## 4 Limitations  
The biggest limitation for using DTI to guide radiotherapy planning is the lack of controlled trials. The only controlled trial the authors, and a recent systematic review, have identified is in AVM, and this is a non-randomised retrospective study [22]. This poses an issue, as while the majority of the SRT pre-treatment plans using DTI guidance deliver the same dose to the pathology, this does not necessarily mean the treatment will have the same success rate on follow up. Additionally, while reduced radiation doses overall to eloquent WM tracts will likely mean reduced complications, control trials are still highly desirable.  
An issue posed by gliomas is that due to infiltration along WM tracts, if it infiltrates into an eloquent tract that is included as an OAR, then the dose may be reduced and increase the risk of recurrence. Therefore, further research in gliomas is required to evaluate when and when not to include WM tracts as OAR.  
An additional issue with gliomas is that their infiltration leads to reductions in FA, which may reduce the tractography algorithm's accuracy. This is due to tractography algorithms typically using an FA threshold, with tracts not including voxels below the threshold. This could be accounted for by reducing the FA threshold, but this may lead to an increase in false positive tracts. These downsides can be overcome using a combination of more advanced diffusion acquisitions (i.e., with more directions and b-values), diffusion models (e.g., spherical deconvolution), and probabilistic tractography.  
Another limitation is that the accuracy of the dissected tracts is dependent on the registration of the MRI images to the planning CT, as CT is used for the radiotherapy planning. CT MRI fusion is more difficult than simply registering different MRI sequences, and quality control is likely difficult due to different tissue contrasts. A recent systematic  
Figure 6: A proposed idealised pipeline for DTI-guided SRT planning, which would be fully automated.  
review on the topic found many different methods for CT/MRI registration with no standardisation and poor comparability of the validation of methods [40]. Although this article was assessing the issue in Stereotactic Electroencephalography, and there are only a small number of radiotherapy treatment planning systems that have their own in-built co-registration algorithms.  
A practical limitation is that the integration of dissected WM tracts into the SRT treatment workstation may be difficult. [PERSON] et al., 2016 give a detailed step-by-step example of how they integrated the tractography results into their 'GammaPlan' workstation [20]; however, due to varying software, standardisation will likely be difficult.  
A consideration also required is the additional resources and time needed. Logistics may be particularly difficult, as the DTI MRI scan will need to happen shortly before the SRT to reduce error from brain changes over time and that DTI requires incredibly computationally complex processing, which can take a long time. DTI application will additionally require highly skilled both technical and clinical operators to apply it correctly. The decision of which tracts to include is additionally highly subjective, as this is operator-dependent. However, despite these limitations, an institution in Japan introduced tractography prior to the SRT of AVMs into routine clinical practice, using it in almost 50% of cases. One way the group achieved this is by performing the DTI sequences the day prior [22].