Synopsis

Early assessment of glioblastoma (GBM) response to standard 6-week chemo-radiation enables changing or adjusting therapy in patients with progressive tumors. Chemical Exchange Saturation Transfer (CEST) probes the concentration and exchange of labile proteins and peptides in ht tumor and is more sensitive to treatment-induced effects. CEST was capable of differentiating progressors from non-progressors as early as two weeks into the treatment. Moreover, certain CEST metrics (i.e. MTR_NOE, MTR_Amide, CEST_NOE) were capable of characterizing GBM aggressiveness even before the start of the treatment.

Purpose

Introduction

Materials & Methods

Patients: 19 patients were recruited (REB approved) and were treated for six weeks with concurrent radiation (2Gy/day) and daily Temozolomide. Patients were MRI-scanned 4 times:

1. before treatment (Day₀),

2. After 10 treatment sessions (Day₁₄),

3. After 20 treatment sessions (Day₂₈),

4. One month after last treatment day (Day₇₀).

MRI: was performed on a 3T Philips Achieva scanner. An axial slice passing through the tumor was imaged with TFE (TR/TE=7.78/4.5ms, Matrix=144×144, FOV=20×20cm, slice=3mm).

CEST imaging covered offsets between -5.9ppm and 5.9ppm with 0.2ppm increments, with 4 references at ~780ppm at the beginning and another 4 references at the end of the spectrum. RF saturation included 4 block pulses of 242.5ms each (970ms total), and B₁=0.52µT^4,5. CEST imaging was repeated twice for a total of 4.8min.

Analysis: All images (CEST, T₁, T₂, post Gd-T_1w, FLAIR were co-registered to the first acquired CEST image. Tumor ROI was identified at each scan on the post-Gd T_1w. Metrics were calculated voxel-by-voxel and then averaged over ROI.

CEST: B₀ and Drift correction was performed4 followed by decomposition of CEST spectrum into a constant MT (for ‑5.9ppm to 5.9ppm) and four Lorentzian line-shapes (Amide, NOE, Amine, bulk water). Area under the curve of NOE & Amide CEST peaks (CEST_NOE & CEST_Amide), the constant MT, MTR at -3.5ppm (MTR_NOE) and -3.5ppm (MTR_Amide) were used as CEST metrics.

Results

Tumor progression was determined by an oncologist blinded to the MRI analysis at 3-8 months after the end of the 6-week chemo-radiation treatment based on clinically used RANO criteria. Data of three patients were discarded due to incomplete scans or presence of imaging artifacts. Six patients had tumor progression (progressors cohort) and 10 patients did were classified as non-progressors.

Figure1 shows CEST spectrums of tumor and contralateral normal appearing white matter (cNAWM) of a representative patient. Figure2 shows the parametric maps of CEST metrics Day₀ scan of one patient along with the T₁ and T₂ relaxation time maps.

Table1 reports the CEST metrics parameters for cNAWM averages over all patients. Table2 reports CEST metrics for tumor ROI showing at Day₀ the MTR_NOE (p=0.015), MTR_Amide (p=0.028), MT (p=0.019), and CEST_NOE (p=0.044) at baseline (Day₀) were statistically significantly different between the progressors and non-progressors.

Figure3 plots the ratio of each metric at each time point over its value at Day₀ (which represents the change in these parameters) for MTR_NOE, MTR_Amide, MT, and tumor volume.

Discussions

All the CEST metrics reported in Table2 for Day₀ of non-progressors were lower (except for APT) showing they have lower metabolic activity compared to progressors. Several of these metrics were able to differentiate progressor from non-progressor before the start of the treatment. Thus, CEST is capable of characterizing GBM tumor aggressiveness and identifying patients that will not benefit from standard chemo-radiation therapy, even before treatment.

When considering the changes in metrics during treatment (shown in Figure3 by the ratio of each metric over its Day₀ value), there was statistically significant difference between progressors and non-progressors (for changes between Day₀ and Day₁₄) for MTR_NOE (Non-progressors=1.35±0.18, Progressors=0.97±0.22, p=0.006), and MTR_Amide (Non-progressors=1.25±0.17, Progressors=0.99±0.10, p=0.017). Furthermore, although there were large differences in the CEST metrics at baseline, at later time-points there were no statistically significant differences between the two cohorts. Thus, two weeks into treatment is the best time-point to evaluation GBM response to chemo-radiation. The lack of statistical significance at later time points could also be associated with the fact that fewer progressors participated in the later scans (3 at Day₇₀ compared to 6 at Day₀).

It is worth noting that tumor volume or its changes were not capable of differentiating the two cohorts at any time points which emphasizes on the need for longer follow-ups when relying on clinically used response evaluation markers (which are based on tumor size).

Conclusions

Acknowledgements

References

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