Serial 3D H-1 MRSI of Patients with Newly Diagnosed GBM being Treated with Radiation, Temozolomide, Erlotinib and Bevacizumab
Sarah Nelson1, Yan Li1, Janine Lupo1, Marram Olson1, Jason Crane1, Annette Molinaro2, Ritu Roy3, Soonmee Cha1, and Susan Chang2

1Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, 2Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States, 3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States

Synopsis

Patients with newly diagnosed GBM are typically treated with a combination of radiation and temozolomide in conjunction with a variety of investigational agents. Assessing the effectiveness of such therapies is complicated by differences in their mechanisms of action that lead to ambiguities in the interpretation of conventional anatomic images and difficulties in assessing the spatial extent of tumor. The results of this study demonstrate that integrating 3D lactate edited H-1 MRSI into routine MR examinations and applying quantitative analysis methods allows for the objective evaluation of changes in tumor burden and the early assessment of outcome.

Purpose

The purpose of this study was to develop and apply strategies for monitoring serial changes in parameters derived from H-1 MRSI for patients with newly diagnosed GBM being treated with combination therapy. This is particularly important for situations where anti-angiogenic agents such as bevacizumab are included because they cause a reduction in the size of the lesion observed with post-gadolinium T1-weighted images and mean that the assessment of response depends upon the identification and evaluation of non-enhancing tumor1.

Methods

Thirty-one patients being treated with radiation (RT), temozolomide, erlotinib and bevacizumab as part of a single institution Phase II clinical trial, received serial 3T scans. Anatomic imaging sequences comprised FLAIR T2-weighted, pre- and post-gadolinium T1-weighted scans. Lactate edited 3D H-1 MRSI data were obtained with CHESS water suppression, VSS outer volume suppression and PRESS volume selection (TE=144ms, TR= 1.3s, acquisition matrix of 16x16x16 or 18x18x16 and nominal spatial resolution =1cm3). Fly-back trajectories were applied in the S/I dimension as described previously2. The contrast enhancing (CEL) and T2 lesion were defined from anatomic images. The spectral data were processed3 to provide levels of choline (Cho), creatine (Cre), N-acetylaspartate (NAA), lactate (Lac) and lipid (Lip), as well as indices such as the CNI that describes the increase in Cho and decrease in NAA relative to values from normal appearing brain tissue4. Serial changes in imaging parameters were evaluated using Wilcoxon rank sign tests and association with progression free survival (PFS) and overall survival (OS) was assessed using Cox proportional hazards analysis, taking into account patient age, extent of resection and KPS.

Results

As reported in other clinical studies5, the PFS for these patients was longer (median 404 days, 27 events, 4 censored) but the OS was similar to patients receiving standard of care (median 603 days, 23 events, 8 censored). The mean T2 lesion volume decreased from 36.2cm3 at pre-RT to 15.3cm3 (post-RT, p<0.0001) and to 14.7cm3 (Fup1, p=0.0002). The mean CEL volume decreased from 5.2 cm3 (pre-RT) to 3.0 cm3 (mid-RT, p=0.018), 2.1 cm3 (post-RT,p=0.0002) and 0.7cm3 (Fup1, p <0.0001). Figure 1 shows changes in metabolite parameters from these first 4 exams for sub-populations with PFS either greater or less than the median value. Overall these metrics of abnormal metabolism showed a continued reduction with time, and values for the sub-group with longer PFS were lower than those with shorter PFS. Figures 2 and 3 show examples of serial anatomic images and overlays of CNI maps from baseline to the time of progression for 2 subjects with similar PFS but different OS. Note that there was minimal residual enhancement for both subjects and the clinical assessment of treatment response relied upon changes in the T2 lesion. The metabolic (CNI) lesion at the time of recurrence was relatively small for patient A (OS=706 days), but much larger and increasing in size for patient B (OS=434 days). When considering the population as a whole, a number of imaging parameters were associated with PFS and OS. These included the volume of the CEL at mid-RT (p=0.025 for PFS and p=0.039 for OS) but not other time points. For metabolic parameters such as the volume with CNI>2, the sum(CNI), sum(Lac/nNAA) and sum(Lip/nNAA) values from the Fup1 examination showed strong associations with PFS and OS (see Table 1). There was no association of the T2 lesion volume with outcome detected these time points.

Discussion

The RANO criteria for assessing response to therapy in patients with GBM depend upon changes in the CEL, with secondary evaluation of the T2 lesion6. This is problematic for treatments including anti-angiogenic agents because the enhancing portion of the lesion may disappear, leaving behind a mixture of non-enhancing tumor and non-specific treatment effects. An alternative approach to assessing tumor burden is to use 3-D H-1 MRSI to monitor changes in regions with abnormal metabolism. The results of this study indicate that maps of the CNI were able to visualize temporal changes in the spatial extent of tumor and that metrics based upon CNI values and levels of Lac and Lip within the region with abnormal CNI are able to predict outcome.

Conclusions

Integrating 3D H-1 MRSI and the metabolic parameters that they provide into serial MR scans of patients with GBM would be helpful for resolving ambiguities cause by non-specific treatment effects and for determining at an early stage whether alternative therapies should be considered.

Acknowledgements

This research was supported by NIH grants RO1 CA127612 and P01 CA118816.

References

1. Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 2006;66:1258-60.

2. Park I, Chen AP, Zierhut ML, et al. Implementation of 3T lactate-edited 3D 1H MR spectroscopic imaging with flyback echo-planar readout for glioma patients. Ann Biomed Eng. 2011;39:193 – 204.

3. Crane JC, Olson MP, Nelson SJ. SIVIC: Open-Source, Standards-Based Software for DICOM MR Spectroscopy Workflows. Int J Biomed Imaging. 2013;2013:169526.

4. McKnight TR, von dem Bussche MH, Vigneron DB, et al. Histopathological validation of a three-dimensional magnetic resonance spectroscopy index as a predictor of tumor presence. J. Neurosurg. 2002;97(4):794–802.

5. Mark R. Gilbert, James J. Dignam, Terri S. Armstrong, et al. A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma. N Engl J Med 2014; 370:699-708.

6. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963-72.

Figures

Figure 1: Changes in mean metabolite parameters at serial MR examinations. The CNI is reflects increased Cho and decreased NAA relative to normal. The sum values are integrals of parameters indicated within the region with CNI>2. The asterisk shows parameters with a significantly decrease relative to their pre-RT values.

Figure 2: Serial post-Gad T1-weighted, FLAIR images and overlaid CNI maps for patient A (50 year old male, PFS=330 days, OS=706 days). The yellow boxes indicating PRESS selected volumes are oblique for follow-up scans due to registering data to the pre-RT exam to aid in making visual comparisons.

Figure 3: Serial post-Gad T1-weighted, FLAIR images and overlaid CNI maps for patient B (30 year fold female, PFS=, OS=434 days). The yellow boxes indicating PRESS selected volumes are oblique for follow-up scans due to registering data to the pre-RT exam to aid in making visual comparisons.

Table 1: Association of anatomic and metabolic imaging parameters with PFS and OS, accounting for age, extent of resection and KPS score. The symbol ‘ns’ represents that the association was not significant for a p value cut-off of 0.05.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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