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Brain volume loss in glioblastoma patients following photon and proton radiochemotherapy

Jan Petr¹, Frank Hofheinz¹, Andreas Gommlich^2,3,4, Felix Raschke², Esther Troost^2,3,5,6,7, Bettina Beuthien-Baumann^1,8, Annekatrin Seidlitz^2,5,6,7, Ivan Platzek⁹, Michael Baumann^2,3,5,6,7, Mechthild Krause^2,3,5,6,7, and Jörg van den Hoff^1,8

¹PET center, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany, ²OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Dresden, Germany, ³Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany, ⁴NCT - National Center for Tumor Disease, Dresden, Germany, ⁵Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany, ⁶German Cancer Consortium (DKTK), Dresden, Germany, ⁷German Cancer Research Center (DKFZ), Heidelberg, Germany, ⁸Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany, ⁹Department of Radiology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany

Synopsis

Gray matter (GM) atrophy in healthy brain tissue following radiochemotherapy was shown in brain-tumor patients in several studies. Here, we aimed to study GM and white matter (WM) changes in glioblastoma patients undergoing photon (n=43) and proton (n=12) radiochemotherapy. In photon-therapy patients, a statistically significant decrease of both GM (~2%) and WM (1.3-2.3%) volume was found with a positive influence of the RT-dose on the GM volume loss. In proton-therapy patients, no significant changes in GM and WM volumes were observed after therapy. This indicates that the proton-therapy has the potential to reduce structural GM changes in healthy tissue.

Introduction

Structural changes in healthy brain tissue¹ and cognitive deficits² following radiochemotherapy (RCT) in brain-tumor patients have long been recognized. Loss of gray matter (GM) volume after chemotherapy was shown for both non central-nervous-system tumor patients³, and brain-tumor patients⁴. Recently, the longitudinal changes on MRI were thoroughly examined using automated segmentation tools in glioblastoma⁵, and in high-grade glioma⁶ patients receiving RCT. Progressive GM volume loss and its dependence on radiation (RT) dose was shown. Both studies, however, suffered from small numbers of patients. Our aim was thus to study GM and white matter (WM) changes in healthy brain tissue of glioblastoma patients undergoing RCT in a larger population. We also compared the results between photon- and proton-therapy patients to assess whether proton-therapy reduces the healthy-tissue atrophy.

Methods

Fifty-five patients with histologically confirmed glioblastoma multiforme, unilateral tumor presence on PET/MRI imaging, and no previous RCT were studied. Fractionated radiotherapy with a total dose 60 Gy (2 Gy fractions 5 days/week) and concomitant Temozolomide chemotherapy (75 mg/m²) plus 6 months of adjuvant Temozolomide (150 mg/m2) was delivered to all patients⁷. Intensity modulated radiation therapy with photon beams was applied in 43 patients (mean age 55.2±13.9 years), and therapy with proton beams was applied in 12 patients (mean age 55.5±15.3 years). MRI measurements were performed with a 3T Philips Ingenuity TF PET/MR scanner with an 8-channel head-coil. 3D-TFE (Turbo Field Echo) T1-weighted images were obtained in the sagittal orientation with 1 mm isotropic resolution. First imaging (Pre-RCT) was performed after tumor resection and before the RCT start. The second and third sessions were performed in 3-months intervals after the end of the RCT. Data were processed using SPM12 toolbox (Wellcome Trust Centre for Neuroimaging) and in-house routines written in Matlab (MathWorks). The T1-w images were segmented to GM, WM, and cerebro-spinal fluid maps. The planning CT and associated RT-dose plans were co-registered with the T1-w images for each session. Inter-session GM and WM volume changes were evaluated in the unaffected hemisphere contralateral to the tumor. The GM volume changes were also assessed regionally according to received RT-dose (using the subdivisions 0-10-20-30-60 Gy and 0-10-60 Gy for the photon- and proton-therapy patients, respectively).

Results

Signs of brain atrophy were observed in most photon-therapy patients, see Figure 1. In photon-therapy patients, significant decrease of both GM (~2%) and WM (1.3-2.3%) volume was found, see Tables 1 and 2. On the contrary in proton-therapy patients, no significant global changes in GM and WM volumes were observed. For photon-therapy patients, GM volume loss in high RT-dose regions was 3-4 fold higher than in the low RT-dose regions, see Figure 2. The effect of GM volume loss was heterogeneous across patients with range between +5 and -10% for most of the patients, see Figure 3.

Discussion and conclusions

We have shown a GM volume loss after RCT that is higher than what is attributable to healthy aging (0.3-0.4% per year^8,9). The results were in concordance with the results by Prust⁵ with the same type of patients and treatment, although, we have observed smaller decreases (1.9-2.1% compared with ~3-4% by Prust et al.). The current study, however, used a larger patient group (42 compared with 8) and we excluded patients with bilateral tumor presence where changes in the vicinity of the tumor could be mistaken for GM loss. Contrary to results by Prust, we have observed significant loss in WM volume. Our findings confirm those of Karunamuni⁶ that higher RT-dose increases the level of GM atrophy. In proton-therapy patients, no significant changes in GM and WM (except for GM volume loss on second post-RCT sessions in high-dose regions) were observed. This, however, needs to be confirmed in a larger group. Accuracy of the GM volume estimation is influenced by errors in segmentation, co-registration, and hydration status (10% difference in ventrical volume measured on MRI was reported between dehydration and hyperhydration¹⁰). We assume that this does on average not affect the results, however, it can explain individual measured increase in GM volume. Decrease of atrophy level with lower RT-dose in both photon- and proton-therapy patients, and minor structural changes in proton-therapy patients in general indicate that brain atrophy in RCT patients is mainly dose-dependent. The slight trend of atrophy progress in time and volume loss in low RT-dose regions of photon-therapy patients might be attributed to low doses of chemotherapy crossing the blood-brain barrier in healthy tissue causing DNA damage or cumulative effect of chemo- and radio-therapy. To confirm this, we plan to include more proton-therapy patients and investigate atrophy in latter sessions as well.

Acknowledgements

M.K. and J. vdH. contributed equally to this work.

References

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5. Prust, M. J., Jafari-Khouzani, K., Kalpathy-Cramer, J., Polaskova, P., Batchelor, T. T., Gerstner, E. R., & Dietrich, J. Standard chemoradiation for glioblastoma results in progressive brain volume loss. Neurology. 2015; 85(8):683–691.

6. Karunamuni, R. A., Moore, K. L., Seibert, T. M., Li, N., White, N. S., Bartsch, H., … Hattangadi-Gluth, J. A. Radiation sparing of cerebral cortex in brain tumor patients using quantitative neuroimaging. Radiotherapy and Oncology. 2016; 118(1):29–34.

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Figures

Figure 1. Rigidly co-registered T1-w images of a subject with 7.8% GM volume loss (left – before RCT therapy, right – 1^st post therapy session). Ventricular dilation and expansion of CSF space in cortex is clearly visible on both sides. Note that the right image appears less noisy and slightly blurred due to the realignment.

Table 1. GM volume changes in the healthy hemisphere on the first three sessions (pre-RCT, post-RCT session 1, post-RCT session 2) for the photon- and proton-therapy patients. Time interval, relative change (mean and standard deviation) of the GM volume, and p-value of a paired t-test are shown relative to the first session. Negative value of relative GM change indicates GM volume loss relative to the first session. Note that not all patients were measured on all sessions.

Table 2. WM volume changes in the healthy hemisphere on the first three sessions (pre-RCT, post-RCT session 1, post-RCT session 2) for the photon- and proton-therapy patients. Time interval, relative change (mean and standard deviation) of the WM volume, and p-value are shown relative to the first session. Negative value of relative WM change indicates WM volume loss relative to the first session.

Figure 2. GM volume changes in the healthy hemisphere for different RT-dose regions. Decrease in GM-volume relative to the first session is shown for the first post-RCT session (blue) and second post-RCT session (red). For the photon-therapy (left), the mean size of the region with dose between 0-10 Gy was 29% of the healthy hemisphere volume (for 10-20 Gy 27%, for 20-30 Gy 19%, and for 30-60 Gy 25%). For the photon-therapy (right) patients dose regions between 0-10 (90%), and 10-60 Gy (10%) were used. Significant changes are marked with a * for p<0.05, and with + for p<0.01.

Figure 3. Relative GM volume change between the pre- and first post-RCT sessions is plotted against the mean RT-dose in the healthy hemisphere for photon (blue) and proton (red) therapy patients. The range of change is between 7% and -12%. The measurements contain errors probably caused by segmentation and co-registration issues and apparent GM volume variability caused by changes in hydration. The measured increase in GM volume is thus rather a statistical error than growth of new tissue. A general GM volume loss is visible in photon-therapy patients, while no clear change is visible in proton-therapy patients.

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)

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