PURPOSE

Medulloblastoma is the most common brain tumor in children, and five-year survival has increased to over 80% in standard risk subjects.¹ Effective therapy to reach this increased survival is associated with both imaging changes² and neurocognitive deficits.^3,4 In this study, we attempt to confirm earlier findings of disrupted microstructural white matter integrity in an independent cohort of children with medulloblastoma compared to age similar controls.

PATIENTS AND METHODS

Three subject cohorts were utilized in this study. The historical comparison cohort (HCC) included 146 patients diagnosed with medulloblastoma (3.2-21.6 years at diagnosis; median=8.7 years; average/high-risk 93/53) and treated with maximal surgical resection, risk-adapted craniospinal irradiation (CSI), and high-dose chemotherapy (NCT00085202). Seven MRI examinations were collected: baseline (after surgery but before additional therapy); after CSI; 12, 18, 24, 30, and 36 months after diagnosis. The current treatment cohort (CTC) (NCT01878617) included 141 patients treated for medulloblastoma (3.3-22.8 years at diagnosis; median=9.3 years; average/high-risk 57/84) with surgery, CSI, and chemotherapy also. Five MRI examinations were collected for this cohort: baseline; after CSI; 12, 18, and 24 months after diagnosis. An age-similar healthy control cohort included 92 subjects (6.2-25.8 years at baseline) who were able to tolerate repeat MR scans at three time points: baseline, 12, and 24 months later. Imaging and treatment protocols were approved by the local Institutional Review Board, and written informed consent was obtained from the patient, subject, parent, or guardian, as appropriate.
Diffusion tensor imaging (DTI) was collected on all subjects using a 1.5T or 3.0T whole-body system (Siemens Medical Systems, Iselin, NJ). Depending on the time of image collection, a 12 direction, four average acquisition [TR=6500-10000ms; TE=100-120ms, b=700-1000s/mm², 1.5x1.5x3mm or 1.8x1.8x3mm resolution], a 30 direction, two average acquisition [TR/TE=14000/120ms, b=700s/mm², 1.8x1.8x2mm resolution], or a 64 direction, two average acquisition [TR/TE=4000/77.4ms, b=1500s/mm², 1.8x1.8x1.8mm resolution] was collected. Twelve and 30 direction acquisitions were processed with the DTI toolkit under SPM8 (http://www.fil.ion.ucl.ac.uk/spm/) to generate maps of fractional anisotropy (FA). Sixty-four direction data was collected with reversed phase-encode blips and was therefore processed with FSL (http://fsl.fmrib.ox.ac.uk/fsl/) to generate parametric maps.^5,6
Voxelwise statistical analysis of the FA data was carried out using TBSS (Tract-Based Spatial Statistics⁷), part of FSL.⁶ TBSS projects all subjects' FA data onto a mean FA tract skeleton, before applying voxelwise cross-subject statistics. After mapping the FA onto the TBSS skeleton, linear mixed-effects modeling was performed for each skeleton voxel using the restricted maximum–likelihood estimation method to analyze the longitudinal data. Estimates were computed for baseline value, change over time, and interaction between time and subject group (patient vs. control), controlling for age effects using a baseline age term for each subject. To investigate whether the change of FA values over time differs between patients and controls, we used an F-test with Kenward Roger approximation⁸ to find significant pixels. After correcting for multiple testing,⁹ p=0.05 was considered significant.

RESULTS

The skeleton created in the analysis of the HCC was based on 1089 examinations and included 89,456 voxels.² The TBSS analysis of the CTC was based on 758 examinations with 99,601 skeleton voxels. Further analysis was limited to the skeleton voxels with a statistically different change in FA over time between patients and controls. While there was an 11% increase in the size of the skeleton for the CTC, the percentage of significant skeleton voxels increased from 12% in the HCC to 27% in the CTC (Table 1). These additional significant voxels can be appreciated in the display of the skeletons side by side (Figure 1). Both cohorts had greater than 95% of voxels with a baseline FA value smaller in the patient group than in controls. Breaking the significant voxels into those with a change over time greater in patients than controls, we see similar proportions of pixels from each cohort. Further examining these pixels and estimating the FA value two years after baseline shows a large increase in the percentage of pixels where the patients at least reach the level of controls.

DISCUSSION

This data confirms the previously reported result that after surgery and before additional therapy, both patient cohorts have lower FA values compared to controls. This result also serves to highlight the limited impact of the various DTI acquisitions on the interpretation of results of this historical data. Additionally, we are reporting a large increase in the percentage of skeleton voxels where the patient cohort meets or exceeds the control cohort two years after diagnosis. This suggests the possibility that the newer therapy is having a less toxic impact on microstructural integrity in this pediatric population. While there are many therapy differences, the primary differences include the move from photon to proton irradiation for tumor control and a molecularly guided chemotherapy regimen.

CONCLUSION

This work confirms a previous report showing a reduction of FA after surgery and before additional therapy in an independent cohort of patients treated for pediatric medulloblastoma. Additionally, preliminary analysis suggests the modifications to the molecularly guided risk adapted therapy and proton beam irradiation may result in less damage two years after diagnosis. Further study is need to confirm these findings and the impact they have on neurocognitive performance and the quality of life of these young subjects.

Acknowledgements

We acknowledge the valuable contributions of Rhonda Simmons, advanced signal processing technician, and funding in part by the Cancer Center Support Grant P30 CA-21765 from the National Cancer Institute, grant HD049888 from the National Institute of Child Health and Human Development, grant RR029005 from the National Center for Research Resources, and ALSAC.