Original paper| Volume 84, P72-79, April 2021

Download started.


Investigating DWI changes in white matter of meningioma patients treated with proton therapy

Published:April 16, 2021DOI:


      • Evaluation of DWI changes in white matter after proton therapy.
      • Significant diffusion changes were found in high-dose regions.
      • Linear-mixed models unveiled significant dependencies of ADC on dose and time.
      • Perfusion-related parameters presented mixed results.
      • Diffusion restriction may characterize radiation-induced cellular injury.



      To evaluate changes in diffusion and perfusion-related properties of white matter (WM) induced by proton therapy, which is capable of a greater dose sparing to organs at risk with respect to conventional X-ray radiotherapy, and to eventually expose early manifestations of delayed neuro-toxicities.


      Apparent diffusion coefficient (ADC) and IVIM parameters (D, D* and f) were estimated from diffusion-weighted MRI (DWI) in 46 patients affected by meningioma and treated with proton therapy. The impact on changes in diffusion and perfusion-related WM properties of dose and time, as well as the influence of demographic and pre-treatment clinical information, were investigated through linear mixed-effects models.


      Decreasing trends in ADC and D were found for WM regions hit by medium–high (30–40 Gy(RBE)) and high ( > 40 Gy(RBE)) doses, which are compatible with diffusion restriction due to radiation-induced cellular injury. Significant influence of dose and time on median ADC changes were observed. Also, D* showed a significant dependency on dose, whereas f consistently showed no dependency on dose and time. Age, gender and surgery extent were also found to affect changes in ADC.


      These results overall agree with those from studies conducted on cohorts of mixed proton and X-ray radiotherapy patients. Future work should focus on relating our findings with clinical information of co-morbidities and thus exploiting such or more advanced imaging data to build normal tissue complication probability models to better integrate clinical and dose information.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Physica Medica: European Journal of Medical Physics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Newhauser W.D.
        • Zhang R.
        The physics of proton therapy.
        Phys Med Biol. 2015; 60: R155-R209
        • Tommasino F.
        • Durante M.
        Proton radiobiology.
        Cancers (Basel). 2015; 7: 353-381
        • Paganetti H.
        Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer.
        Phys Med Biol. 2014; 59: R419-R472
        • Tommasino F.
        • Nahum A.
        • Cella L.
        Increasing the power of tumour control and normal tissue complication probability modelling in radiotherapy: recent trends and current issues.
        Transl Cancer Res. 2017; 6: S807-S821
        • Durante M.
        • Orecchia R.
        • Loeffler J.S.
        Charged-particle therapy in cancer: clinical uses and future perspectives.
        Nat Rev Clin Oncol. 2017; 14: 483-495
        • Unkelbach J.
        • Alber M.
        • Bangert M.
        • Bokrantz R.
        • Chan T.C.Y.
        • Deasy J.O.
        • et al.
        Robust radiotherapy planning.
        Phys Med Biol. 2018; 63: 22TR02
        • Wilke C.
        • Grosshans D.
        • Duman J.
        • Brown P.
        • Li J.
        Radiation-induced cognitive toxicity: pathophysiology and interventions to reduce toxicity in adults.
        Neur Oncol. 2018; 20: 597-607
        • Rahman R.
        • Alexander B.M.
        • Wen P.Y.
        Neurologic Complications of Cranial Radiation Therapy and Strategies to Prevent or Reduce Radiation Toxicity.
        Curr Neurol Neurosci Rep. 2020; 20
        • Greene-Schloesser D.
        • Robbins M.E.
        • Peiffer A.M.
        • Shaw E.G.
        • Wheeler K.T.
        • Chan M.D.
        Radiation-induced brain injury: A review.
        Front Oncol. 2012; 2: 1-18
        • Bolsi A.
        • Peroni M.
        • Amelio D.
        • Dasu A.
        • Stock M.
        • Toma-Dasu I.
        • et al.
        Practice patterns of image guided particle therapy in Europe: A 2016 survey of the European Particle Therapy Network (EPTN), Radiother.
        Oncology. 2018; 128: 4-8
        • Connor M.
        • Karunamuni R.
        • McDonald C.
        • Seibert T.
        • White N.
        • Moiseenko V.
        • et al.
        Regional susceptibility to dose-dependent white matter damage after brain radiotherapy.
        Radiother Oncol. 2017; 123: 209-217
        • Raschke F.
        • Wesemann T.
        • Wahl H.
        • Appold S.
        • Krause M.
        • Linn J.
        • et al.
        Reduced diffusion in normal appearing white matter of glioma patients following radio(chemo)therapy.
        Radiother Oncol. 2019; 140: 110-115
        • Kurz C.
        • Buizza G.
        • Landry G.
        • Kamp F.
        • Rabe M.
        • Paganelli C.
        • et al.
        Medical physics challenges in clinical mr-guided radiotherapy.
        Radiat Oncol. 2020; 15: 1-16
        • Hoffmann A.
        • Oborn B.
        • Moteabbed M.
        • Yan S.
        • Bortfeld T.
        • Knopf A.
        • et al.
        MR-guided proton therapy: a review and a preview.
        Radiat Oncol. 2020; 15: 1-13
        • Gurney-Champion O.J.
        • Mahmood F.
        • van Schie M.
        • Julian R.
        • George B.
        • Philippens M.E.
        • et al.
        Quantitative imaging for radiotherapy purposes.
        Radioth Oncol. 2020; 146: 66-75
        • Chen L.
        • Liu M.
        • Bao J.
        • Xia Y.
        • Zhang J.
        • Zhang L.
        • et al.
        The correlation between apparent diffusion coefficient and tumor cellularity in patients: a meta-analysis.
        PloS one. 2013; 8
        • Le Bihan D.
        What can we see with IVIM MRI?.
        Neuroimage. 2019; 187: 56-67
        • Zampini M.A.
        • Buizza G.
        • Paganelli C.
        • Fontana G.
        • D’Ippolito E.
        • Valvo F.
        • et al.
        Perfusion and diffusion in meningioma tumors: a preliminary multiparametric analysis with Dynamic Susceptibility Contrast and IntraVoxel Incoherent Motion MRI.
        Magn Reson Imaging. 2020; 67: 69-78
        • Vieni C.
        • Ades-Aron B.
        • Conti B.
        • Sigmund E.E.
        • Riviello P.
        • Shepherd T.M.
        • et al.
        Effect of intravoxel incoherent motion on diffusion parameters in normal brain.
        NeuroImage. 2020; 204 (116228)
        • Altabella L.
        • Broggi S.
        • Mangili P.
        • Conte G.M.
        • Pieri V.
        • Iadanza A.
        • et al.
        Integration of Diffusion Magnetic Resonance Tractography into tomotherapy radiation treatment planning for high-grade gliomas.
        Phys Med. 2018; 55: 127-134
        • Alexander D.C.
        • Dyrby T.B.
        • Nilsson M.
        • Zhang H.
        Imaging brain microstructure with diffusion MRI: Practicality and applications.
        NMR Biomed. 2017; : 1-26
        • Karunamuni R.A.
        • White N.S.
        • McDonald C.R.
        • Connor M.
        • Pettersson N.
        • Seibert T.M.
        • et al.
        Multi-component diffusion characterization of radiation-induced white matter damage.
        Med Phys. 2017; 44: 1747-1754
        • Petr J.
        • Platzek I.
        • Hofheinz F.
        • Mutsaerts H.J.
        • Asllani I.
        • van Osch M.J.
        • et al.
        Photon vs. proton radiochemotherapy: Effects on brain tissue volume and perfusion.
        Radiother Oncol. 2018; 128: 121-127
        • Ray S.
        • Cekanaviciute E.
        • Lima I.P.
        • Sørensen B.S.
        • Costes S.V.
        Comparing Photon and Charged Particle Therapy Using DNA Damage Biomarkers.
        Int J Part Ther. 2018; 5: 15-24
        • Federau C.
        • Maeder P.
        • O’Brien K.
        • Browaeys P.
        • Meuli R.
        • Hagmann P.
        Quantitative Measurement of Brain Perfusion with Intravoxel Incoherent Motion MR Imaging.
        Radiology. 2012; 265: 874-881
        • Fedeli L.
        • Belli G.
        • Ciccarone A.
        • Coniglio A.
        • Esposito M.
        • Giannelli M.
        • et al.
        Dependence of apparent diffusion coefficient measurement on diffusion gradient direction and spatial position - A quality assurance intercomparison study of forty-four scanners for quantitative diffusion-weighted imaging.
        Phys Med. 2018; 55: 135-141
        • Shukla-Dave A.
        • Obuchowski N.A.
        • Chenevert T.L.
        • Jambawalikar S.
        • Schwartz L.H.
        • Malyarenko D.
        • et al.
        Quantitative imaging biomarkers alliance (QIBA) recommendations for improved precision of DWI and DCEGÇÉMRI derived biomarkers in multicenter oncology trials.
        J Magn Reson Imaging. 2019; 49: e101-e121
      1. QIBA Diffusion Weighted Imaging (DWI) MR Biomarker, QIBA Profile: Diffusion-Weighted Magnetic Resonance Imaging (DWI), 2019.

      2. Sharp GC, Li R, Wolfgang J, Chen G, Peroni M, Spadea MF, et al. Plastimatch: an open source software suite for radiotherapy image processing. In: Proceedings of the XVIGÇÖth International Conference on the use of Computers in Radiotherapy (ICCR), Amsterdam, Netherlands, 2010.

      3. Yushkevich PA, Gao Y, Gerig G. Itk-snap: An interactive tool for semi-automatic segmentation of multi-modality biomedical images. In: 2016 38th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), IEEE, 2016, pp. 3342–3345.

        • Li C.
        • Gore J.C.
        • Davatzikos C.
        Multiplicative intrinsic component optimization (MICO) for MRI bias field estimation and tissue segmentation.
        Magn Resonan Imaging. 2014; 32: 913-923
        • Bates D.
        • Mächler M.
        • Bolker B.
        • Walker S.
        Fitting Linear Mixed-Effects Models Using lme4.
        J Stat Softw. 2015; 67 (arXiv:1406.5823)
        • Brown H.K.
        • Kempton R.A.
        The application of REML in clinical trials.
        Stat Med. 1994; 13: 1601-1617
        • Kessler A.T.
        • Bhatt A.A.
        Brain tumour post-treatment imaging and treatment-related complications.
        Insights Imaging. 2018; 9: 1057-1075
        • Grebenkov D.S.
        Use, misuse, and abuse of apparent diffusion coefficients.
        Concepts Magn Reson A. 2010; 36A: 24-35
        • Le Bihan D.
        Intravoxel Incoherent Motion Perfusion MR Imaging: A Wake-Up Call.
        Radiology. 2008; 249: 748-752
        • Federau C.
        Intravoxel incoherent motion MRI as a means to measure in vivo perfusion: A review of the evidence.
        NMR Biomed. 2017; 30 (e3780)
        • Connor M.
        • Karunamuni R.
        • McDonald C.
        • White N.
        • Pettersson N.
        • Moiseenko V.
        • et al.
        Dose-dependent white matter damage after brain radiotherapy.
        Radiother Oncol. 2016; 121: 209-216
      4. Kłos J, van Laar PJ, Sinnige PF, Enting RH, Kramer MC, van der Weide HL, et al. Quantifying effects of radiotherapy-induced microvascular injury; review of established and emerging brain MRI techniques, Radiother Oncol 2019;140:41–53. Doi:

        • Kanaan R.A.
        • Allin M.
        • Picchioni M.
        • Barker G.J.
        • Daly E.
        • Shergill S.S.
        • et al.
        Gender Differences in White Matter Microstructure.
        PLoS One. 2012; 7 (e38272)
        • Paganelli C.
        • Meschini G.
        • Molinelli S.
        • Riboldi M.
        • Baroni G.
        Patient-specific validation of deformable image registration in radiation therapy: Overview and caveats.
        Med Phys. 2018; 45: e908-e922
        • Monti S.
        • Paganelli C.
        • Buizza G.
        • Preda L.
        • Valvo F.
        • Baroni G.
        • et al.
        A novel framework for spatial normalization of dose distributions in voxel-based analyses of brain irradiation outcomes.
        Phys Med. 2020; 69: 164-169
        • Palma G.
        • Monti S.
        • Cella L.
        Voxel-based analysis in radiation oncology: A methodological cookbook.
        Phys Med. 2020; 69: 192-204
        • Constanzo J.
        • Midavaine É.
        • Fouquet J.
        • Lepage M.
        • Descoteaux M.
        • Kirby K.
        • et al.
        Brain irradiation leads to persistent neuroinflammation and long-term neurocognitive dysfunction in a region-specific manner.
        Prog Neuro-Psychopharmacol Biol Psychiatry. 2020; 102 (109954)
        • Dutz A.
        • Agolli L.
        • Bütof R.
        • Valentini C.
        • Baumann M.
        • Lühr A.
        • et al.
        Neurocognitive function and quality of life after proton beam therapy for brain tumour patients.
        Radiother Oncol. 2020; 143: 108-116
        • Palma G.
        • Monti S.
        • Conson M.
        • Pacelli R.
        • Cella L.
        Normal tissue complication probability (NTCP) models for modern radiation therapy.
        Semin Oncol. 2019; 46: 210-218
        • Köthe A.
        • van Luijk P.
        • Safai S.
        • Kountouri M.
        • Lomax A.
        • Weber D.
        • et al.
        Combining clinical and dosimetric features in a pbs proton therapy cohort to develop a ntcp model for radiation-induced optic neuropathy.
        Int J Radiat Oncol Biol Phys. 2021;