B. Understanding radiation- and chemotherapy-induced changes after treatment of brain tumours

B. Understanding radiation- and chemotherapy-induced changes after treatment of brain tumours Poster No.: A-083 Congress: ECR 2015 Type: Invited Speaker Authors: Y. Özsunar; Aydin/TR Keywords: Neuroradiology brain, MR-Diffusion/Perfusion, Radiation therapy / Oncology, Neoplasia DOI: 10.1594/ecr2015/A-083 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 19

Learning objectives MRI is the imaging modality of choice for the investigation of after treatment brain changes. Radiotherapy (RT) and chemotherapy (CT) in cancer treatment are standard approach. Radiation necrosis (RN) may occur as late side effects of radiotherapy. The main dilemma is the differential diagnosis of tumor recurrence and necrosis. Because of this, cutting edge MRI are usually applied for reliable diagnosis of the remnant brain lesion. Those include perfusion, diffusion and spectroscopic MRI examination. In this review, we aimed to explain causes, pathophysiology and radiological characteristics' of post radiotherapy and chemotherapy changes after treatment of brain brain tumors. Main 1.RADIATION (RT) INDUCED CHANGES RT-related neurological changes are observed in various clinical and radiological findings. These clinical pictures can be classified as, acute side effects during RT, subacute side effects, late side effects after RT(1) (Figure 1). Radionecrosis (RN) is a late complication of RT which mainly affects white matter (2,3) and is a severe radiationinduced complication that is neuropathologically defined as necrosis with severe vascular lesions (stenosis, thrombosis, haemorrhage, fibrinoid vascular necrosis). The vascular changes play a major role during the management of intracranial lesions with RT. Following RT, vascular endothelial thickening, thrombosis, fibrinoid necrosis of the vascular wall and inflammatory response adjacent to vessels may be observed. Paranchymal changes in the brain are visible with conventional diagnostic tools especially as the ischemia and inflammation of white matter progresses in the meantime (4-6). IMAGING FINDINGS A- CONVENTIONAL MR FINDINGS Focal radionecrosis or paranchymal atrophy - leucoencephalopathy are generally observed in brain parenchyma up to 1/3 of the cases. During the early phase of RT, corpus callosum and subcortical WM is not affected. One of the long term results of RT treatment is disseminated necrotizing leucoencephalopathy (Figure 2-3). However,It usually seen during combination with chemotheraphy. Page 2 of 19

It has been stated that, all radiological findings are detected on RT tract (Figure 4). A simple conventional MRI may be insufficient to differenciate between recurrence and normal tissue changes. Radionecrosis (RN) may be visible with progressive enlargement with mass effect, which also brings out high suspect for tumor recurrence (6). Given to the findings of Kumar et al (5) The MR imaging features commonly seen in RN are a soap bubble-like and Swiss cheese like. On the other hand, Swiss cheese pattern may also be seen as a result of diffuse necrosis of white matter and the cortical border. Compared to the soap bubble lesions, Swiss cheese lesions are prominent and variable in size. Therefore, Swiss cheese or spreading wavefront pattern are closely related to radiation necrosis (5) (Figure 5). Following RT, central opacification starts to be obvious after 5 to 18 months for benign, and 2 to 3 months for malignant tumors. B- FUNCTIONAL MR FINDINGS The most sensitive diagnostic tool to differenciate RN and tumor is perfusion MRI with a proven sensitivity of 80-95% (7). Perfusion of the irradiated tumor is related to angiogenesis and microvascular proliferation. So, radiotherapy regresses the tumor by effecting microvascular density and capillary perfusion. Thereore, rcbv treshold value of 1.3 seems as an indicator of perfusion in differential diagnosis of tumor (8). In addion to rcbv treshold value, the sensitivity of ASL is also high (94%) (Figure 6-7). Increased tumor cellularity, which can inhibit the effective motion of water molecules, thereby can cause to restricted diffusion. In diffusion MRI (DWI) ADC values are decreased in recurrent tumor. Hein et al (9) showed that ADC value is very low in tumor, while ADC values are higher in RN (Figure 8). The role of MR spectroscopy (MRS) in distinguishing recurrent tumor from RN has also been extensively discussed in the literature. Spectroscopic scale of the lesion is extremely important to understand the nature of the lesion, given to the increased Choline/Creatine (Cho/Cr) value (i.e. 3) in malignant lesions. In contrast, Cho/Cr ratio below 2 is not diagnostic for recurrent tumor but possibly for RN (10,11) (Figure 9). 2.CHEMOTHERAPHY INDUCED CHANGES Among reversible clinicoradiologic syndromes, posterior reversible encephalopathy syndrome (PRES) is a the most frequent one that causes cortical and subcortical white matter changes after chemotheraphy (12). PRES usually shows hyperintensity on FLAIR images in the parietooccipital and posterior frontal cortical and subcortical white matter. Page 3 of 19

Therefore, imaging findings of PRES are most apparent on the brainstem, basal ganglia and cerebellum (13) (Figure 10) The reasons of acute toxic leukoencephalopathy (ATL) in heavily medicated patients are chemotherapy, immunosuppressive therapy, and overuse of antimicrobial medications (e.g., metronidazole) Clinical outcome is sometimes better as the effects of drug-induced ATL is potentially reversible. Methotrexate and 5-flourouracil injures microvasculature of the WM and may also have indirect effects (Figure 11). The agents that are commonly associated with leukoencephalopathy are shown on Table 1. (14-16). The acute changes develop during therapy, such as transient diffuse WM hyperintensity. Long term effects of chemotherapy ranges from asymptomatic white matter hyperintensities to necrotizing leukoencephalopathy. Patchy involvement of the periventricular white matter and centrum semiovale are diagnostic findings of MR imaging. Symmetrical calcifications are seen around basal ganglia (Figure 12) The combination intravenous and intrathecal chemotherapy may cause necrotizing leukoencephalopathy and aseptic menengitis (Figure 13). CONCLUSION Magnetic resonance imaging (MRI) is a usefull noninvasive modality for evaluating post treatment brain tumors. Both conventional and functional MRI methods The signal intensity, morphology, and location of findings on MRI can be used to provide more accurate diagnoses, to guide treatment, and to follow therapy-related changes. Images for this section: Page 4 of 19

Fig. 1: The clinical syndrome that encounter during and after radiotheraphy over time Page 5 of 19

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Fig. 2: Vasogenic edema and sulcal paucity are observed in FLAIR-MRI during radiotheraphy. The findings consistent with acute encephalopathy Fig. 3: Signal increase was observed in mesencephalone and white matter in radiated case on DWI (A-B). At 18th month after RT (C-D) enlargement of perimesencephalic cistern due to generalised atrophy. Page 7 of 19

Fig. 4: The white matter MRI signal changes are detected on parietooccipital RT tract (arrow) on FLAIR (A) T2W (B) Postcontrast T1W (C) and DWI (D-E) images Page 8 of 19

Fig. 5: The radiation necrosis cavity is enhanced on noncontrast (A) and contrast (B) T1 W imaging (*). Swiss cheese enhancement (arrow) was observed adjacent to the lesion Page 9 of 19

Fig. 6: The patient was operated for brain tumor located in occipital lob. The recurrent tumor was highly perfused and located subcutanously (red arrow). However, the location of the tumor was observed as an empty cavity (yellow arrow). Fig. 7: A 47-year-old man with a history of attempted resection of grade IV glioma and proton-beam therapy with new abnormal enhancing lesion on follow-up. Positron emission tomographic imaging (A) shows hypermetabolism at the site of the lesion on Page 10 of 19

contrast-enhanced T1 axial imaging (B). Arterial spin-labeled (ASL) (C) and dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) (D) images show hyperperfusion that correlates with the axial postcontrast T1-weighted image. Note that the lesion is more conspicuous on ASL than on DSCE-CBV imaging. Subsequent surgical resection confirmed predominantly tumor recurrence. Fig. 8: Breast cancer metastases that shows restricted diffusion in right cerebellum. Restriction decreases after radiotheraphy and chemotheraphy Page 11 of 19

Fig. 9: MRS evaluation: Cho/Cr ratio is over 3 in patients with recurrence while this ratio is under 2 in radionecrosis. In addition, lipid lactate peak in evident in radionecrosis. Page 12 of 19

Fig. 10: PRES in occipital lobe (T2 and FLAIR images) Page 13 of 19

Fig. 11: Periventriculary white matter changes is shown after chemotheraphy in breast cancer case T2 (E), FLAIR (D) and DWI (B-C) signal increase Page 14 of 19

Table 1: Table 1: The agents that causes leukoencephalopathy following overuse. Page 15 of 19

Fig. 12: Symmetrical calcification in basal ganglia following chemotherapy Page 16 of 19

Fig. 13: Figure 10: Aseptic menengitis is shown in T1 W CE images after intrathecal chemotheraphy (Metotrexate and Cytarabine) and radiotheraphy Page 17 of 19

Personal information Yelda Özsunar Prof. Dr. Department of Radiology, Adnan Menderes University School of Medicine, Aydin, Turkey; yeldaozsunar@gmail.com Özüm Tunçyürek Assist Prof, EDIR Department of Radiology, Adnan Menderes University School of Medicine, Aydin, Turkey; ozum.tuncyurek@gmail.com Ersen Ertekin Assist Prof, Department of Radiology, Adnan Menderes University School of Medicine, Aydin, Turkey; drersen@hotmail.com References 1. Sheline G. Radiation therapy of brain tumors. Cancer 1977; 39: 873-81. 2. Perry A, Schmidt RE. Cancer therapy-associated CNS neuropathology: an update and review of the literature. Acta Neuropathol 2006; 111: 197-212. 3. Lee AW, Foo W, Chappell R, et al. Eff ect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1998; 40: 35-42. 4. Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY. CNS complications of radiotherapy and chemotherapy. Lancet. 2009;374(9701):1639-51. 5. Kumar AJ, Leeds NE, Fuller GN, et al. Malignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapy-induced necrosis of the brain after treatment. Radiology. 2000;217(2):377-84. 6. Shah R, Vattoth S, Jacob R, et al. Radiation necrosis in the brain: imaging features and differentiation from tumor recurrence. Radiographics. 2012;32(5):1343-59. 7. Barajas RF, Chang JS, Sneed PK, Segal MR, McDermott MW, Cha S. Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AJNR Am J Neuroradiol. 2009;30(2):367-72. 8. Ozsunar Y, Mullins ME, Kwong K, et al. Glioma recurrence versus radiation necrosis? A pilot comparison of arterial spin-labeled, dynamic susceptibility contrast enhanced MRI, and FDG-PET imaging. Acad Radiol. 2010;17(3):282-90. Page 18 of 19

9. Hein PA, Eskey CJ, Dunn JF, Hug EB. Diffusion-weighted imaging in the follow-up of treated high-grade gliomas: tumor recurrence versus radiation injury. AJNR Am J Neuroradiol. 2004;25(2):201-9. 10. Sundgren PC. MR spectroscopy in radiation injury. AJNR Am J Neuroradiol. 2009;30(8):1469-76. 11. Kimura T, Sako K, Gotoh T, Tanaka K, Tanaka T. In vivo single-voxel proton MR spectroscopy in brain lesions with ring-like enhancement. NMR Biomed. 2001;14(6):339-49. 12. McKinney A.M, Short J, Truwit C.L, McKinney Z.J, Kozak O.S, Karen S. SantaCruz K.S, Teksam M. Posterior Reversible Encephalopathy Syndrome: Incidence of Atypical Regions of Involvement and Imaging Findings. AJR 2007; 189:904-912 13. McKinney A.M, Jagadeesan B.D, Truwit C.L. Central-Variant Posterior Reversible Encephalopathy Syndrome: Brainstem or Basal Ganglia Involvement Lacking Cortical or Subcortical Cerebral Edema. AJR 2013; 201:631-638 14. McKinney A.M, Kieffer S.A, Paylor R.T, SantaCruz K.S, Kendi A, Lucato L. Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging. AJR 2009; 193:192-206 15. Aydin K, Donmez F, Tuzun U, et al. Diffusion MR findings in cyclosporin-a induced encephalopathy. Neuroradiology 2004; 46:822-824 16. Munoz R, Espinoza M, Espinoza O, et al. Cyclosporine-associated leukoencephalopathy in organ transplant recipients: experience of three clinical cases. Transplant Proc 2006; 38:921-923 Page 19 of 19