Introduction

MR-linear accelerators (MR-Linacs) enable daily imaging for radiotherapy guidance. Radiation dose distributions could be adapted according to tumor response; however, current treatment response assessment methods for glioblastoma rely on gadolinium enhanced imaging which has poor specificity¹. Additionally, repeated administration of gadolinium-based contrast agents can lead to adverse effects² and may affect the dose profile of the radiation delivered³.

Quantitative magnetization transfer (qMT) imaging can detect early changes in white matter microstructures which may be used to assess tumor response^4,5. However, common qMT protocols which rely on off-resonance RF pulses are too slow to achieve 3D coverage in an MR-Linac treatment session.

In this abstract, we implement and evaluate the repeatability of a 3D balanced steady-state free precession (bSSFP) qMT sequence for use with an MR-Linac. While bSSFP qMT has been previously implemented on a 1.5T MRI⁶, hardware limitations from combining a scanner and an accelerator may affect qMT parameter quality.

Methods

Patients and data acquisition: Six glioblastoma patients received fractionated radiotherapy on a 1.5T Elekta Unity MR-Linac (Elekta, Stockholm, Sweden). A 3D bSSFP-based qMT protocol was acquired while during treatment at weekly intervals^6,7. Sequences include a series of 14 bSSFP scans with varying flip angle and RF pulse duration (T­_RF) to modulate magnetization transfer contrast and T₁/B₀/B₁ mapping (sequence parameters in Figure 1).

Parameter fitting and analysis: The exchange rate (k_f), free pool T₂ (T_2f) and macromolecular fraction (F) were estimated voxelwise by fitting the bSSFP scans to an analytical Bloch equation solution as the offset frequency approaches zero⁷ using a non-linear least-squares solver (MATLAB 2018b lsqcurvefit). The signal curve and the fitted model is shown in Figure 2. The free pool T₁ is estimated using the T₁ map and flip angle correction was applied using the B₁ map. Due to the poor signal-to-noise ratio in the bSSFP scans, k_f was constrained to 4.5 s^-1 while fitting the data to improve the quality of the parameter maps.

Four regions of interest (ROIs) were defined: contra-lateral normal appearing white matter (cNAWM), contra-lateral normal appearing gray matter (cNAGM), cerebrospinal fluid (CSF) and the gross tumor volume (GTV). The cNAWM, cNAGM and CSF were created using automated segmentation with FSL FAST⁸. The GTV was defined at treatment planning by a radiation oncologist. The median F was calculated for each ROI.

Repeatability was evaluated in cNAWM, cNAGM and CSF. following recommendations for technical performance assessment of quantitative imaging biomarkers⁹. The parameter values within these ROIs to be stable across several weeks. A one-way random effects model Y_ij = μ + u_i + ε_ij is used to compute the within-subject standard deviation (wSD) and the within-subject coefficient of variation (wCV); Y_ij is the measurement, μ is the overall mean, u_i is the contribution from random effects and ε_ij is the error term. For each ROI, the median F values are fit to the model using lme, which returns the wSD. wCV can then be calculated using wSD/μ.

Results

Figure 3 shows the T_2f and F maps in a single patient. There is clear contrast between white matter and gray matter. However, the values of across all ROIs are lower than what is reported in literature⁶.

Figure 4 shows the macromolecular fraction in different ROIs. Apart from CSF, the median F appears to change between patients and treatment sessions. While the distribution of F in cNAWM appears normal in all patients, the distribution of F in GTV changes with each patient.

Repeatability metrics in cNAWM, cNAGM and CSF are shown in Figure 5.

Discussion

The previous qMT protocol we implemented on the MR-Linac took 18 minutes to acquire three 5mm thick slices^5,10. In comparison, this bSSFP qMT protocol takes only 10 minutes to acquire whole brain qMT. F maps produced using bSSFP qMT show similar contrast to the previous qMT protocol. While differences in macromolecular fraction in the GTV between subjects was observed, no significant changes to macromolecular fraction within the same subject across weeks was found. The scans may be too late in treatment to be able to resolve such changes, or patients scanned may not have had progressing tumors.

The wCV in cNAWM was 8.8%, which is considerably higher than the value reported in white matter ROIS in literature (4.7%)¹¹. Several factors may contribute to the difference in repeatability metrics in this study compared to literature. Measurements were done in patients, which adds additional variability due to disease progression and ongoing chemoradiation. The use of an on-resonance bSSFP pulse sequence and the use of a MR-Linac also differs from literature. More thorough test-retest studies of bSSFP qMT on both an MR-Linac and diagnostic MRI are necessary to better estimate variability caused by these different factors.

Conclusion

bSSFP qMT was implemented on a 1.5T MR-Linac and provided 3D parameter maps within 10 minutes. Repeatability metrics were measured in six patients. The wCV in cNAWM was higher than literature values obtained with an off-resonance RF pulse. More thorough studies are necessary to conclusively determine repeatability and determine if bSSFP qMT can assess tumor treatment response.

Acknowledgements

We thank the MR-Linac radiation therapists Shawn Binda, Danny Yu, Renée Christiani, Katie Wong, Helen Su, Monica Foster, Rebekah Shin, Khang Vo, Ruby Bola, Susana Sabaratram, Christina Silverson, Danielle Letterio, and Anne Carty for scanning and for their assistance with the protocol; Mikki Campbell and Aimee Theriault for study coordination; Brian Keller and Brige Chugh for MR-Linac operations; and James Stewart for data retrieval. We gratefully acknowledge the following sources of funding: Natural Sciences and Engineering Research Council (NSERC); Canadian Institutes of Health Research.

References

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