Dose-Painting Radiotherapy Guided By 3D-ASL Perfusion Magnetic Resonance For Non-Enhancing Gliomas

Background and Objective:At present,the main challenges in nonenhancing gliomas（NEGs）during radiotherapy are as follows:（1）In clinical practice,the abnormal high signal（edema area）of T2 fluidattenuated inversion recovery（T2 Flair）is usually used as the standard for delineating the target volume during radiotherapy,resulting in the large target volume and increasing the risk of radiation damage for healthy tissue.（2）The recurrence of glioma after conventional radiotherapy predominantly occurs in the radiation field,which is significantly associated with insufficient doses to the tumor target volume.How to effectively identify the area of enrichment tumor cell and ensure that the individualized dose escalation is the key challenge during radiotherapy for NEGs.The dose-painting radiotherapy and proton radiotherapy（PRT）are expected to achieve dose increase on the premise of ensuring safety and accuracy.This study aimed to quantify the perfusion difference of GTV based on threedimensional arterial spin labeling（3D-ASL）perfusion magnetic resonance imaging and evaluate the feasibility of radiotherapy sub-volume segmentation in NEGs.Meanwhile the feasibility and dosimetric characteristics of dosepainting photon and proton radiotherapy guided by 3D-ASL was explored and analyzed.Methods:Included three parts:Part 1:Sub-volume segmentation of radiotherapy guided by 3D-ASL perfusion magnetic resonance for non-enhancing low-grade gliomas.Fifteen adult patients with NEGs were included in the study.MR images,including T1-weighted imaging（T1WI）,T2 Propeller,T2 Flair,3D-ASL,and contrast-enhanced T1WI（CE-T1WI）,were obtained.The gross tumor volume（GTV）was delineated according to the hyperintensity on T2 Flair.The GTV was divided into high-and low-perfusion areas,namely GTV-ASL and GTVSUB,respectively,based on the differences in cerebral blood flow（CBF）value.The volumes and CBF values of high-and low-perfusion areas were measured and compared.The least absolute shrinkage and selection operator（LASSO）regression was used to select the optimal features of all MR maps.Receiver operating characteristic（ROC）curve analysis was used to evaluate the diagnostic accuracy of the absolute CBFmean（aCBFmean）,relative CBFmean（rCBFmean）and screened features in differentiating high-and low-perfusion areas.Part 2:Dose-painting photon radiotherapy guided by 3D-ASL perfusion magnetic resonance for non-enhancing low-grade gliomas.Eighteen patients with NEGs were enrolled.3D-ASL,T2 Flair and CE-T1WI were obtained.The GTV was delineated on the T2 Flair.The hyper-perfusion region of the GTV（GTV-ASL）was determined by 3D-ASL,and the GTV-SUB was obtained by subtracting the GTV-ASL from the GTV.The clinical target volume（CTV）was created by isotropically expanding the GTV by 1 cm.The planning target volume（PTV）and PTV-ASL were obtained by expanding the external margins of the CTV,GTV-ASL,respectively.PTV-SUB was generated by subtracting PTV-ASL from PTV.Three plans were generated for each patient:a conventional plan（plan 1）without dose escalation delivering 95%110%of 45-60 Gy in 1.8-2 Gy fractions to the PTV and two dose-painting plans（plan 2 and plan 3）with dose escalating by 10%-20%（range,50-72 Gy）to the PTV-ASL based on plan 1.The plan 3 was obtained from plan 2 without the maximum dose constraint.The dosimetric differences among the three plans were compared.Part 3:Dose-painting proton radiotherapy guided by 3D-ASL perfusion magnetic resonance for non-enhancing high-grade gliomas.The 3D-ASL,T2 Flair and CE-TWI MR images of ten patients with NEGs before radiotherapy were studied retrospectively.The hyperintensity on T2 Flair was used to generate the PTV,and the high-perfusion volume on 3D-ASL（PTV-ASL）was used to generate the simultaneous integrated boost（SIB）volume.Each patient received pencil beam scanning PRT and intensitymodulated photon radiotherapy（IMRT）.There were five plans in each modality:（1）Uniform plans（IMRT60 vs.PRT60）:60 Gy in 30 fractions to the PTV.（2）（5）SIB plans（IMRT72,84,96,108 vs.PRT72,84,96,108）:Uniform plan plus additional dose boost to PTV-ASL in 30 fractions to 72,84,96,108 Gy.The dosimetric differences between various plans were compared.The clinical effects of target volume and organs at risk（OARs）were assessed using tumor control probability（TCP）and normal tissue complication probability（NTCP）.Results:1.Among the enrolled patients,3（20%）patients with NEGs showed focal intra-and post-radiotherapy contrast enhancement within a prior high-perfusion area of 3D-ASL.The volume ratio of the GTV-ASL to the GTV was（37.08 ±17.88）%（P=0.000）.The CBFmean in the high-perfusion area was approximately two times of that in the edema area or normal gray matter（P=0.000）.2.13 features were screened,7 of which were extracted from 3D-ASL.The area under curve（AUC）values of aCBFmean,rCBFmean and 3DASL_firstorder₁0Percentile were more than 0.9,of which 3DASL_firstorder₁0Percentile was the highest.Their cut-off values were 44.16 mL/100 g/min,1.49 and 31,respectively.3.In the study of dose-painting photon radiotherapy guided by 3D-ASL,the volume ratio of the PTV-ASL to the PTV was（23.49±11.94）%（P=0.000）.Compared with plan 1,D2%,D98%and Dmean of PTV-ASL increased by 14.67%,16.17%and 14.31%in plan 2 and 19.84%,15.52%and 14.27%in plan 3,respectively（P<0.05）;the D2%of the PTV,PTV-SUB increased by 11.89%and 8.34%in plan 2,15.89%and 8.49%in plan 3,respectively（P<0.05）.4.The PTV coverages were comparable among the three photon plans（P>0.05）.In plan 2 and plan 3,the conformity indexes decreased by 18.60%and 12.79%;while the homogeneity index increased by 1.43 and 2 times（P<0.05）.Compared with plan 1,the D0.1cc of brain stem and Dmax of optic chiasma were slightly increased in plan 2 and plan 3,and the absolute doses met the dose constraint.The doses of the other organs at risk（OARs）were similar among the three plans（P>0.05）.5.In the study of dose-painting proton radiotherapy guided by 3D-ASL,compared with the IMRT plan,the D2%and D50%of the PRT plan with the same prescription dose increased by（1.27-4.12）%and（0.64-2.01）%,respectively;the R30 decreased by>32%;the dose of brainstem and chiasma decreased by>27%and>32%;and the dose of normal brain tissue（Br-PTV）,optic nerves,eyeballs,lens,cochlea,spinal cord,and contralateral hippocampus decreased by>50%（P<0.05）.6.The maximum necessary dose was 96 GyE to achieve>98%TCP for PRT,and it was 84 Gy to achieve>91%TCP for IMRT,and the average NTCP of Br-PTV was 1.30%and 1.90%for PRT and IMRT,respectively at the maximum dose escalation.Conclusion:The difference of blood perfusion in the GTV can be quantified and analyzed based on 3D-ASL images for NEGs,which could guide the subvolume segmentation of the GTV.Dose escalation delivered to high-perfusion volume of 3D-ASL can be achieved using IMRT and PRT while sparing normal tissue,with PRT being more favorable.3D-ASL can serve as a routine MR imaging sequence for defining the target volume,providing a reliable basis for individualized radiotherapy in NEGs patients.