WP12 – Dti mri for radiation treatment planning in glioblastom
The aim of this project is to improve the radiation target for glioblastoma patients by using information on the preferred spread along white matter fibres. We will apply mathematical modelling including advanced MRI to create an improved target based on the patients’ own white matter fibres. It is expected that this new improved target leads to more precise radiation of the microscopic part of the tumour meaning irradiating more microscopic tumour cells on one hand, and irradiating less healthy brain cells unnecessarily on the other hand. Consequently, improvement in the target may translate into better tumour control, and decrease of treatment related toxicity. Furthermore, a better target definition is necessary for exploring novel treatment strategies, such as radiation dose escalation and radiation using protons.
Glioblastoma is assumed to be a loco-regional disease as most of recurrences occur within the radiation field. Radiotherapy has been used to treat GBM for a long time, but defining the exact target for irradiation remains challenging as the infiltrative part of the tumour cannot be visualised by current medical imaging. The radiation target (GTV) is currently defined as the surgical cavity and any residual contrast enhancement on T1-weighted MRI. To account for any microscopic disease, the GTV is expanded by 2 cm to the clinical target volume (CTV). This general approach seems reasonable as most of the recurrences are within the radiation field. However, selected subgroups of patients experience higher frequency of non-central recurrences (Minniti et al., 2010). On the other hand, irradiation of “unnecessary” large CTV may result in increased toxicity in other groups of patients. Therefore, incorporating additional biological information may improve and individualise irradiation in GBM. Several studies have shown that glioma cells preferentially spread along the white matter tracts (WMT). This information can be used for computing a DTI based CTV. DTI MRI uses the tensor of water diffusion to define the WMTs. In the model, the water diffusion tensor can be incorporated to simulate tumour growth. Retrospective work on mathematical models in RT showed potential, but is limited by a small and heterogenous study cohorts (Jensen, Guldberg, Harboll, Lukacova, & Kallehauge, 2017; Trip, Jensen, Kallehauge, & Lukacova, 2019). Therefore, further development and validation on large patient population is needed.
- validation and comprehensive development of the mathematical model for DTI target on large clinical data-set
- to investigate the potential of DTI target for assessing microscopic disease.
- to assess specific benefit in pre-defined sub-groups
This is a national non-interventional single arm study with a target accrual of 300 patients with newly diagnosed GBM referred to long course RT. Planning RT MRI will be prolonged to allow for DTI acquisition. RT will be planned and delivered according national guidelines. Imaging (planning MRI with DTI, recurrence MRI), RT plans and clinical parameters will be collected. The Fisher-Kolmogorov growth model assuming uniform proliferation rate and difference in white and grey matter diffusion of a factor 10 incorporating tensor directionality using an anisotropy weighting parameter will be used to compute DTI derived targets (Trip et al., 2019). Volumetric comparison will be done. Wilcoxon signed-rank test will be used for evaluation of recurrence coverage. Multiple logistic regression will be used for the sub-group analysis.
- Optimizing parameters in the model using test and validation data set
- Marginal recurrence coverage by DTI target compared to standard target
- Recurrence coverage in predefined sub-groups (MGMT methylation and GTR)
Jensen, M. B., Guldberg, T. L., Harboll, A., Lukacova, S., & Kallehauge, J. F. (2017). Diffusion tensor magnetic resonance imaging driven growth modeling for radiotherapy target definition in glioblastoma. Acta Oncol, 56(11), 1639-1643. doi:10.1080/0284186X.2017.1374559
Minniti, G., Amelio, D., Amichetti, M., Salvati, M., Muni, R., Bozzao, A., . . . Enrici, R. M. (2010). Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiother Oncol, 97(3), 377-381. doi:10.1016/j.radonc.2010.08.020
Trip, A. K., Jensen, M. B., Kallehauge, J. F., & Lukacova, S. (2019). Individualizing the radiotherapy target volume for glioblastoma using DTI-MRI: a phase 0 study on coverage of recurrences. Acta Oncol, 58(10), 1532-1535. doi:10.1080/0284186X.2019.1637018