation treatment if only contrast-enhanced 3D MPRAGE had been used. This would have led later to a poorer clinical outcome of the patients, as a total of 197 metastases were not detected in conventional 3D MPRAGE. Another advantage is the administration of one dose of MR contrast with a good signal-to-noise ratio of 3D SPACE even in the submillimeter range. The administration of three times as much gadolinium, as described by Donahue et al. when using 1‑mm thick MPRAGE sequences, is not necessary with 3D SPACE [18]. The good spatial resolution allowed false-positive lesions such as cortical veins to be recognized and excluded from the radiation treatment planning [10].

Image acquisition for radiation treatment planning places special demands on MRI. For radiation treatment planning for CyberKnife radiosurgery on the cranium in particular, slice thicknesses less than 1 mm are required with three-dimensional resolution and a good signal-to-noise ratio. This would not be possible with conventional 2D T1 spin echo sequences. In addition to good spatial resolution, low geometric distortion in the MR image is also important. The sharp delineation of the contrast enhancement of a metastasis in 3D SPACE allows precise determination of the target volume with a steep dose gradient, while simultaneously protecting the surrounding brain tissue. For the radiotherapist, detection and target volume contouring of small BM are considerably easier in 3D SPACE, as there is no interference from cortical veins.

Our patients were treated between 2016 and 2018, at a time when SRS of brain metastases was limited to up to four brain metastases. Now it is not uncommon to treat up to 10 metastases or more [19]. Therefore, the change in treatment concept based on SPACE imaging needs to be considered in the current management of BM, as many centers would still offer SRS for more brain lesions. We assume that the more lesions are included in the treatment concept, the greater the benefit of SPACE imaging.

One limitation of the study is that as in earlier studies, there is no histopathological confirmation of the irradiated brain lesion. Due to the poor prognosis and high mortality rate, not all patients were available for follow-up examinations.

Another limitation is that we used a 12-channel head coil for acquisition of the 3D SPACE and 3D MPRAGE sequences for radiation treatment planning. According to Reichert et al., we would have needed 30% less time if a 32-channel head coil had been used [20].

Using 3D SPACE is a practical alternative to the routinely used T1-weighted 3D MPRAGE, especially for radiosurgery treatment planning for BM. Our data show that 3D SPACE allows detection of significantly more cerebral metastases that can be included in radiation treatment planning. For radiotherapists, the increasing use of SRS even for patients with up to 10 BM increases the importance of precise pretherapeutic detection of all cerebral lesions in the MRI examination for radiation treatment planning [19, 21]. The further clinical significance of using 3D SPACE for radiation treatment planning on patient outcome and quality of life after radiosurgery is currently being tested in an ongoing two-armed prospective randomized phase II study at our center (Clinical Trial Code: NCT03303365).